tag:blogger.com,1999:blog-42875604912110250992024-03-06T15:00:55.779-05:00Antibiotics - The Perfect StormWe need new antibiotics to fight infections caused by resistant bacteria. But the marketplace, the structure of the pharmaceutical industry, regulatory agencies, and difficult science are conspiring to deny us the products we need. This blog will present perspectives and developments in the fight for new antibiotics.David Shlaeshttp://www.blogger.com/profile/00228776693058791618noreply@blogger.comBlogger433125tag:blogger.com,1999:blog-4287560491211025099.post-29186532023567898822023-03-19T09:02:00.003-04:002023-03-19T09:02:38.314-04:00I am moving my blog<p> You can find archived articles and new blogs on davidshlaes.substack.com. Blogger has just become too restrictive. I apologize for any inconvenience. </p>David Shlaeshttp://www.blogger.com/profile/00228776693058791618noreply@blogger.com0tag:blogger.com,1999:blog-4287560491211025099.post-90426633210113334292023-03-14T12:43:00.000-04:002023-03-14T12:43:29.879-04:00Antibiotic Biotech Execs Share Their Concerns<p><span style="font-size: large;"> <span style="font-family: Calibri, sans-serif;">Since the vast majority of products in the antibiotic pipeline, from early discovery through late-stage clinical development, comes from biotech, According to the 2021 WHO analysis, 84% of pre-clinical antibacterial projects come from companies with under 50 employees. 79% of clinical stage (phase I and beyond) come from biotech. Given these observations, I thought it would be worth exploring the health of antibiotic biotech in today's depressing environment. Originally, one of the questions I wanted to explore was the effect of rising interest rates on their ability to raise funds. To do this, I discussed the situation with a number of biotech executives including CEOs and CMOs.</span><span style="font-family: Calibri, sans-serif;"> </span><span style="font-family: Calibri, sans-serif;"> </span><span style="font-family: Calibri, sans-serif;">My original question rapidly became irrelevant. (Since some executives asked to remain nameless, I am keeping everyone anonymous).</span><span style="font-family: Calibri, sans-serif;"> </span></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;"><o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">Everyone agreed that the availability of funds to support discovery research and early clinical development has improved enormously over the past decade. CARB-X, Novo, Beam, NIH and others were cited as examples of sources of non-dilutive funding for their companies. One executive lamented that several products that could be clinically very useful failed to attract funding from these sources because they were insufficiently “novel.” <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">The unanimous opinion was that the space is collapsing slowly but surely from the commercial end backwards. One executive described his company as a “tale of two cities.” While funding for early-stage products was available, once projects attained late development stage, it was more and more difficult to obtain support. All were extremely appreciative of the efforts of BARDA in this regard. The AMR Action Fund was established in 2020 with a goal of investing $1B in the clinical development of needed new antibiotics during the decade. So far, it has invested in three biotechs, VenatoRx, Adaptive Phage Therapeutics and Bioversys but the amount of funding seemingly remains secret. Some executives were skeptical of the efforts of the AMR Action Fund and complained about the speed of their response. (AMR Action Fund did not reply to my inquiries). Private investors will simply not touch the tremendous expense of late-stage development knowing that their financial return might not occur for 10 years or more if at all assuming the product is approved. “Why would I spend $200M to have a<span class="apple-converted-space"> </span><u>successful</u><span class="apple-converted-space"> asset that the market is literally valuing at $20M at best?<span class="apple-converted-space">”</span></span><o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">From another executive - “I have to confess that I have given up on reflecting on those things. Time is for action, from where I stand. No choice but to dedicate 150% of my time to saving my company. And I mean finding money wherever it can be found, tap into government subsidies, get creative and think outside of the AMR community box. We are not succeeding as a community, so we'll need to find solutions elsewhere. That's how cynical and slightly desperate I am being right now.”<o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">And another - “It’s a national security risk now given the bankruptcies and company/product failures in the sector. The total absence of a regulatory or legislative 'fix' is also a major factor……we have learned nothing about pandemic preparedness writ large. The next pandemic will be bacterial and we do not have solutions- the pre-penicillin era is here today!”<o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">The antibiotic biotech executives expressed a level of frustration and desperation that I have not heard before and that you generally do not hear in public forums. For clinical stage antibiotic biotechs, regulatory approval, instead of being an exciting and celebratory accomplishment, becomes the beginning of the end. Bankruptcy looms driven by the expense of supporting a newly approved product including post-approval regulatory requirements, manufacturing and marketing in the face of a fatally broken market. While I’m not ready to agree that the antibiotic era has already drawn to a close, I do agree that this is the likely conclusion if nothing is done to address the antibiotic market. The end of antibiotics starts and ends with the market. All the regulatory reform in the world (as much as it might be needed) will not change that. And, sadly, I find I share the pessimism and frustration of these antibiotic company executives in that I do not see the US or Europe providing a solution to the dead market anytime soon. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p>David Shlaeshttp://www.blogger.com/profile/00228776693058791618noreply@blogger.com2tag:blogger.com,1999:blog-4287560491211025099.post-14401789406463929602023-01-16T08:29:00.000-05:002023-01-16T08:29:19.106-05:00The Fate of Another Antibiotic Biotech - Nabriva<p><span style="font-size: large;"> <span style="font-family: Calibri, sans-serif;">Last week, a small, publicly held antibiotic biotech, Nabriva, announced that they would wind down their operations. Everyone still there lost their jobs. This occurred just a few years after getting approval for Lefamulin, an antibiotic available both orally and by injection that was active against MRSA and, mostly, shared no cross resistance with other antibiotics. Was this the inevitable result of a biotech with another drug that did not meet medical needs, or one that followed a deluded strategy, or is this just another tale of a broken antibiotic market?</span><span style="font-family: Calibri, sans-serif;"> </span><span style="font-family: Calibri, sans-serif;"> </span><span style="font-family: Calibri, sans-serif;">Whatever the cause, this is another blow to the world of antibiotic R&D.</span></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;"><o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">I have personal history with Nabriva that I would like to share with you. When I left Idenix (an antiviral biotech) in 2005, had no idea what I would be doing next. We sold our house in the Boston area and moved to France while I tried to formulate a plan. Shortly after our move, I received a call from a member of the board of Idenix asking if I could look at a plan to spin out an antibiotic biotech from Sandoz in Vienna. I agreed and my consulting business was born. This small group within Sandoz was mainly working on trying to identify a pleuromutilin compound that would be safe and effective for use in humans. These compounds had been used in animals for decades, but always remained too toxic for human use. The Sandoz group had made hundreds of compounds some of which even had drug-like properties and were potent antimicrobials. I helped this group spin out. The company was named Nabriva and remained located in Vienna. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">During the discovery process, we learned that these compounds suffered from problems of solubility, bioavailability, cardiotoxicity (prolonged QT) and spectrum. The first compound that went into development was BC3205. It was active against community respiratory pathogens and staphylococci including MRSA. The problem was that it had highly variable oral bioavailability and caused prolongation of QT (cardiotox). That was not a good combination. The team quickly searched through their database of compounds and identified BC3781 that had even better antimicrobial potency, was more soluble and had a lower propensity for cardiotoxicity. This backup compound became Lefamulin. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">During my later consulting years, Nabriva debated their development strategy for Lefamulin. They were comparing it to linezolid. Linezolid, an oxazolidinone, was famous for its anti-MRSA activity and oral bioavailability – that filled a huge unmet medical need at the time. But Nabriva noted, surprisingly, that linezolid was used mostly for patients with pneumonia. They also observed that there were many many more pneumonia patients treated with antibiotics than those with typical staphylococcal infections. They decided that they would go after that population rather than the staph infection market. As I saw it, the problem was that the pneumonia market was satisfied and saturated with existing compounds and that any new entry would struggle for market share. I was almost alone in opposing this strategy and was overruled.<o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">So, yes, I still think Nabriva was misguided in their strategy. I still think Lefamulin could be a useful alternative to other anti-staphylococcal treatments – but its really too late now to go back. A recent conversation with an old friend in the infectious diseases world reminded me that some of these biotechs deserve their fate. If that is the case for Nabriva, its still sad and it still will provide another nail in the coffin of antibiotic R&D funding. Many will see this as more evidence that no good deed shall go unpunished and that antibiotic R&D is to be avoided at all costs even if this may not really be correct in the case of Nabriva. </span><o:p></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;"><br /></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;"><br /></span></p>David Shlaeshttp://www.blogger.com/profile/00228776693058791618noreply@blogger.com0tag:blogger.com,1999:blog-4287560491211025099.post-70389413409912428882022-12-23T09:36:00.001-05:002022-12-23T09:36:49.163-05:00The Grinch Stole PASTEUR<p><span style="font-size: large;"> <span style="font-family: Calibri, sans-serif;">Antibiotic resistant infections are rising.</span><span style="font-family: Calibri, sans-serif;"> </span><span style="font-family: Calibri, sans-serif;"> </span><span style="font-family: Calibri, sans-serif;">Deaths from these infections are rising.</span><span style="font-family: Calibri, sans-serif;"> </span><span style="font-family: Calibri, sans-serif;"> </span><span style="font-family: Calibri, sans-serif;">The US is no exception. The dwindling antibiotic pipeline is almost uniformly filled with products from small biotechs whose financial status is never secure. The antibiotic market has failed. Most companies that have brought a new antibiotic to the market over the last decade have gone bankrupt. Investors, having lost money in the area, continue their flight. Government and other support for research and development of new antibiotics has increased, but these funds cannot compensate for the market failure that awaits products that make it all the way to the market.</span><span style="font-family: Calibri, sans-serif;"> </span></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;"><o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">The perfect storm has intensified since I wrote my book (Antibiotics – the Perfect Storm) back in 2010. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">The defense against the destruction wrought by this storm is government support for the broken market. Our best hope for this was the PASTEUR Act here in the US that provided for a subscription plan to purchase new and needed antibiotics for physicians and their patients. The Infectious Diseases Society first called for such an intervention back in 2004. The problem is that we have waited so long for this market intervention that we have approached the edge of the precipice. This week, the US Congress turned grinch and refused to include the PASTEUR Act in the 2023 omnibus spending bill that was just passed. We now start our descent into a post-antibiotic era. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="margin: 0in;"><span style="font-size: large;"><span style="font-family: Calibri, sans-serif;">I wrote many letters supporting PASTEUR to my congressmen. They were always answered with pre-digested drivel on their commitment to healthcare and research. I even spoke to their healthcare staffers who usually ended our conversations being unable to commit to supporting PASTEUR. The optimism of others much more active than me bolstered my hopes. Realistically, though, I was never optimistic that the US congress would support PASTEUR. I thought them incapable of providing such an incentive to the pharmaceutical industry. <o:p></o:p></span></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">The consequences of inaction, especially after so many years of neglect, will be dramatic. The few companies with products close to market approval will, upon approval, face immediate financial distress. Their ability to support the market expense as well as post-approval commitments will be severely limited or non-existent. Any brave and optimistic investors still supporting antibiotic research and development will finally be forced to admit defeat and move their support to oncology or other more profitable areas of endeavor. While investors never counted on passage of the PASTEUR Act, as they often recounted to me, I’m sure that they all harbored a secret hope that help was on the way. But, like Lucy, congress has pulled the football out from under the kicker at the last minute. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">There are so many exciting initiatives on the antibiotic research and development front. So many new grant opportunities have arisen in response to the emerging crisis in resistance. But I fear that without a market intervention of consequence (PASTEUR), this investment will be a bridge to nowhere. </span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">PASTEUR will be re-introduced during the next congressional session. I am afraid that this will be too late if it does pass, and I’m still not optimistic about its fate. Color me depressed.<o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;"> </span><o:p></o:p></p>David Shlaeshttp://www.blogger.com/profile/00228776693058791618noreply@blogger.com1tag:blogger.com,1999:blog-4287560491211025099.post-13376961721569201622022-10-10T02:43:00.002-04:002022-10-10T02:43:31.734-04:00PASTEUR, Do or . . .<p><span style="font-size: large;"> <span style="font-family: Calibri, sans-serif;">A recent article in Politico (blogger won’t let me use links for some reason), suggests that there is a good chance PASTEUR won’t pass this legislative session. I just don’t get it. The US is losing more and more lives to antibiotic-resistant infections. The antibiotic pipeline is a shambles.</span><span style="font-family: Calibri, sans-serif;"> </span><span style="font-family: Calibri, sans-serif;"> </span><span style="font-family: Calibri, sans-serif;">The few pipeline products that hold the promise of new activity against highly resistant pathogens also hold the very high risk of bankruptcy for their corporate sponsors in the absence of new investment in the antibiotic market.</span><span style="font-family: Calibri, sans-serif;"> </span><span style="font-family: Calibri, sans-serif;"> </span><span style="font-family: Calibri, sans-serif;">PASTEUR is designed to provide that investment. Apparently, our representatives in congress are worried about spending. The cost of PASTEUR, a subscription payment plan to incentivize antibiotic R&D, was estimated to be $11 billion over 10 years.</span><span style="font-family: Calibri, sans-serif;"> </span><span style="font-family: Calibri, sans-serif;"> </span><span style="font-family: Calibri, sans-serif;">After negotiations, the cost in the most recent draft of the bill has been reduced to $6 billion by reducing the term of the bill to 5 instead of 10 years (according to John Rex and Kevin Outterson). Other aspects of the bill have remained intact. We are now talking about $6 billion spread across a population of over 330 million souls over a five-year period. Compare that to the US healthcare budget of $3.2 trillion per year.</span><span style="font-family: Calibri, sans-serif;"> </span><span style="font-family: Calibri, sans-serif;"> </span><span style="font-family: Calibri, sans-serif;">You’ve got to be kidding, right?</span><span style="font-family: Calibri, sans-serif;"> </span><span style="font-family: Calibri, sans-serif;"> </span><span style="font-family: Calibri, sans-serif;">This does not even amount to a rounding error.</span><span style="font-family: Calibri, sans-serif;"> </span></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;"><o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">In my view we are at a do or die moment for a number of antibiotic biotechs and for the few investors still supporting antibiotic research and development. No amount of research support from BARDA, AMR Action Fund, CARB-X, or BARDA will make up for the disincentive of the broken and absent antibiotic market. The only hope for us is an intervention like PASTEUR to provide a market for needed new antibiotics. The market intervention envisioned by PASTEUR is a subscription plan where a sponsor that successfully brings a new and needed antibiotic to the marketplace is guaranteed the purchase of a certain number of treatment courses for a prescribed period of time and is based on contractual obligations undertaken by the sponsor. This is well designed legislation that would be successful if enacted. It has been under consideration in one form or another for about a decade. But I fear that the sands of time will run out this year. This is it. No more chances. Now or never. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">The market incentive that may be contemplated by Europe is still a glint in their eye. They are aiming for something in 2024. This will be too late and possibly not big enough depending on what they enact. In the absence of Europe – the US is it. Outside Europe, the US is the only economy large enough to provide an incentive that is sufficient to actually function as an incentive. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;"><br /></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;"><o:p> </o:p>Kevin Outterson says he feels better about PASTEUR now than ever. He is definitely closer to this entire process than me. But having worked for the Department of Veterans Affairs as an infectious diseases physician for 16 years, I am a little more cautious in my view. My daughter keeps reminding me of all the positive and important things government can accomplish. My own experience is one of a government that has difficulty tying its own shoelaces. During my 16 years at the VA, I think I can remember three where the budget was passed on time without a continuing resolution and the resulting end of year dysfunction. I am therefore more afraid that PASTEUR will either never see the light of day or will be too little too late. But I am also mindful and hopeful that PASTEUR will be an incredibly important contribution to the public health.</span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;"><br /></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">So, my message to all who might see this is – make sure your representatives know how strongly you feel about passing PASTEUR in the US and about providing a real incentive in Europe before it’s too late. </span><o:p></o:p></p>David Shlaeshttp://www.blogger.com/profile/00228776693058791618noreply@blogger.com2tag:blogger.com,1999:blog-4287560491211025099.post-43391464505570241172022-08-22T09:45:00.001-04:002022-08-22T09:45:57.864-04:00Why Antibiotics Don't Work - Implications for Clinical Trial Design<p><span style="font-size: large;"> </span></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjeGJlNFl00tCXpGfIZjgWxaJ0OSFKFKtFRQ-0MY_qKYyy29r5csOJ4gBsHmaDf5LbRhC7x32cf2dZT-O01ecX9ojt6BG7GDPMqizvd6Gv6AUzavW6T69AMqVLrzotbtXqkGVEeIc15nPzoEeQV3aJ0UIe2vSel1CLIcCe6R9CEjNdah9K4NG2Gy-6L/s268/contrafect%20logo.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><span style="font-size: large;"><img border="0" data-original-height="188" data-original-width="268" height="188" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjeGJlNFl00tCXpGfIZjgWxaJ0OSFKFKtFRQ-0MY_qKYyy29r5csOJ4gBsHmaDf5LbRhC7x32cf2dZT-O01ecX9ojt6BG7GDPMqizvd6Gv6AUzavW6T69AMqVLrzotbtXqkGVEeIc15nPzoEeQV3aJ0UIe2vSel1CLIcCe6R9CEjNdah9K4NG2Gy-6L/s1600/contrafect%20logo.png" width="268" /></span></a></div><p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">I want to discuss the idea of superiority trials for antibiotics and some of the issues that many experienced researchers fail to consider when thinking about this topic. I am grateful to George Drusano for his input here. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;"><br /></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">Before I get into this topic, I want to say that I know I haven’t written a blog since April. That is because I feel that if we do not have an important pull incentive such as is being contemplated in the PASTEUR Act in front of the US Congress – all else is futile including questions of antibiotic trial design . . .<o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">There are many reasons why antibiotics don’t work and, most of the time, it is not related to resistance. Consideration of this question will be important in the design of clinical trials for antibacterials as Contrafect just learned the hard way. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">Yes, resistance to antibiotic treatment is an important concern, but it is hard to design trials around this issue for several reasons. Resistance to gold standard comparator antibiotics remains uncommon. Even when this occurs, in a double blinded randomized trial, we usually exclude those patients whose infection is resistant to a comparator antibiotic such that they can be treated with something more likely to be effective. There are some occasional exceptions to this, but this problem makes trial design challenging. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">Some experts believe, based on some data, that so called bactericidal antibiotics like beta-lactams are generally superior to bacteriostatic antibiotics like tetracyclines. Others believe that this is mainly an issue of choosing an appropriate dose for the indication being studied. Still others believe that this is only true for certain situations like nosocomial pneumonia or serious infections occurring in severely immunocompromised patients. But proving this in the context of a clinical trial remains very challenging. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">Of course, other obvious problems exist. We try and exclude patients with non-bacterial infections from study when possible since antibiotics will not be effective – but we do not always succeed. Including these patients tends to drive the result to the “nul” or -no difference. This would be a big problem in a superiority trial. We also try and exclude patients who are not likely to respond even to effective antibiotic treatment such as those unlikely to survive long enough to provide sufficient time on study and those who are severely immunocompromised where antibiotic treatment may be less effective. But this still leaves many patients with susceptible infections who will respond poorly to antibiotic treatment. Why and how?<o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">Let’s look at one example - serious infections caused by <i>Staphylococcus aureus</i>. Disseminated infections with<i>S.aureus</i> tend to involve multiple foci of infection including abscesses of various sizes. Because there may be multiple such foci, drainage is not possible. Antibiotics may not penetrate well into these areas and may not work well in the local environment of the abscess where the pH may be low. Left-sided staphylococcal endocarditis still carries a 30% mortality rate in spite of appropriate therapy. I personally think this is more likely caused by mechanical problems and multiple abscesses rather than any issue with the lack of killing activity of the antibiotic. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">Sometimes, patients slip into a septic state where a systemic inflammatory response is triggered. While this might not be immediately fatal, even with antibiotic therapy, the inflammatory response could progress and might ultimately lead to organ failure and death. Again, protected sites of infection might be the problem here. Yet these patients will be entered into clinical trials and the antibiotic itself will be destined to fail without other interventions such as surgery. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">Animal models in the antibiotic world are incredibly helpful in predicting efficacy and efficacious dosing. In vitro pharmacodynamic models using the hollow fiber system can also be useful and are frequently more “conservative” than traditional animal models since you can study more long term effects including that of slowly emerging resistance. But these models cannot be used, in general, to predict superiority as it is studied in the context of a clinical trial. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">What I am trying to argue here is that superiority trials for antibiotics will be confounded by infections where the antibiotic is not the issue. Most antibiotics will work well in the absence of such intractable problems. Therefore, even in the absence of resistance, it will be challenging to show superiority clinically even with an antibiotic that might look superior in vitro or in various model sysems. </span><o:p></o:p></p>David Shlaeshttp://www.blogger.com/profile/00228776693058791618noreply@blogger.com0tag:blogger.com,1999:blog-4287560491211025099.post-52830669368975058212022-04-12T08:29:00.002-04:002022-04-12T08:29:52.795-04:00ASM Microbe - Antimicrobial Agents and Resistance<p><span style="font-size: large;"> Guest Blogger</span></p><p><span style="font-size: large;"><br /></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;"><span style="font-family: Arial, sans-serif;">Krisztina M. Papp-Wallace</span><span style="font-family: "Times New Roman", serif;"><o:p></o:p></span></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;"><b><span style="font-family: Arial, sans-serif;">Introducing the ASM Microbe 2022 Antimicrobial Agents and Resistance Program<u1:p></u1:p></span></b><o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><u1:p><span style="font-size: large;"> <o:p></o:p></span></u1:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;"><span style="font-family: Arial, sans-serif;">Dear AAR community,<u1:p></u1:p></span><o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;"><span style="font-family: Arial, sans-serif;"> </span><o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;"><span style="font-family: Arial, sans-serif;">As an AAR track member of the ASM Microbe 2022 program committee, I would like you introduce you to this year's AAR programming of sessions and our speakers from around the world (see Tables below). We have an amazing meeting planned for you with cutting-edge science and the latest developments in the field. We look forward to seeing you in-person from June 9th-June13th in Washington, D.C.!<u1:p></u1:p></span><o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;"><span style="font-family: Arial, sans-serif;"> </span><o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;"><span style="font-family: Arial, sans-serif;">Please register today:<span class="apple-converted-space"> </span><a href="https://asm.org/Events/ASM-Microbe/Registration" style="color: #954f72;"><span style="color: #0563c1;">https://asm.org/Events/ASM-Microbe/Registration</span></a></span><o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p></o:p></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh5GRyx8wXiiNcZgX_aroO12TfpnEFKHGiAOX0Op4x9Y7CA3T3ESITpmJy25Sd3E7mCdy6n3YTjFXdpc4S0OcPljcnX9r8TvAvrlYuH_wuoEANUxidF-JAjuMI0ZGK9OLI8Bid1onT12X40U20rg7af0z9u2addKrgW2At1AeJT7x1zD_boNuTJ1th3/s960/AAR%20Figure%201.jpg" imageanchor="1" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img border="0" data-original-height="960" data-original-width="960" height="509" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh5GRyx8wXiiNcZgX_aroO12TfpnEFKHGiAOX0Op4x9Y7CA3T3ESITpmJy25Sd3E7mCdy6n3YTjFXdpc4S0OcPljcnX9r8TvAvrlYuH_wuoEANUxidF-JAjuMI0ZGK9OLI8Bid1onT12X40U20rg7af0z9u2addKrgW2At1AeJT7x1zD_boNuTJ1th3/w426-h509/AAR%20Figure%201.jpg" width="426" /></a></div><br /><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEivdsNDXCwc-7vwwvPXcnfzHZqO97WQLQaW77Fnij3ym0U195cTBc8lTAMJU9Ua6XDaGXRLHGfZBoN47lElhBof343eQg_0Dw2bIVTSGS-oGo9fGQDv-OaMB__mvwGTs3f4OiBFmr66n9QZUUlZ_UrfKmtuxmVljjPho2-Wn1wY5OQW6McoUCFS2yl3/s960/AAR%20Figure%202.jpg" imageanchor="1" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img border="0" data-original-height="960" data-original-width="960" height="438" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEivdsNDXCwc-7vwwvPXcnfzHZqO97WQLQaW77Fnij3ym0U195cTBc8lTAMJU9Ua6XDaGXRLHGfZBoN47lElhBof343eQg_0Dw2bIVTSGS-oGo9fGQDv-OaMB__mvwGTs3f4OiBFmr66n9QZUUlZ_UrfKmtuxmVljjPho2-Wn1wY5OQW6McoUCFS2yl3/w435-h438/AAR%20Figure%202.jpg" width="435" /></a></div><br /><span style="font-size: large;"><br /></span><p></p>David Shlaeshttp://www.blogger.com/profile/00228776693058791618noreply@blogger.com0tag:blogger.com,1999:blog-4287560491211025099.post-52170882058382019992022-03-28T08:35:00.000-04:002022-03-28T08:35:58.637-04:00Pull Incentives for Antibiotic R&D and Private Investment<p><span style="font-size: large;"> <span style="font-family: Calibri, sans-serif;">John Rex (thank you) just sent out an email highlighting a</span><span style="font-family: Calibri, sans-serif;"> </span><a href="https://milkeninstitute.org/report/antimicrobial-resistance-antibiotic-development" style="font-family: Calibri, sans-serif;"><span style="color: red;">paper</span></a><span style="font-family: Calibri, sans-serif;"> </span><span style="font-family: Calibri, sans-serif;">emanating from the Milliken Institute on how private investment could augment government sponsored pull incentives for antibiotic R&D. Even though I consider myself an ex-PhRMA executive and, as such, I thought I could understand the basics of the pharmaceutical business and investment strategies, this paper is beyond me. (Its important to know what you don’t know, right?) But, as you might have surmised, I have my own thoughts on this subject.</span><span style="font-family: Calibri, sans-serif;"> </span><span style="font-family: Calibri, sans-serif;"> </span><span style="font-family: Calibri, sans-serif;">They are not new.</span><span style="font-family: Calibri, sans-serif;"> </span><span style="font-family: Calibri, sans-serif;"> </span><span style="font-family: Calibri, sans-serif;">They are not surprising.</span><span style="font-family: Calibri, sans-serif;"> </span><span style="font-family: Calibri, sans-serif;"> </span><span style="font-family: Calibri, sans-serif;">And I think I understand what I’m thinking . . .</span></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;"><o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">Historically and even today, private investment in biotech is based on the belief that outright purchase or a lucrative licensing deal from large PhRMA is the ideal exit providing the highest return on investment. Reliance on a public market exit is a distant second best – although clearly a large pull incentive would increase the attractiveness of a pubic market exit. Assuming this dynamic is still generally in place, how would a significant pull incentive interact with a large pull incentive in this situation?<o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">As I’ve noted <a href="https://antibiotics-theperfectstorm.blogspot.com/2018/03/pfizer-antibiotics-and-incentives.html"><span style="color: red;">previously</span></a>, large PhRMA is interested in large pull incentives. The PASTEUR Act being considered in the US congress envisions pull incentives from $750 million (not enough) to $3 billion (yes) per high priority antimicrobial approved by the FDA. A transferable exclusivity voucher would provide, in my view, an even more attractive option for PhRMA given the opportunity for prolonged exclusivity on multi-billion-dollar products. Since most antibiotic discovery and development is now occurring in biotech, if a product in late-stage development were known to be the recipient of such a pull incentive upon approval, large PhRMA would certainly consider an investment. As has always been true, the earlier the investment (where the risk is greater), the lower the amount of investment required. As the product nears NDA and that valuable pull incentive, the cost of any investment will rise while the value of any early investment will also rise. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">Given this dynamic, let’s go back to private investors like venture capitalists. Today, antibiotic R&D is avoided, shunned by venture capital. But what happens when interest by large PhRMA is stimulated by the prospect of significant pull incentives? Venture will come back to the table to try and take advantage of this opportunity. Again, the earlier they get involved, the lower the initial investment becomes. In the presence of continued non-dilutive support for R&D (push incentives) such as are available through CARB-X, Wellcome, BARDA and others, the private investment required becomes even more attractive. But this all depends on the availability of that important pull incentive at the end of the road. This all falls apart without that. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">I would like to spend a few words discussing the urgency of pull incentives for antibiotic R&D. Entasis, a truly important antibiotic biotech, appears to be in <a href="https://antibiotics-theperfectstorm.blogspot.com/2022/02/entasis-antibiotics-and-dodo.html"><span style="color: red;">trouble</span></a>. VenatoRx is an antibiotic biotech with a remarkable product (partnered with GARDP), cefepime-taniborbactam, that has just completed its phase 3 trials. An NDA is <a href="https://www.venatorx.com/pipeline/"><span style="color: red;">imminent</span></a>. Will VenatoRx survive the crucible of commercialization? How many more antibiotic biotech bankruptcies will investors tolerate? The level of investment in this space shows they are already very spooked. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">I have always thought and continue to believe that one major rationale for pull incentives is to attract large PhRMA, and with it, venture capital back to antibiotic research. To me, any pull incentive that fails the PhRMA attractiveness test will diminish its success in stimulating investment in antibiotic R&D. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">What comes next? PASTEUR must pass the US congress this year! Europe must provide a significant pull incentive ahead of its 2024 timeframe. We must all work to achieve these goals.<o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p>David Shlaeshttp://www.blogger.com/profile/00228776693058791618noreply@blogger.com1tag:blogger.com,1999:blog-4287560491211025099.post-40356948120527037932022-02-14T08:24:00.001-05:002022-02-14T08:25:21.706-05:00The Future of Antibiotics<p><span style="font-family: inherit; font-size: large;"> Spoiler alert – get out the anti-depressants.</span></p><p class="MsoNormal" style="margin: 0in;"><span style="font-family: inherit; font-size: large;"><o:p></o:p></span></p><p class="MsoNormal" style="margin: 0in;"><o:p><span style="font-family: inherit; font-size: large;"> </span></o:p></p><p class="MsoNormal" style="margin: 0in;"><o:p><span style="font-family: inherit; font-size: large;"><br /></span></o:p></p><p class="MsoNormal" style="margin: 0in;"><span style="font-family: inherit; font-size: large;"><o:p></o:p></span></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEjcbLY8tGu6MhrFlwnYbvOyduNjXtBKkAOZfwPD3SO85lWCYRfpvtyCx6ht8H1t06-0YqJrvWy4Rg3JaGV0UndqUKEhWOO63i1G08rgns6MD-qKXhX7RygMGRUBmy-6Un8mBc-TdStdinc4_TkpL7O1Vt8HYl7VBxglksfTFEir6GUv5B2mwJwkyAp_=s225" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><span style="font-family: inherit; font-size: large;"><img border="0" data-original-height="225" data-original-width="225" height="225" src="https://blogger.googleusercontent.com/img/a/AVvXsEjcbLY8tGu6MhrFlwnYbvOyduNjXtBKkAOZfwPD3SO85lWCYRfpvtyCx6ht8H1t06-0YqJrvWy4Rg3JaGV0UndqUKEhWOO63i1G08rgns6MD-qKXhX7RygMGRUBmy-6Un8mBc-TdStdinc4_TkpL7O1Vt8HYl7VBxglksfTFEir6GUv5B2mwJwkyAp_" width="225" /></span></a></div><span style="font-family: inherit; font-size: large;"><br /><span><br /></span></span><p></p><p class="MsoNormal" style="margin: 0in;"><span style="font-family: inherit; font-size: large;">Before I get to the issue at hand, I need to share with you my recent experience posting blogs on Google’s Blogger – something I’ve been happily doing, trouble-free, free of charge since 2009 (thank you, Google). My last <a href="https://antibiotics-theperfectstorm.blogspot.com/2022/02/entasis-antibiotics-and-dodo.html"><span style="color: red;">post</span></a>, which garnered almost a record 6000 views (thank you readers), has been taken down by Google every day for the last week because it “violates our guidelines.” I have read the guidelines carefully and been unable to understand this. Nevertheless, each day, I removed or modified something and requested a re-review. Each day, the blog was re-approved only to be taken down the next day. Have you ever seen the movie, Groundhog Day? I have tried to communicate with Google – seems like trying to speak to a deity of some sort – but so far without success. All this to say that I may have to find another outlet for my blog after 13 years depending on what happens with this posting . . .<o:p></o:p></span></p><p class="MsoNormal" style="margin: 0in;"><o:p><span style="font-family: inherit; font-size: large;"> </span></o:p></p><p class="MsoNormal" style="margin: 0in;"><span style="font-family: inherit; font-size: large;"><br /></span></p><p class="MsoNormal" style="margin: 0in;"><span style="font-family: inherit; font-size: large;"><br /></span></p><p class="MsoNormal" style="margin: 0in;"><span style="font-family: inherit; font-size: large;"></span></p><div class="separator" style="clear: both; text-align: center;"><span style="font-family: inherit; font-size: large;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEgL8dKliuW99SLi2UmdfiC_DERHzRTp2qwyoTtPRU5K-SQhD0-ojcCShLwYGx1K2R_7lORRFaZgPVI3LpGB21nTWxDWk8TByjE6-DuxAMxFj5utFC0tG4QLFfPAjoJmOejYF7QNI3NAEDeqpcku4FLa7MpJtYa7zotYURenBv_ZS3zKMIipdaamWDam=s720" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="405" data-original-width="720" height="180" src="https://blogger.googleusercontent.com/img/a/AVvXsEgL8dKliuW99SLi2UmdfiC_DERHzRTp2qwyoTtPRU5K-SQhD0-ojcCShLwYGx1K2R_7lORRFaZgPVI3LpGB21nTWxDWk8TByjE6-DuxAMxFj5utFC0tG4QLFfPAjoJmOejYF7QNI3NAEDeqpcku4FLa7MpJtYa7zotYURenBv_ZS3zKMIipdaamWDam=s320" width="320" /></a></span></div><span style="font-family: inherit; font-size: large;"><br />Let’s imagine that 10 years from now, in 2032, both the US and Europe implement significant pull incentives for the discovery, development and marketing of new and needed antibacterial drugs. Investors and large PhRMA are trolling for opportunities. But there are none. <o:p></o:p></span><p></p><p class="MsoNormal" style="margin: 0in;"><o:p><span style="font-family: inherit; font-size: large;"> </span></o:p></p><p class="MsoNormal" style="margin: 0in;"><span style="font-family: inherit; font-size: large;"><span>All the small biotechs that had products in late-stage development since 2022 have gone bankrupt or simply re-organized to something other than an antibacterial company. Their products were not marketed or are only available in small amounts in a few countries. There are no strong biotech discovery programs out there because investors abandoned the space so completely over the last decade. There are a few academic research programs still around but they have no products in clinical development and the academic groups still working in the area do not have the expertise to bring their products into development and certainly not all the way to the marketplace. All the experts in the translational aspects of antibiotic research have either found other employment, have retired or are writing blogs about the antibiotic disaster now facing patients and physicians around the world. The few chemists with expertise in antibacterial work are now either retired or working in oncology or </span>some<span> other more secure field. Those expert consultants who were approaching or had passed retirement age back in 2022 are no longer available to help. <o:p></o:p></span></span></p><p class="MsoNormal" style="margin: 0in;"><o:p><span style="font-family: inherit; font-size: large;"> </span></o:p></p><p class="MsoNormal" style="margin: 0in;"><span style="font-family: inherit; font-size: large;">So what has to happen in 2032? One starts all over again. Investors, though, once they carry out a little due diligence, might realize that any opportunity they might have had to take advantage of these new pull incentives and the hunger of large PhRMA for that largess, is gone in 2032. The effort to start over will be long and any return will not come for at least another 10 years. Investors with patience exist, but there are so many competing and more attractive options that antibiotics will, once again, take a back seat. <o:p></o:p></span></p><p class="MsoNormal" style="margin: 0in;"><o:p><span style="font-family: inherit; font-size: large;"> </span></o:p></p><p class="MsoNormal" style="margin: 0in;"><span style="font-family: inherit; font-size: large;"><span>No, I do not think that academic research can replace the antibiotic biotechs of today – at least not without a significant investment in learning the translational pathways to get from laboratory findings to an antibiotic on the market - to say nothing of acquiring the chemistry resources and </span>expertise<span>. I know that this opinion will not be a popular one – but I’m sharing an honest belief having spent half of my career in both worlds (and I have been saying this for many years now). How many of those in academics have taken an antibacterial drug from the laboratory all the way through to regulatory approval all the while remaining in academia. OK, I’m not talking about those of us who we given “adjunct” professorships during our industry careers. I’m talking about someone like me who, instead of pursuing a career in industry stayed on in their academic research lab, discovered a new antibacterial and successfully achieved regulatory approval for their discovery. How many have “been there, done that” as George Drusano might say? Sadly, in my view, it doesn’t work like that. The breadth of expertise that one can bring together in an industrial setting does not really exist in academia (in spite of efforts by NIAID). And this kind of depth of experience is simply a basic requirement for success. Could that change? Maybe – but not the way we currently approach the problem in academia. Perhaps we could quickly cobble together internships and sabbaticals for academics to work in industry for 3-12 months so that they understand what is required and how to get things done. (I proposed this to NIAID in 2004). But it seems a little late to try and get that started now. <o:p></o:p></span></span></p><p class="MsoNormal" style="margin: 0in;"><o:p><span style="font-family: inherit; font-size: large;"> </span></o:p></p><p class="MsoNormal" style="margin: 0in;"><span style="font-family: inherit; font-size: large;">What about public-private partnerships? Sure. But you must have the funding for the private part . . .I rest my case. <o:p></o:p></span></p><p class="MsoNormal" style="margin: 0in;"><o:p><span style="font-family: inherit; font-size: large;"> </span></o:p></p><p class="MsoNormal" style="margin: 0in;"><span style="font-family: inherit; font-size: large;">In 2032 there will be an antibacterial research, discovery and development desert if there is not a significant intervention in the marketplace within the next year or maybe two at most. Our pipeline will go from pathetic to non-existent. Our opportunity will be lost entirely or the opportunity cost will become too high to attract investors in spite of any pull incentives that might exist by 2032. </span></p><p class="MsoNormal" style="margin: 0in;"><span style="font-family: inherit; font-size: large;"><br /></span></p><p class="MsoNormal" style="margin: 0in;"><span style="font-family: inherit; font-size: large;">This is urgent. This needs to change now!<o:p></o:p></span></p><p class="MsoNormal" style="margin: 0in;"><o:p><span style="font-family: inherit; font-size: large;"> </span></o:p></p>David Shlaeshttp://www.blogger.com/profile/00228776693058791618noreply@blogger.com0tag:blogger.com,1999:blog-4287560491211025099.post-9381110180878768502022-02-07T08:59:00.032-05:002022-02-16T14:21:54.369-05:00Entasis, Antibiotics and the Dodo<p><span style="font-family: inherit; font-size: large;"> </span></p><div class="separator" style="clear: both; text-align: center;"><span style="font-family: inherit; text-align: left;"><br /></span></div><div class="separator" style="clear: both; text-align: center;"><span style="font-family: inherit; font-size: large;"><span style="text-align: left;">And again! Entasis Therapeutics has been</span><span style="text-align: left;"> struggling in the public marketplace. There is certainly a risk that it will be going the way of Melinta, Achaogen, Tetraphase and the Dodo bird. Investors just do not believe that antibiotics companies can provide a return on their investment – and they are probably correct. </span></span></div><p></p><p class="MsoNormal" style="margin: 0in;"><span style="font-family: inherit; font-size: large;"><o:p></o:p></span></p><p class="MsoNormal" style="margin: 0in;"><o:p><span style="font-family: inherit; font-size: large;"> </span></o:p></p><p class="MsoNormal" style="margin: 0in;"><span style="font-family: inherit; font-size: large;"><span style="caret-color: rgb(255, 0, 0);">Entasis</span> is a spin-out from Astra-Zeneca established in 2015. The company was based on pre-clinical assets and recruited a number of smart and dedicated scientists. Their IPO in 2018 was disappointing even though they raised $75 million. Their <span style="caret-color: rgb(255, 0, 0);">pipeline</span> includes sulbactam-durlobactam for infections caused by antibiotic-resistant Acinetobacter that has completed its phase 3 trials and zoliflodacin that is undergoing its phase 3 trials for uncomplicated gonorrhea including highly resistant infections. While both of these products are greatly needed by a few, they may be market flops because of the small patient numbers involved. <o:p></o:p></span></p><p class="MsoNormal" style="margin: 0in;"><o:p><span style="font-family: inherit; font-size: large;"> </span></o:p></p><p class="MsoNormal" style="margin: 0in;"><span style="font-family: inherit; font-size: large;">Entasis has done much to secure financial success. They have partnered with a Chinese firm for the development and marketing of sulbactam-durlobactam and have partnered with GARDP, a non-profit based in Geneva, SW for the development and marketing of zoliflodacin (I was on the GARDP advisory board at the time). </span></p><p class="MsoNormal" style="margin: 0in;"><o:p><span style="font-family: inherit; font-size: large;"> </span></o:p></p><p class="MsoNormal" style="margin: 0in;"><span style="font-family: inherit; font-size: large;">Investors, though, have not been impressed. Entasis’ market cap has been constrained since the IPO and recently their financial runway was compressed to months. Their major investor, Innoviva, may come to the rescue by taking the company private once again. But will they and other investors ever realize a reasonable, if any, return? Previous examples of similar pathways for antibiotic biotech are not encouraging. Even if BARDA comes to Entasis’ rescue as they did for Paratek, their ultimate destiny may only be delayed without a more important market intervention. <o:p></o:p></span></p><p class="MsoNormal" style="margin: 0in;"><o:p><span style="font-family: inherit; font-size: large;"> </span></o:p></p><p class="MsoNormal" style="margin: 0in;"><span style="font-family: inherit; font-size: large;">The story of Entasis is not new, not unique, and in fact, will be the rule for all of antibiotic biotech if something does not change. And this is dangerous! It’s a danger that we all have seen coming, that we have all been warning about from the rooftops for years. Antibiotic resistance is now thought to directly contribute to <span style="caret-color: rgb(255, 0, 0);">1.7 million deaths </span>per year globally with most coming from lower respiratory infections. Our antibiotic pipeline to deal with the problem of resistance remains <span style="caret-color: rgb(255, 0, 0);">pathetic</span>. 95% of new antibiotics are being discovered and developed in small biotech companies like Entasis. The antibiotic market failure is the sword of Damocles hanging over antibiotic biotech and their products. Their doom is inevitable without rescue from this failed market. <o:p></o:p></span></p><p class="MsoNormal" style="margin: 0in;"><o:p><span style="font-family: inherit; font-size: large;"> </span></o:p></p><p class="MsoNormal" style="margin: 0in;"><span style="font-family: inherit; font-size: large;">Many are encouraged by the subscription plans in the UK and Sweden. Although these plans may serve as models, they cannot provide the kind of market intervention we need to save antibiotic biotechs. This must come from large economies like Europe and the US. The US effort to provide a government-based market intervention has been foundering for years. I continually lose track of the various different congressional efforts (Cure 2.0, PASTEUR, DISARM, etc) that go nowhere, obtain no co-sponsors, are not debated and never become law. Europe is also planning on something – but apparently they don’t know what it will be and whatever it is won’t occur before 2024. <o:p></o:p></span></p><p class="MsoNormal" style="margin: 0in;"><o:p><span style="font-family: inherit; font-size: large;"> </span></o:p></p><p class="MsoNormal" style="margin: 0in;"></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEizoYb2x2J0uEp29uie1S--XGC5sefcyQpviGujsP5mJEOhaBpUm7O1CtKUtK71lLWRcogX5JPhS8o0TEOyGcaRjNKcYTSTSiULw2rJIZHEsRJPw1pfMsWS-XxBm2s9BkMxmhfwyWEAAWxK-12skbLCSN_HZbM2Gg8C5U5n3ukJnkr3z-daZ3fFSgwR=s226" style="clear: right; float: right; margin-bottom: 1em; margin-left: 1em;"><br /></a></div><span style="font-family: inherit; font-size: large;">It seems like we have learned little from our experience with covid. The idea of thinking ahead to avoid public health crises seems somehow not to apply to bacterial infections and the antibiotics that we use to treat them. Unlike covid, antibiotic resistant infections is a slow moving process heading inexorably towards global disaster. For antibiotics, if we act now, we can avoid the worst. But we remain ostriches with our heads in the sand. “If I close my eyes, they won’t see me.” <o:p></o:p></span><p></p><blockquote style="border: none; margin: 0px 0px 0px 40px; padding: 0px;"><p class="MsoNormal" style="margin: 0in;"><span style="font-family: inherit; font-size: large;"></span></p></blockquote><p class="MsoNormal" style="margin: 0in;"><o:p><span style="font-family: inherit; font-size: large;"> </span></o:p></p><p class="MsoNormal" style="margin: 0in;"><span style="font-family: inherit; font-size: large;">The US dithers, Europe ponders and the extinction of life-saving antibiotics continues apace. </span><span face="Calibri, sans-serif"><o:p></o:p></span></p>David Shlaeshttp://www.blogger.com/profile/00228776693058791618noreply@blogger.com3tag:blogger.com,1999:blog-4287560491211025099.post-51596369843046525212022-01-31T09:12:00.000-05:002022-01-31T09:12:33.960-05:00To have functioning public health in the US, we must first have national healthcare. <p></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEgXo2vzhBJaXhmaf9gztSgVcHTksskjW5B24tGUr1ur8MeX-ozdJ3cj7bPliK9tsQ2mLfDfpNdD30VLMmth2_4B5L-wRL1Hw074QWYHI8XhPHGV_eTQRrGW2xP53XrP6qzF8oFiT1M4XHoT8SRsI0xsUK7zc2XUoMCRQQ2U46ktsKbxWdhgkgDSgjQg=s225" style="margin-left: 1em; margin-right: 1em;"><span style="font-family: inherit; font-size: large;"><img border="0" data-original-height="225" data-original-width="225" height="225" src="https://blogger.googleusercontent.com/img/a/AVvXsEgXo2vzhBJaXhmaf9gztSgVcHTksskjW5B24tGUr1ur8MeX-ozdJ3cj7bPliK9tsQ2mLfDfpNdD30VLMmth2_4B5L-wRL1Hw074QWYHI8XhPHGV_eTQRrGW2xP53XrP6qzF8oFiT1M4XHoT8SRsI0xsUK7zc2XUoMCRQQ2U46ktsKbxWdhgkgDSgjQg" width="225" /></span></a></div><span style="font-family: inherit; font-size: large;"> <div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEhok4siSrWDMXaDzMEoG8jmL44n-B4F018kifPbDMTYbpCFpe9MJu_anpDjeeqYT99dLvwrDarbCOaVpoKzJ0Xu-9oHbCTrTw2ifY1EjEB-ZLUKl_OOn_vNNJg_zG_gpsYDf2upRuYFzaCK0jy_YtUmd2JJJ8pvigLrpgNkg6qu_wJDcYwUt20t0k70=s225" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="225" data-original-width="225" height="225" src="https://blogger.googleusercontent.com/img/a/AVvXsEhok4siSrWDMXaDzMEoG8jmL44n-B4F018kifPbDMTYbpCFpe9MJu_anpDjeeqYT99dLvwrDarbCOaVpoKzJ0Xu-9oHbCTrTw2ifY1EjEB-ZLUKl_OOn_vNNJg_zG_gpsYDf2upRuYFzaCK0jy_YtUmd2JJJ8pvigLrpgNkg6qu_wJDcYwUt20t0k70" width="225" /></a><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEgvmnwlSpqveTQH4bRUr4AjG2QmL0JD4gS1Jo8LQIFbHLUWEPb0UCZzOx3AN0M6w5FHEA70rBobovpcl-9DenMUnsAGVH5Kt_HqDeo5rE0J0H4TRUmoofOs2gn2nEH4-pHxtg4GoNhgJcMv6U92mRDAhI0t_1LaJbd_2cF8d9qxYdRmW5HHgCDUpZAM=s236" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="214" data-original-width="236" height="214" src="https://blogger.googleusercontent.com/img/a/AVvXsEgvmnwlSpqveTQH4bRUr4AjG2QmL0JD4gS1Jo8LQIFbHLUWEPb0UCZzOx3AN0M6w5FHEA70rBobovpcl-9DenMUnsAGVH5Kt_HqDeo5rE0J0H4TRUmoofOs2gn2nEH4-pHxtg4GoNhgJcMv6U92mRDAhI0t_1LaJbd_2cF8d9qxYdRmW5HHgCDUpZAM" width="236" /></a></div><br /></div><br /><br /><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEitFtzcaqm3rA5mF2Tl45igQxSygdcdxMEDxBQyZnoD00IgWj9M9tzS-egWbCXoV7IrTbvRDS9GrWvAoXcbQcqBhe5R75rCsNyVn52FyJXfpX2t_or2tlvjnuLB3PV2s66jee4mWlDIep9O3IbhHda3vPRR4ktuSkNU5vqt6EOkr8t1IWNKOXMcwDth=s320" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="158" data-original-width="320" height="158" src="https://blogger.googleusercontent.com/img/a/AVvXsEitFtzcaqm3rA5mF2Tl45igQxSygdcdxMEDxBQyZnoD00IgWj9M9tzS-egWbCXoV7IrTbvRDS9GrWvAoXcbQcqBhe5R75rCsNyVn52FyJXfpX2t_or2tlvjnuLB3PV2s66jee4mWlDIep9O3IbhHda3vPRR4ktuSkNU5vqt6EOkr8t1IWNKOXMcwDth" width="320" /></a></div><br /><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEi-ndLCITM_N92rDKq85elF3q1kM_u5-xty5YVJnPhqV83VuHTgD-CQm5Buy5-cXyO4arNvfT5FPbSGLC54a-Rx1Z9Z_t5HXLFBbAVJpW-b_pxOIc_Pxw9hhlAjjn8G5AqwK3Qbb8X8jjGsx8t9bcmzkDncro-ol8F89LzoTROrF1yNX-BSkp37ocs4=s266" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="189" data-original-width="266" height="189" src="https://blogger.googleusercontent.com/img/a/AVvXsEi-ndLCITM_N92rDKq85elF3q1kM_u5-xty5YVJnPhqV83VuHTgD-CQm5Buy5-cXyO4arNvfT5FPbSGLC54a-Rx1Z9Z_t5HXLFBbAVJpW-b_pxOIc_Pxw9hhlAjjn8G5AqwK3Qbb8X8jjGsx8t9bcmzkDncro-ol8F89LzoTROrF1yNX-BSkp37ocs4" width="266" /></a></div><br /></span><p></p><p><span style="font-size: large;"><span face="Calibri, sans-serif" style="font-family: inherit;"><br /></span></span></p><p><span style="font-family: inherit; font-size: large;"><span face="Calibri, sans-serif">A recent report by the US Government Accountability Office (GAO) highlights risks associated with the response to pandemics at the US Department for Health and Human Services (HHS) (</span><a href="https://www.gao.gov/assets/gao-22-105291-highlights.pdf"><span style="color: red;">1</span></a><span face="Calibri, sans-serif">,</span><a href="https://www.washingtonpost.com/health/2022/01/27/gao-hhs-mismanaged-pandemic-response/"><span style="color: red;">2</span></a><span face="Calibri, sans-serif">). These critiques go back the through several administrations and include the response to Zika, Ebola, H1N1 flu and others. They mainly involve issues around the national stockpile, strategy for testing and surveillance. While these critiques are clearly valid, I would like to add some perspective from someone (me) who has interacted with the various agencies of HHS over many years.</span></span></p><p class="MsoNormal" style="margin: 0in;"><span style="font-family: inherit; font-size: large;"><o:p></o:p></span></p><p class="MsoNormal" style="margin: 0in;"><o:p><span style="font-family: inherit; font-size: large;"> </span></o:p></p><p class="MsoNormal" style="margin: 0in;"><span style="font-family: inherit; font-size: large;">The first point I want to make is that HHS is a conglomerate of disparate agencies each with separate responsibilities and several of whom compete for funding. Agencies of HHS include the Centers for Disease Control, FDA, National Institutes of Health, Medicare and Medicaid, Indian Health Service and others. These agencies all are involved in healthcare either directly in terms of patient care or in terms of financing of care, regulation of drugs and public health functions. Back in the 1990s, I was a consultant to the Multi-agency Task Force on Antimicrobial Resistance. The task force published multiple reports, but little was actually accomplished. This was partly because of the competition between agencies and partly, in my humble view, because of the arrogance displayed by some. (Happily, even though we have a long way to go, various federal agencies have made a great deal of progress since the 1990s.)<o:p></o:p></span></p><p class="MsoNormal" style="margin: 0in;"><o:p><span style="font-family: inherit; font-size: large;"> </span></o:p></p><p class="MsoNormal" style="margin: 0in;"><span style="font-family: inherit; font-size: large;">By contrast, the Directors of HHS, throughout its history, have been drawn almost entirely from the worlds of business or politics – not from those involved in the delivery of care. To me, as someone who has been involved directly in patient care or in healthcare-related research, this makes no sense. It also makes no sense that the choice of leadership is not the subject of criticism as far as I can tell. <o:p></o:p></span></p><p class="MsoNormal" style="margin: 0in;"><span style="font-family: inherit; font-size: large;"> <o:p></o:p></span></p><p class="MsoNormal" style="margin: 0in;"><span style="font-family: inherit; font-size: large;">Secondly, we all need to understand that the public health system in the US is anything but . . Most of the key functions of public health including surveillance, needs assessment, delivery of services (and vaccines), execution of policy all devolve to states, counties and even to towns and rural districts. Medicare has made huge difference here by, for example, insisting that hospitals provide certain data within a limited time frame in order to remain certified for medicare reimbursement. Such an approach is difficult to promulgate beyond hospitals. The era of electronic medical records should facilitate such an approach, but the number and variety of different systems that exist today make data-sharing across the US a difficult task to say the least, </span></p><p class="MsoNormal" style="margin: 0in;"><span style="font-family: inherit; font-size: large;"><br /></span></p><p class="MsoNormal" style="margin: 0in;"><span style="font-family: inherit; font-size: large;">A recent viewpoint <a href="https://jamanetwork.com/journals/jama/fullarticle/2787944"><span style="color: red;">article</span></a> in the Journal of the American Medical Association by Emanuel, Osterholm and Grounder emphasizes the problem of obtaining real-time data. The solution they propose is to establish essentially a national, parallel effort that would provide real-time data, would be administered outside local resources, but still able to connect with those resources using modern methods of data gathering (as I understand their paper). I agree that this would be much better than the current weak patchwork of data sources. When I was on the Forum on Emerging Infections of the National Academy of Sciences in the 1990s-2000s, we reached similar <a href="https://www.ncbi.nlm.nih.gov/books/NBK100253/"><span style="color: red;">conclusions</span></a>.<o:p></o:p></span></p><p class="MsoNormal" style="margin: 0in;"><span style="font-family: inherit; font-size: large;"><br /></span></p><p class="MsoNormal" style="margin: 0in;"><span style="font-family: inherit; font-size: large;">I agree with Emanuel et al that such a system would be far superior to our current situation. In fact, in most other developed countries, the solution they propose is a reality on a national level. Why? Because they have national health systems that incorporate public health measures and responses. These national health systems provide real time access to key data for policy-makers. I'd in fact, Centers for Medicare and Medicaid Services provide for this already in a limit way. My conclusion is that we must start there. In order for us to have a national public health system that works, we need a national health system (Medicare for all?) such as many other developed countries already have. </span></p><p class="MsoNormal" style="margin: 0in;"><o:p><span style="font-family: inherit; font-size: large;"> </span></o:p></p><p class="MsoNormal" style="margin: 0in;"><span style="font-size: large;"><span face="Calibri, sans-serif" style="font-family: inherit;">At the same time Emanuel et al propose that we establish thresholds of disease severity (hospitalizations, hospital occupancy rates, deaths) that would trigger mitigation measures. But clearly, such a system is not possible in the US today where the responsibility for public health devolves to local officials. I think it is unlikely that such legislation would pass congress and I think that even if it did, imposing such measures would be next to impossible in many areas of the country. Even under a system of national health insurance with real-time access to rapidly evolving disease, enforcing mitigation measures across the US, as it is today, seems an impossible dream. <o:p></o:p></span></span></p><p class="MsoNormal" style="margin: 0in;"><span style="font-size: large;"><span face="Calibri, sans-serif" style="font-family: inherit;"><br /></span></span></p><p class="MsoNormal" style="margin: 0in;"><span style="font-size: large;"><span face="Calibri, sans-serif" style="font-family: inherit;">Nevertheless, real-time disease surveillance is essential for intelligent policy-making. This is best achieved within the context of a national health insurance system. We need to prioritize that as a goal. </span></span></p><p class="MsoNormal" style="margin: 0in;"><o:p><span style="font-family: inherit; font-size: large;"> </span></o:p></p><p class="MsoNormal" style="margin: 0in;"><o:p><span style="font-family: inherit; font-size: large;"> </span></o:p></p>David Shlaeshttp://www.blogger.com/profile/00228776693058791618noreply@blogger.com0tag:blogger.com,1999:blog-4287560491211025099.post-91298792147670323822021-12-13T08:20:00.000-05:002021-12-13T08:20:44.548-05:00Covid - Thank you to industry - Please do the same for AMR.<p style="text-align: left;"><span style="font-size: large;"> </span></p><blockquote style="border: none; margin: 0px 0px 0px 40px; padding: 0px; text-align: left;"><p><span style="font-size: large;"></span></p><div class="separator" style="clear: both; text-align: center;"><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEg6-vs0PRJx_ka4-cVhKmZc3wBt-xrmPNxO-Fh1idd4tcLGHMy5nZN1l-2Lw_xmF99tQEkYk35fUG5PrISODbQ8dRY261pGXTxUklJAsoYzgSy8_d3KuWqp22ZQMy-5KucQt85J9BT_GUunVqjHRHWoFke9uajTk1UsK_hNHeLDsd-DPiTUqcdFA6A3=s275" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img border="0" data-original-height="183" data-original-width="275" height="183" src="https://blogger.googleusercontent.com/img/a/AVvXsEg6-vs0PRJx_ka4-cVhKmZc3wBt-xrmPNxO-Fh1idd4tcLGHMy5nZN1l-2Lw_xmF99tQEkYk35fUG5PrISODbQ8dRY261pGXTxUklJAsoYzgSy8_d3KuWqp22ZQMy-5KucQt85J9BT_GUunVqjHRHWoFke9uajTk1UsK_hNHeLDsd-DPiTUqcdFA6A3" width="275" /></a><span style="font-size: large;"></span></div></div><p></p></blockquote><p><span style="font-size: large;"></span></p><div class="separator" style="clear: both; text-align: right;"><span style="font-size: large;"></span></div><span style="font-size: large;"><br /><br /></span><p></p><p><span style="font-size: large;"><span face="Calibri, sans-serif"><br /></span></span></p><p><span face="Calibri, sans-serif"><span style="font-size: large;">To all those who are skeptical because they worry that a government sponsored investment in the broken antibiotic marketplace is a give-away to the pharmaceutical industry, I have one word for you – covid! </span></span></p><p><span face="Calibri, sans-serif"><span style="font-size: large;">I would like to begin and end this blog with a big THANK YOU to everyone, in industry and outside industry, who have contributed to providing the tools we need to defeat this covid pandemic!</span></span></p><p><span style="font-size: large;"><span face="Calibri, sans-serif">The</span><span face="Calibri, sans-serif"> </span><a href="https://www.congress.gov/bill/117th-congress/senate-bill/2076/text" style="font-family: Calibri, sans-serif;"><span style="color: red;">Pasteur Act</span></a><span face="Calibri, sans-serif">, currently before the US congress, will provide an advance payment for critical new antibiotics – a so-called subscription. This will de-link (mostly) sales volume from revenue by providing a guaranteed revenue even if sales volume is low. This in turn will guarantee that physicians and patients will have access to life-saving antibiotics even if the numbers of patients needing such a drug are low.<a href="https://blogger.googleusercontent.com/img/a/AVvXsEjc7LWs7vQ2fuBcyObK5nL4jIhX_fD3PI_A-phQhtFf_U5yV9P7-S7yM1TQz-c2ETqm6gQKpL5fC2lu4eg-Gr137KNsApPGX2shoHlkdp4tzerl0sXS5DH3VSQQDv00_5kxXNdpiETGJ5qph4imibaDDbexDyEi3viu50Lb58oUYNBp9gcfdgG9b8gU=s523" style="clear: right; float: right; margin-bottom: 1em; margin-left: 1em;"><img border="0" data-original-height="523" data-original-width="436" height="320" src="https://blogger.googleusercontent.com/img/a/AVvXsEjc7LWs7vQ2fuBcyObK5nL4jIhX_fD3PI_A-phQhtFf_U5yV9P7-S7yM1TQz-c2ETqm6gQKpL5fC2lu4eg-Gr137KNsApPGX2shoHlkdp4tzerl0sXS5DH3VSQQDv00_5kxXNdpiETGJ5qph4imibaDDbexDyEi3viu50Lb58oUYNBp9gcfdgG9b8gU=s320" width="267" /></a></span><span face="Calibri, sans-serif"> </span><span face="Calibri, sans-serif"> </span><span face="Calibri, sans-serif">It will also provide a reserve supply of products that will serve in case of a larger outbreak of infection – John Rex’s fire extinguisher.</span><span face="Calibri, sans-serif"> </span><span face="Calibri, sans-serif"> </span><span face="Calibri, sans-serif">The Pasteur Act is desperately needed if we are to have an assured pipeline of new antibiotics to address the steadily growing threat of bacterial resistance. This threat has even been accelerated during the covid pandemic given the extraordinary use of antibiotics to treat patients with secondary bacterial infections.</span><span face="Calibri, sans-serif"> </span></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;"><o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">I know that those involved in writing this legislation have carefully constructed the bill as a pre-paid subscription. This was partly to assure legislators that it is not a give-away to the pharmaceutical industry. It is just an upfront payment on product the sponsor or company must provide to the US with a number of additional obligations on said company. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">My own discussions with legislators suggest that many still see this as a pharmaceutical company give-away or are clearly worried that their constituents will draw this conclusion. These congresspersons and senators are much more comfortable supporting less costly approaches like funding research and development or like supporting efforts at antimicrobial stewardship to keep our current antibiotic armamentarium viable for a longer period of time. While I agree that research funding and antimicrobial stewardship are important, without a market intervention like the Pasteur Act, the entire antibiotic R&D effort will collapse.<o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">Investors are happy to accept government funding for the research their portfolio companies undertake. Why not? They have to invest less and may still hope for a profitable exit. But without some decrease in market risk, there will be no investors. Why? Because most of the small companies that have brought new antibiotics to the marketplace over the last decade have gone bankrupt. Why? Because the small numbers of patients that need their products today cannot support enough sales to provide a return on the companies’ and sponsors’ investment. If you say “that’s as it should be” you are missing the point that if investors flee the area, we will not have new antibiotics when we truly need them – back to the fire extinguisher. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">To all those who are skeptical because they worry that a government sponsored investment in the broken antibiotic marketplace is a give-away to the pharmaceutical industry, I have one word for you – covid! Look at the miracle wrought by industry to help defeat this deadly pandemic. Before covid, my impression was that the talent, dedication, drive and genius of scientists and others working in the pharmaceutical industry were seriously under-appreciated. We need to recognize that there is often a difference between academic research and the research that is conducted in industry. In industry there is usually a practical goal – a vaccine or a therapeutic – that teams of scientists work towards. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">And for covid, look what industry achieved. In a never-before-heard-of effort, the industry brought safe, effective vaccines to physicians and patients within less than a year of the recognition of the pandemic. What an incredible achievement. And look at the diagnostics (vs the CDC), monoclonal antibody therapies and small molecule therapeutics that have come and are still coming to market in an incredibly short time frame. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">If companies had the same motivation, I’m sure that we could energize antibiotic research and development to the point that our pipeline would once again be robust as it was in the 1980s. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">For covid, the government did provide help by funding research, development and manufacturing in some but not all cases. There was no need for a market intervention here given the pandemic. In the case of antibiotic resistance and our feeble pipeline of new antibiotics, a market intervention is essential. Without it we are lost. Do we want to wait until antibiotic resistance has reached the point where hundreds of thousands of Americans are dying of resistant infection to finally address the market failure that haunts antibiotic R&D? If we wait, since antibiotics are difficult to discover and develop, there may be a longer delay before needed new therapies find their way to patients while resistance continues to extract its toll. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">OK. The pharmaceutical industry is not entirely angelic. There are issues around pricing (especially in the US), direct to consumer advertising, etc. But the pharmaceutical industry has proven that it is capable of miracles – not just for covid but also at the beginning of the antibiotic era (e.g. sulfa drugs, penicillin). We need to provide a robust market to unleash the talent of the industry against antibiotic resistance and we need to do this now. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">I would like to begin and end this blog with a big THANK YOU to everyone, in industry and outside industry, who have contributed to providing the tools we need to defeat this covid pandemic!<o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p>David Shlaeshttp://www.blogger.com/profile/00228776693058791618noreply@blogger.com0tag:blogger.com,1999:blog-4287560491211025099.post-78110895734444153852021-12-02T08:06:00.000-05:002021-12-02T08:06:44.820-05:00Pull Incentives for AMR - Where is Biden?<p><span style="font-size: large;"> This will be a short note . . .</span></p><p></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEj9MhZMXQ6aolI9NGDC2uOLK5WtzfZsDDgrEoE7YTztIZVWWgaz0hjuKmPoGTOrZOgsEHPiqMu47COYoZ0rYC5nguOauszM185Vtb1jFTq_Zg6RFokvOv3-fZuE4kddL6XG776uATDJPeE/s2500/white_house_grounds.jpeg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="1250" data-original-width="2500" height="160" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEj9MhZMXQ6aolI9NGDC2uOLK5WtzfZsDDgrEoE7YTztIZVWWgaz0hjuKmPoGTOrZOgsEHPiqMu47COYoZ0rYC5nguOauszM185Vtb1jFTq_Zg6RFokvOv3-fZuE4kddL6XG776uATDJPeE/s320/white_house_grounds.jpeg" width="320" /></a></div><br /><span style="font-size: large;"><br /></span><p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">We are about to dedicate an entire <a href="https://asm.org/Events/ASM-ESCMID/Home"><span style="color: red;">ASM/ESCMID</span></a> session to planning for the implementation of forthcoming pull incentives. We do this because we all agree that without significant pull incentives to address the broken antibiotics market we will all pay a high price later. But where are these pull incentives and will they arrive in time?<o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">We just celebrated (if you say that) Antibiotics Awareness Week around the world. The White House in the US released a statement that said nothing about pull incentives at all. It referred to antimicrobial stewardship and to the National Action Plan to Combat Antibiotic Resistance (see the Pew <a href="https://www.pewtrusts.org/en/research-and-analysis/articles/2020/12/04/new-national-action-plan-for-combating-antibiotic-resistant-bacteria-lacks-essential-details"><span style="color: red;">summary</span></a> noting its lack of provision for economic incentives). While I know that many working at top levels of the Department of Health and Human Services in the US support the idea of pull incentives, without the additional support of President Biden, I’m not sure whether we will see legislation like the Pasteur Act pass in the foreseeable future. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">After reading the White House release, I turned my attention once again to Europe. I have spoken to several contacts there who are convinced that Europe will devolve any expenditures for antibiotic subscription payments to the various national authorities of the European Union. This may contradict the impression that some (including me) have drawn from public statements coming out of Brussels. And I was just getting ready to submit my <a href="https://ec.europa.eu/info/law/better-regulation/have-your-say/initiatives/12963-Revision-of-the-EU-general-pharmaceuticals-legislation_en"><span style="color: red;">comments</span></a> for the European effort. That Europe will not take on incentives as Europe but rather through the various national authorities would be a wake-up call. A subscription model that depends on 27 national authorities agreeing on criteria and eventual awards for products is doomed from the start. If Europe cannot act as Europe from Brussels, this shuttles the responsibility back to the US (in my view). That means that the US must pass the Pasteur Act. And that means that Biden must get off the sidelines and lead.<o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">I understand that covid with all its variants is taking center seat in the administration’s concerns right now – and that is as it should be. But ignoring the steadily building problem of antimicrobial resistance is just setting the table for another crisis that could be if not avoided then at least diminished in its scope and consequences. Clearly, the presidency of the US is a tough job and comes with many moving parts. That’s why we elect those we think are most competent to take on that job. Biden must step up to antimicrobial resistance. I’m afraid that without his direct support we are headed to disaster. </span><o:p></o:p></p>David Shlaeshttp://www.blogger.com/profile/00228776693058791618noreply@blogger.com0tag:blogger.com,1999:blog-4287560491211025099.post-42129288597657049602021-11-22T08:02:00.001-05:002021-11-22T08:02:49.509-05:00Pull Incentives at ASM/ESCMID<p></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhB78TGRtkbVG1sxAbTVPE-Wox4q3Sx_0HAl69hvJb55nNKv9X5FTXkNwkWR6OBFHgEabOUWB2raboC5GpkaKNDDQ7xq8I-vBLnouARu4V6ZUMJ09Ut6lUXS6Gx0pbcccBrNrQ5GdyQpag/s485/asm%253Aescmid+2021.jpeg" style="margin-left: 1em; margin-right: 1em;"><span style="font-size: large;"><img border="0" data-original-height="104" data-original-width="485" height="69" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhB78TGRtkbVG1sxAbTVPE-Wox4q3Sx_0HAl69hvJb55nNKv9X5FTXkNwkWR6OBFHgEabOUWB2raboC5GpkaKNDDQ7xq8I-vBLnouARu4V6ZUMJ09Ut6lUXS6Gx0pbcccBrNrQ5GdyQpag/s320/asm%253Aescmid+2021.jpeg" width="320" /></span></a></div><span style="font-size: large;"><br /> </span><p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">On a personal note, as I grow older, I find I am likely to be more dependent on physicians and caregivers. I am grateful to have a truly talented, kind and smart team of physicians, nurses, family and friends to provide care and support if needed. As I contemplate this universal issue of aging, given my training and history, I can’t help but reflect on the state of antimicrobial resistance and the antibiotic pipeline designed to meet this challenge. I hope, that should the need arise, my care team will have access to antibiotics that are both safe and effective against whatever resistant pathogen I might encounter. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">Those of us following this field for any length of time understand the critical importance of pull incentives designed to correct the disastrous state of the antibiotic market such that companies and investors risking it all do not have to face bankruptcy after having finally obtained market approval for their precious new antibiotic. The US is apparently seriously considering a generous pull incentive in the form of the <a href="https://www.statnews.com/2021/06/25/pasteur-act-help-fight-superbugs-antimicrobial-resistance/"><span style="color: red;">Pasteur Act</span></a> and the <a href="https://degette.house.gov/sites/degette.house.gov/files/Cures%202.0_DD%20SxS_FINAL1.pdf"><span style="color: red;">21<sup>st</sup>Century Cures Act 2.0</span></a>. Europe has <a href="https://ec.europa.eu/commission/presscorner/detail/en/IP_21_4882"><span style="color: red;">requested</span></a> public comments on a proposal to provide pull incentives of some sort as well. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;"><br /></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">This year, the <a href="https://asm.org/Events/ASM-ESCMID/Program"><span style="color: red;">ASM/ESCMID</span></a> meeting (held virtually) will spend an entire morning devoted to thinking around how such pull incentives can be implemented. The base assumption here is that without such pull incentives we are all, ultimately, doomed. In an optimistic mode, ASM/ESCMID is posing questions around implementation of these incentives. I have been asked to moderate one of these sessions. </span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;"><br /></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">The experts presenting the morning of December 8 include, <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">Christine Ardal (Institute of Public Health, Norway),<o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">Louise Norton-Smith, M.A., (Head of Global AMR Strategy, U.K. Department of Health and Social Care), <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">Kevin Outterson, J.D., (Boston University, School of Law, Boston, Mass), <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">Beth Woods, MSc., (Centre for Health Economics, University of York, U.K.),<o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">Colm Leonard, M.D., (National Institute for Health and Care Excellence UK), <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">Nick Crabb Ph.D., (National Institute for Health and Care Excellence UK),<o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">Emily Wheeler,<b> </b>(Biotechnology Innovation Organization),<b> </b><o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;"><span>Helen Boucher, M.D., FACP, FIDSA,</span><b> (</b><span>Interim Dean Tufts School of Medicine, IDSA Officer).</span></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">Clearly the speakers and panel could hardly be of greater quality. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">I am laser-focused on the questions of “who and how?” We may not get to all the questions I pose here – but I think all are worthy of further consideration. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">Since any pull incentive, to be effective, must be <a href="https://www.healthaffairs.org/doi/10.1377/hlthaff.2021.00688"><span style="color: red;">large</span></a> ($2-4 billion), who should bear the financial burden of such pull incentives? <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">Companies will need to understand how products will be chosen to receive these incentives. What will the criteria be? In this regard, how do considerations of clinical utility and innovation come into these criteria? Do we even have agreed definitions for these two concepts?<o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">If countries/regions pay their "fair share" will all providers of pull incentives have to agree not only on the criteria, but on the ultimate choice of products to receive such an award? The discrepancy between the approaches of the UK and Sweden (where different products were ultimately chosen for subscriptions by the two countries) are instructive in this regard. </span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">Are there regulatory implications for pull incentives? Should regulatory authorities be involved or at least be required to consider that compounds have been chosen for such incentives? Does this also have implications for access? <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">I am sure that we will have a lively discussion. And - there are other very important discussions with key experts to follow this first session. I highly recommend attending the ASM/ESCMID meeting. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;"> </span><o:p></o:p></p>David Shlaeshttp://www.blogger.com/profile/00228776693058791618noreply@blogger.com0tag:blogger.com,1999:blog-4287560491211025099.post-60855348650610026662021-10-11T12:35:00.000-04:002021-10-11T12:35:31.486-04:00Europe, Antibacterials, Pull Incentives and Access<p><span style="font-size: large;"> <span style="font-family: Calibri, sans-serif;"> </span></span></p><div class="separator" style="clear: both; text-align: center;"><span style="font-size: large;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh1KqlH2BpjfQGoHDiM5qOPKFCDpntHyk01XwvbqbpjCigpEMJVjf-8jyKrI3uSHnDrXUg8QddL7Llv8SsPfloSC6Y3cV1FxOPcTvl1Ge4g-DqIT-7C3zCZvbySAjUu7MgWtaFZ5EeyhGo/s276/EU+flag.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="183" data-original-width="276" height="183" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh1KqlH2BpjfQGoHDiM5qOPKFCDpntHyk01XwvbqbpjCigpEMJVjf-8jyKrI3uSHnDrXUg8QddL7Llv8SsPfloSC6Y3cV1FxOPcTvl1Ge4g-DqIT-7C3zCZvbySAjUu7MgWtaFZ5EeyhGo/s0/EU+flag.jpg" width="276" /></a></span></div><span style="font-size: large;"><br /><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhhZaAXLiu1wnLnkeI0XoNVrxWFtrmOefy88ryOZm3afc-fnOHPfAZppERruBSiwM7lQykIgt7A6q26A9lhMiQVYhxpwDiO5AZp8fIEsiWmzDgSAblQ2n7aBz6bduw8EywQx2uOlnkX6mo/s428/EMA_European_Medicines_Agency_logo.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="147" data-original-width="428" height="110" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhhZaAXLiu1wnLnkeI0XoNVrxWFtrmOefy88ryOZm3afc-fnOHPfAZppERruBSiwM7lQykIgt7A6q26A9lhMiQVYhxpwDiO5AZp8fIEsiWmzDgSAblQ2n7aBz6bduw8EywQx2uOlnkX6mo/s320/EMA_European_Medicines_Agency_logo.jpg" width="320" /></a></div><br /></span><p></p><p class="MsoNormal"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal"><span style="font-size: large;"><span style="font-family: Calibri, sans-serif;">Without a significant pull incentive, our pipeline of new antibacterials is doomed. This must be our top priority. If a significant pull incentive for new antibacterial research and development is to occur, there must be a mechanism for choosing which products and sponsors will be its beneficiaries. Product novelty, “value” and potential clinical utility (and others) have been proposed as criteria for making this decision. But clear definitions for these criteria are either lacking, vague or conflicting among various authors, organizations and proposals. One example of the result of this lack of clear criteria is the disparity in choices of products to be included in the UK and Swedish antibiotic subscription programs. <span style="background-color: #fff2cc;">[Sweden - <span style="color: #333333;">Zerbaxa (ceftolozan-tazobactam), Recarbrio (imipenem-cilastatin-relebactam), Fetcroja (cefiderocol), Vaborem (meropenem-vaborbactam) and Fosfomycin infectopharm (fosfomycin).</span></span></span><span style="background-color: #fff2cc;"> UK - <span style="color: #040819;">cefiderocol (Fetcroja) manufactured by Shionogi, and ceftazidime with avibactam (Zavicefta)]<span class="apple-converted-space">. This is also a good argument for a European approach (Brexit notwithstanding). </span></span></span><o:p></o:p></span></p><p class="MsoNormal"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;">It is possible that very targeted therapies for infections caused by specific pathogens or pathogens expressing specific resistance mechanisms will be considered for pull incentive awards. But we have still not yet resolved how such therapies will be approved by regulatory authorities nor how we will furnish sufficient relevant data in support of such products to convince physicians and their patients of the value of such products. While similar considerations might apply to novel adjunctive therapies, a consideration of those products goes beyond the scope of this article. <o:p></o:p></span></span></p><p class="MsoNormal"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;">I would like to offer thoughts bearing on the definition of innovation and clinical utility for the purposes of awarding a pull incentive. I will limit myself to small molecules that act directly against bacteria designed to be used in the acute hospital setting. I would emphasize that considerations for antibacterials designed for use in the community setting might be quite different. <o:p></o:p></span></span></p><p class="MsoNormal"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal"><b><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;">Innovation vs. Clinical Utility<o:p></o:p></span></span></b></p><p class="MsoNormal"><b><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></b></p><p class="MsoNormal"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;">Many have proposed that innovation be a key criterion for awarding a significant pull incentive to a sponsor. How could that be defined?<o:p></o:p></span></span></p><p class="MsoNormal"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;">Does it mean that the drug acts via a novel mechanism? If so, the assumption is that a new mechanism provides an advantage not seen with drugs exploiting known mechanisms of action. The usual justification for this choice is the avoidance of known resistance mechanisms. The flaw in this argument is that many compounds exploiting traditional mechanisms of antibacterial activity achieve that goal and they do so with less inherent risk of failure. <o:p></o:p></span></span></p><p class="MsoNormal"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;">Does innovation mean that the chemistry is novel? But innovation in this regard must be placed in context since to acquire a basic patent on composition of matter, the chemistry must have at least some novelty. <o:p></o:p></span></span></p><p class="MsoNormal"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;">These questions can be explored using current examples of pipeline and recently marketed antibacterials. There are a number of examples of B-lactamase inhibitors utilizing either DABCO (<span style="color: #202122;">diazabicyclooctane)</span> or boron chemistry (see <a href="https://www.entasistx.com/"><span style="color: red;">Entasis</span></a>, <a href="https://www.venatorx.com/"><span style="color: red;">VenatoRx</span></a> and <a href="https://www.qpexbio.com/"><span style="color: red;">Qpex</span></a>). These approaches would not be considered by many as novel at this point. But what about boron beta-lactamase inhibitors that inhibit both serine- and metallo-enzymes by assuming different binding modes for each class? To me – this is novel. The chemistry might not be novel. The basic mechanism of inhibition might not be novel. But the overall result is clearly novel – and not only that – but will be enormously useful for physicians and their patients. <o:p></o:p></span></span></p><p class="MsoNormal"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;">DABCO chemistry is not only useful for finding inhibitors of beta-lactamase but can also be used to find inhibitors of penicillin binding proteins (PBPs). This approach goes back to the 1990s (Roussel, Novexel, <a href="https://www.entasistx.com/"><span style="color: red;">Entasis</span></a>). Does that render it non-innovative? I would say that if such a PBP inhibitor offered clear advantages over our armamentarium of beta-lactam PBP inhibitors, it would be clinically useful. Examples of such advantages might include avoidance of allergic cross-reaction (up to 10% of patients will give a history of beta-lactam allergy), avoidance of efflux-based resistance or avoidance of hydrolysis by key beta-lactamases.<o:p></o:p></span></span></p><p class="MsoNormal"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;">Let’s put ourselves on the place of a physician in an intensive care unit. Our intubated, ventilated patient had just developed fever, confusion and lowered blood pressure. We know that Pseudomonas is a potential pathogen here and we know that in our hospital about 15%, of our isolates are resistant to carbapenems and multiple other drugs. We also know that some of these isolates harbor a metallo-beta-lactamase. Are we going to care whether our antibiotic choice is "novel" or not as long as it is fit for purpose?<o:p></o:p></span></span></p><p class="MsoNormal"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;">I would argue that our major criterion in selecting compounds deserving of a pull incentive reward should be clinical utility. This clearly takes activity against resistant infections into account. It also can include lower toxicity, avoidance of serious allergic reactions, ease of use (e.g. both oral and IV formulations available), and the potential to avoid the rapid selection of resistance. Compounds that are difficult to fit into current clinical paradigms for use should not receive our highest priority without a clear consideration as to their clinical use, utility and acceptance by physicians and patients. <o:p></o:p></span></span></p><p class="MsoNormal"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal"><span style="font-size: large;"><b><span style="font-family: Calibri, sans-serif;">Access and EMA</span></b><span style="font-family: Calibri, sans-serif;"><o:p></o:p></span></span></p><p class="MsoNormal"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;">In thinking about Europe, I must turn to the new European Medicines Agency. In brief, the US FDA <a href="https://antibiotics-theperfectstorm.blogspot.com/2012/05/fda-reboot.html" target="_blank"><span style="color: red;">learned</span></a> after six (some would say 12) long years of stifled antibacterial development, that requiring clinical trial designs that were practically and financially infeasible would kill our antibiotic pipeline. Apparently, Europe has yet to learn this lesson. I am referring to the EMA’s <a href="https://antibiotics-theperfectstorm.blogspot.com/2021/02/pull-incentives-and-amr-is-europe-up-to.html"><span style="color: red;">requirement</span></a> that plazomicin and omadacycline undertake trial commitments that would have been financially infeasible given current market conditions. These drugs were both pulled from consideration and are not marketed in Europe. While one might argue over the value of these particular drugs in the treatment of patients, it is clear that EMA’s action was yet another nail in the coffin of investment in antibacterial research and resulted in a loss of access to these drugs for countries that might have wanted to have them available. <o:p></o:p></span></span></p><p class="MsoNormal"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><style class="WebKit-mso-list-quirks-style">
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</style>David Shlaeshttp://www.blogger.com/profile/00228776693058791618noreply@blogger.com0tag:blogger.com,1999:blog-4287560491211025099.post-23966224251530455072021-10-05T17:07:00.000-04:002021-10-05T17:07:05.896-04:00Empiric broad spectrum antimicrobial therapy is here to stay. <p><span style="font-size: large;"> <span style="font-family: Calibri, sans-serif;">Recent discussions on the economics of innovation in rapid diagnostic testing for bacterial infections in the hospital setting have inspired me to once again take pen (keyboard) in hand. In most of these discussions, the key variable in the utility of any diagnostic test has been ignored. I’m talking about basic aspects of physician thinking and behavior,</span><span style="font-family: Calibri, sans-serif;"> </span></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;"><o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">The basic premise is that if accurate, <i>bedside</i> tests were available either in the hospital or in the physician’s office, we could avoid broad spectrum empiric antibacterial therapy and focus on the specific pathogen causing the infection. There are, though, a number of flaws that undermine this premise. The first is that antibacterials that are more specific for either pathogens or resistance mechanisms exist and can replace so-called broad-spectrum agents. In general, this is simply not true. Even amoxicillin, to which there is a high level of resistance among Gram-negatives, has a relatively broad spectrum. The other assumption is that reducing the use of “broad-spectrum” antibacterials and increasing the use of pathogen-specific antibacterials will lead to a slower rate of rise of resistance. While this may be a reasonable hypothesis, the quantitative effect remains to be determined and there will be other variables at play (eg – how long did it take for vancomycin resistance to emerge in the clinic?). <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">The other part of the discussion is economic. It seems that the technology to provide rapid tests capable of identifying pathogens in primary specimens such as blood, sputum and urine exist today. But the investment to bring them to market is much greater than the projected market since it is likely to be cheaper to use “broad-spectrum” empiric therapy than it would be to use the diagnostic tests to narrow therapy assuming such pathogen-specific therapy existed. The implication is that broad-spectrum empiric therapy is “bad.” We need to understand that a major reason for this lack of a market is based on well-justified physician hesitancy.<o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">An additional issue relates to hospital and physician practice logistics. As I have noted in the past, if the diagnostic is not easily used (like a covid antigen test or a strep test for e.g.) and is designed to be carried out in a laboratory, there is the delay between obtaining the specimen, transportation to the lab, carrying out the test and reporting the result. In most cases, this delay would eliminate the potential advantage of the rapidity of the test. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">But let’s talk about physician behavior. Speaking as a physician who has spent time in the ICU caring for critically ill patients, I think I am qualified to address this issue. I admit that this experience is now quite dated. But in recent years I spent time working in a local hospital on antimicrobial stewardship and based on that experience, I don’t think things have changed that much since my own ICU attending days. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">Physicians see patients as individuals and the take their responsibility for each one extremely seriously. When a patient becomes acutely and severely ill in the hospital and where infection is a likely cause, I am not sure that even a reliable bedside test would be enough to prevent a physician from using additional or broad-spectrum antimicrobial therapy to be sure that all pathogens, likely and not so likely, will be attacked. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">Our best approach, in my view, will be to discontinue antibiotic therapy as soon as we can based on good clinical evidence. Unfortunately, that evidence is still lacking for many infections. It goes without saying that in the absence of further evidence of bacterial infection in the cold light of day, antibiotics should be discontinued in any case. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">This approach is validated by multiple clinical guidelines discussing appropriate empiric antibiotic therapy for various infections. I don’t see physicians changing their approach to empiric antimicrobial therapy of severely ill hospitalized patients regardless of the accuracy or rapidity of new diagnostic tests – and I’m not sure they should change.<o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p>David Shlaeshttp://www.blogger.com/profile/00228776693058791618noreply@blogger.com0tag:blogger.com,1999:blog-4287560491211025099.post-1542386092376888892021-04-26T08:20:00.003-04:002021-04-26T08:20:37.542-04:00Antibiotic Strategies for Success - A Bridge to Nowhere?<p><span style="font-size: large;"> <span style="font-family: Calibri, sans-serif;">This blog was inspired by a recent conversation with a CEO of a clinical phase antibiotic biotech. Among other things, we pursued a discussion of various strategies that companies developing antibiotics might pursue to avoid post-approval bankruptcy (the “no good deed shall go unpunished” avoidance strategy).</span><span style="font-family: Calibri, sans-serif;"> </span></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;"><o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">Have a portfolio of antibiotics covering various groups of pathogens – all where there is medical need. This could include an orally available drug active against resistant Gram positives, an oral plus IV drug active against resistant urinary pathogens, an IV only drug active against hospital acquired pneumonia, etc. The problem with this strategy is the existing, (relatively) inexpensive and diverse antibiotic armamentarium combined with the relatively small number of patients with high medical need. Caveat - a large PhRMA that needs additional products for a limited hospital sales force might be interested in such a portfolio - post-launch (e.g. Pfizer and the AZ antibiotics).<o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">Market your antibiotics as drugs for rare diseases and garner a very high price per course of therapy. This strategy will smack into the wall of hospital budgets, the history of antibiotic commercialization globally and the general under-valuation of antibiotics. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">What if you offered the possibility of empiric in-hospital IV therapy that included not only all other resistant Gram-negative pathogens (like metallo-B-lactamase producers and Pseudomonas) but also highly resistant Acinetobacter? Would that be enough to provide a return on your investment? I’m not sure given the low numbers of highly resistant Acinetobacter infections encountered by physicians. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;"> How about if you balance your antibiotic portfolio with drugs targeting other diseases? But then what priority would your antibiotic projects garner? Why would you need an antibiotic portfolio at all? <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">Sorry. These strategies all seem to me like bridges to nowhere. . .<o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><br /></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"><br /></span></o:p></p><div class="separator" style="clear: both; text-align: center;"><span style="font-size: large;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiMsRdaLwz093W483m4Q7mqjhO1D0Lce-IBC8J-z0XuZBIPQB3ePVz7aKnLAJIm3TPBZ8LPhTUx2b6udfKySANuIi-xTHMa-A_olrI0zAh4J5IVBB_S2Hk-BVxRFCjaRSPXk0QZUsdTHoo/s1080/bridge+to+nowhere.jpg" imageanchor="1" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img border="0" data-original-height="719" data-original-width="1080" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiMsRdaLwz093W483m4Q7mqjhO1D0Lce-IBC8J-z0XuZBIPQB3ePVz7aKnLAJIm3TPBZ8LPhTUx2b6udfKySANuIi-xTHMa-A_olrI0zAh4J5IVBB_S2Hk-BVxRFCjaRSPXk0QZUsdTHoo/s320/bridge+to+nowhere.jpg" width="320" /></a></span></div><span style="font-size: large;"><br /> </span><p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"><br /></span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">To all you antibiotic biotech CEOs out there, I only see a single strategy that will work. We must provide a market incentive for the approval and commercialization of needed new antibiotics that is of such size that large PhRMA will once again pursue these drugs and the small companies that develop them. I just don’t see any other choice that will incentivize private investment and provide a welcoming environment for antibiotic R&D once again. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;"></span></p><div class="separator" style="clear: both; text-align: center;"><span style="font-size: large;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjkgcBrZQgYcM4ziPcYZKp-Oytei7X-p00D5MZEjjnYZx8vGV58aGCathMHduaRXPnOwdEeqrNd9sZoIjKKtWGVguMwo2UaEV1d9suhRg_HngOiRkDC8nY3zuWHPPToOFxc-_VgznxrbxY/s2048/bridge+to+nowhere+2.webp" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="1536" data-original-width="2048" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjkgcBrZQgYcM4ziPcYZKp-Oytei7X-p00D5MZEjjnYZx8vGV58aGCathMHduaRXPnOwdEeqrNd9sZoIjKKtWGVguMwo2UaEV1d9suhRg_HngOiRkDC8nY3zuWHPPToOFxc-_VgznxrbxY/s320/bridge+to+nowhere+2.webp" width="320" /></a></span></div><span style="font-size: large;">Not only that, but I only see a single choice in terms of a country or region that could provide such an incentive – the good old US of A! Europe has the resources as a region with a population of 500 million and a GDP of $19 trillion (in 2019). But it has demonstrated that it does not have the competence to provide a unified strategy across all 27 national authorities. Not only that, but the judgement of the European Medicines Agency has also been brought into question with the decision of two antibiotic biotechs not to market their products in Europe because EMA’s regulatory requirements exceeded the market value of the projects under discussion. <o:p></o:p></span><p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">This leaves us with the US with its GDP or $21 trillion. Total spending on healthcare in the US is estimated to be $3.8 trillion (2019 numbers). US government spending on healthcare approaches $2 trillion. So, an incentive approaching $4 billion for up to 2 new and needed antibiotics per year would be a rounding error in our national budget. But, whether we like it or not, something like this is the only way forward to assure that we have an adequate antibiotic pipeline for today and for tomorrow. Without this, antibiotic biotechs are doomed to financial failure sometime in the several years following product launch. As more antibiotic biotechs fail in this manner, the limited investment that still exists for antibiotic R&D will completely disappear. <o:p></o:p></span></p><div class="separator" style="clear: both; text-align: center;"><span style="font-size: large;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg4yS6h6fukWMvg8I3woRXGmeWMVt9q9Z-UunrBjY9EgrzjQ1rfMiX5GoQoznxUWNebWE_hN79sVz-91NM4kZec62ct8kWdgEnFin2IOYz_2eQxj9J0DRtDNQ5-7QvahtWdLi9Hp4ds4aM/s423/amr+action+fund.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="119" data-original-width="423" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg4yS6h6fukWMvg8I3woRXGmeWMVt9q9Z-UunrBjY9EgrzjQ1rfMiX5GoQoznxUWNebWE_hN79sVz-91NM4kZec62ct8kWdgEnFin2IOYz_2eQxj9J0DRtDNQ5-7QvahtWdLi9Hp4ds4aM/s320/amr+action+fund.png" width="320" /></a></span></div><p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">The AMR Action Fund, now over $1 billion, is dedicated to driving deserving antibiotic projects through late stage, expensive, clinical development to regulatory approval. When the fund was announced, the sponsors <a href="https://amractionfund.com/amr-innovation-challenge/#page-section-2"><span style="color: red;">warned</span></a> that their effort was merely a holding strategy and that market incentives would be required to support a sustainable antibiotic pipeline. I can only laud their effort and echo their warning. I don’t see any other viable strategy . . . .<o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p>David Shlaeshttp://www.blogger.com/profile/00228776693058791618noreply@blogger.com2tag:blogger.com,1999:blog-4287560491211025099.post-28856802115144147852021-04-05T10:00:00.003-04:002021-04-05T10:00:55.298-04:00Pull American - Why Not?<p><span style="font-size: large;"> <span style="font-family: Calibri, sans-serif;">In a sleepy moment I had an inspiration. Funding a pull incentive for antibiotic R&D in the US (like a market entry reward for example) would be more attractive to our representatives in congress if we required that all manufacturing and supply chains for the beneficiary product be physically located in the US. Great idea, right?</span><span style="font-family: Calibri, sans-serif;"> </span><span style="font-family: Calibri, sans-serif;"> </span><span style="font-family: Calibri, sans-serif;">Not exactly.</span></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;"><o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">I raised this with two biotech CEOs. Both, politely, told me I was out of my mind. The US currently does not have a sufficient small molecule manufacturing infrastructure to either provide for the entire manufacturing chain from API to finished product nor do we have sufficient availability of raw materials here. This is an especially acute problem for the manufacture of B-lactams (like penicillins and cephalosporins) which must be physically separate from all other drug manufacturing facilities because of concerns over allergic reactions.<o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">This then leads to another thought. The US needs to invest in pharmaceutical manufacturing infrastructure. Now there’s a novel idea . . .. (??). The investment must include everything from provision of raw materials to manufacture of finished drug product, packaging and labeling. When I first started working in the industry in the 1990s, we were actually able to do this for some drugs, but rarely for B-lactams. My understanding is that today, as a result of competition from places like India, China and even the UK and Europe, US small molecule pharmaceutical manufacturing is nothing like it was 25 years ago. Of course, the problem is not just an antibiotics issue – this problem extends to all drug classes. And the US is not the only country that wants its drug supply chain to be domestic – India and China often insist on it. The global experience with the manufacture and distribution of vaccines for covid have emphasized the urgency of this problem. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;"><br /></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><br /><span style="font-size: large;"><br /></span></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEizDVsKg67nfTth7ibrqi1eLW7GefM1W7beF9Sk7yGj6UOTmGsWjmjCrRY_RF-yfBtMDN0QrjXjVtln7lHuJEybWEupq-bSIIem_OLI-akFkoOwWhcsYGt0Ifu-r-1_28elT5bWIrHmcU4/s1600/API+and+drug+product+manufacture.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="995" data-original-width="1600" height="257" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEizDVsKg67nfTth7ibrqi1eLW7GefM1W7beF9Sk7yGj6UOTmGsWjmjCrRY_RF-yfBtMDN0QrjXjVtln7lHuJEybWEupq-bSIIem_OLI-akFkoOwWhcsYGt0Ifu-r-1_28elT5bWIrHmcU4/w415-h257/API+and+drug+product+manufacture.png" width="415" /></a></div><p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;"> This topic has been the subject of a number of articles (<a href="https://cen.acs.org/business/outsourcing/Bringing-drug-production-back-US/98/i25"><span style="color: red;">1</span></a>,<a href="https://www.fiercepharma.com/manufacturing/pharma-pushes-back-u-s-legislation-to-bring-drug-manufacturing-stateside"><span style="color: red;">2</span></a>,<a href="https://www.npr.org/sections/health-shots/2020/04/24/843379899/pandemic-underscores-u-s-dependence-on-overseas-factories-for-medicines"><span style="color: red;">3</span></a>) and of a <a href="https://www.fda.gov/news-events/congressional-testimony/securing-us-drug-supply-chain-oversight-fdas-foreign-inspection-program-12102019"><span style="color: red;">report</span></a> from the FDA. Last year, the FDA released data on drug manufacturing. Only 28% of API (raw drug powder) for the US market is manufactured in the US while the EU, China and India account for most of the rest. I have not seen data on the global distribution of the supply of raw materials for API production – but I suspect that again there are few US suppliers. Forty-six percent of the final drug product (the pills or vials that are actually used) for the US market is made in the US. I have not seen similar data specific for antibiotic manufacture, but I suspect the situation is no better and may be worse. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: large;">Of course, adding US manufacturing capacity to bolster our domestic drug supply chain is a good idea. All that is required is money. In the case of antibiotic manufacture, the need may be even more critical. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p>David Shlaeshttp://www.blogger.com/profile/00228776693058791618noreply@blogger.com1tag:blogger.com,1999:blog-4287560491211025099.post-38409821315661477522021-03-12T09:40:00.001-05:002021-03-16T10:54:33.614-04:00The Pew Trust Analysis of the Antibacterial Pipeline<p><span style="font-size: large;"> </span></p><div class="separator" style="clear: both; text-align: center;"><span style="font-size: large;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhUwIyqZ6ioSpEnHRIdU0CP_i20dHOEy5-Sq_JWPVQ0fivGorv4vpw4Kuu1UN_n-Bmjt7yvMOK8TYGqcqJHNfxdPh4OjDka6-jNZSl-71Q1c4MAK3C00w8hRsIyOWBPgdZQPDJLP5HEb2k/s303/Pew+logo.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="166" data-original-width="303" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhUwIyqZ6ioSpEnHRIdU0CP_i20dHOEy5-Sq_JWPVQ0fivGorv4vpw4Kuu1UN_n-Bmjt7yvMOK8TYGqcqJHNfxdPh4OjDka6-jNZSl-71Q1c4MAK3C00w8hRsIyOWBPgdZQPDJLP5HEb2k/s0/Pew+logo.jpg" /></a></span></div><span style="font-size: large;"><br /></span><p></p><p><span style="font-size: large;"><span style="font-family: Cambria, serif;"><br /></span></span></p><p><span style="font-size: large;"><span style="font-family: Cambria, serif;">The Pew Charitable Trust just posted their analysis of the antibacterial pipeline.</span><span style="font-family: Cambria, serif;"> </span><span style="font-family: Cambria, serif;"> </span><span style="font-family: Cambria, serif;">They provide two separate analyses, one for</span><span style="font-family: Cambria, serif;"> </span><a href="https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development?utm_campaign=LM+-+ARP+-+Innovation+Update+March+2021+-+3+11+21&utm_medium=email&utm_source=Pew" style="font-family: Cambria, serif;"><span style="color: red;">antibiotics</span></a><span style="font-family: Cambria, serif;"> </span><span style="font-family: Cambria, serif;">and the other for</span><span style="font-family: Cambria, serif;"> </span><a href="https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2017/nontraditional-products-for-bacterial-infections-in-clinical-development?utm_campaign=LM+-+ARP+-+Innovation+Update+March+2021+-+3+11+21&utm_medium=email&utm_source=Pew" style="font-family: Cambria, serif;"><span style="color: red;">non-traditional</span></a><span style="font-family: Cambria, serif;"> </span><span style="font-family: Cambria, serif;">therapies.</span><span style="font-family: Cambria, serif;"> </span></span></p><p class="MsoNormal" style="font-family: Cambria, serif; margin: 0in;"><span style="font-size: large;"><o:p></o:p></span></p><p class="MsoNormal" style="font-family: Cambria, serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Cambria, serif; margin: 0in;"><span style="font-size: large;">I will ignore entirely whether the pipeline products were considered to be innovative or not since I am focused solely on their potential clinical utility. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Cambria, serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Cambria, serif; margin: 0in;"><span style="font-size: large;">Of 43 antibiotics in development, 17 are phase 2 and beyond. Of those, only five target resistant Gram-negative pathogens. One compound in phase 3 is solithromycin, an old and controversial ketolide antibiotic being investigated for treatment of gonorrhea. Another more innovative compound in phase 3 for the treatment of gonorrhea is zoliflodacin. (I was on the advisory board for GARDP, a co-developer of the compound). Of the six antibiotics in phase 2 development, five target C. difficile. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Cambria, serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Cambria, serif; margin: 0in;"><span style="font-size: large;">For those antibiotics that target resistant Gram-negative pathogens, what will their ultimate market look like? Some have already suggested there is really only room for one such compound given the number of patients available for treatment. I can’t help but wonder what the investors in these companies and independent market analysts think about their chances of commercial success. Or is everyone betting on a significant pull incentive for their product? <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Cambria, serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Cambria, serif; margin: 0in;"><span style="font-size: large;">The same comment might apply for all those phase 2 compounds targeting C. difficile. Here the market probably revolves around efficacy in preventing recurrence following initial therapy. But how many products can this market support and at what price? Again, I am curious to understand the thinking of these companies, their investors, and market analysts.<o:p></o:p></span></p><p class="MsoNormal" style="font-family: Cambria, serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="margin: 0in;"><span style="font-size: large;"><span style="font-family: Cambria, serif;">The non-traditional therapies include 19 products in phase 2 or beyond. One is an interesting immunomodulator from AtoxBio for the treatment of sepsis and organ failure in patients suffering from necrotizing fasciitis. The company has filed an NDA based on somewhat mixed </span><a href="https://www.atoxbio.com/wp-content/uploads/2020/09/UPDATED-Atox-Bio-Phase-3-Publication-Press-Release-FINAL-10-July-2020-Updated-Link.pdf" style="font-family: Cambria, serif;"><span style="color: red;">data</span></a><span style="font-family: Cambria, serif;">. To me, this is potentially the most interesting, novel and more importantly, useful of the late-stage non-traditional pipeline products. (I used to consult for them). Two compounds are lysins targeting S. aureus infections. Two are orally non-absorbable antibiotic inactivators to prevent C. diff or other resistant infections. A number of antibodies targeting bacterial virulence or toxins are on the list. Five compounds modulate the microbiome – but to what end? Of the 19 non-traditional products in late-stage development five target resistant Gram-negative infections. <o:p></o:p></span></span></p><p class="MsoNormal" style="font-family: Cambria, serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Cambria, serif; margin: 0in;"><span style="font-size: large;">For the non-traditional therapies, we come down to two related issues.(See my previous blog on this <a href="https://antibiotics-theperfectstorm.blogspot.com/2019/03/non-traditional-antibacterials.html"><span style="color: red;">here</span></a>). One revolves around clinical considerations in terms of how these products will be used by physicians to treat infected patients and whether the products offer clear clinical advantages. This also becomes a regulatory question. Can these products be used as stand-alone therapy? If not, will sponsors need to provide superiority data? Then there is the issue of whether the non-traditional therapy offers clear advantages over other products with similar targets already marketed at a low price. This seems especially important in the case of products targeting C. diff and those targeting Gram-negative infections as noted above. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Cambria, serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Cambria, serif; margin: 0in;"><span style="font-size: large;">While I have my own thoughts and biases regarding particular products in the antibacterial pipeline, I want to simply consider here whether this pipeline, given normal attrition rates, is adequate to our needs. If our unmet needs include, most importantly, resistant Pseudomonas and Acinetobacter infections, the answer is a resounding NO! There are only two late-stage antibiotics in the pipeline addressing these infections! Among late-stage non-traditional products, there are virulence inhibitors targeting Pseudomonas and bacteriophage capable of targeting these pathogens. But the use of such virulence inhibitors in clinical practice, for me, remains somewhat opaque. Bacteriophage therapy seems promising, but so far seems limited to an almost case-by-case custom therapy approach similar to some cancer therapies. So, again, this pipeline, to address Paseudomonas and Acinetobacter, is NOT adequate. But then, neither is the market available to support such products without a significant pull incentive. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Cambria, serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Cambria, serif; margin: 0in;"><span style="font-size: large;">Am I starting to sound like a broken record? (You remember vinyl, right?) <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Cambria, serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Cambria, serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoNormal" style="font-family: Cambria, serif; margin: 0in;"><o:p><span style="font-size: large;"> </span></o:p></p>David Shlaeshttp://www.blogger.com/profile/00228776693058791618noreply@blogger.com0tag:blogger.com,1999:blog-4287560491211025099.post-33327680360779436622021-02-15T08:57:00.000-05:002021-02-15T08:57:13.642-05:00Pull Incentives and AMR - Is Europe up to the Task?<p></p><span style="font-family: helvetica; font-size: large;"><br /></span><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjTaCB0nYJpN2-VmaYNUsLgMH_pEbXGzB2QgZgf_RE42fLOFcFfu9ElwhdraO_0lGTQp-JwWJhA5kBSST7fNx0odlcSDLIMq_kIkIkHOchYxK8FMK3_UZIcxIWFrbKLrPSaH4abCyugr10/s428/EMA_European_Medicines_Agency_logo.jpg" style="margin-left: 1em; margin-right: 1em;"><span style="font-family: helvetica; font-size: large;"><img border="0" data-original-height="147" data-original-width="428" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjTaCB0nYJpN2-VmaYNUsLgMH_pEbXGzB2QgZgf_RE42fLOFcFfu9ElwhdraO_0lGTQp-JwWJhA5kBSST7fNx0odlcSDLIMq_kIkIkHOchYxK8FMK3_UZIcxIWFrbKLrPSaH4abCyugr10/s320/EMA_European_Medicines_Agency_logo.jpg" width="320" /></span></a></div><span style="font-family: helvetica; font-size: large;"><br /></span><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEipov8q2BqdvbO2RN795ubr4J8Spyrtz8DfjEQ0JWE2N84qWBo1wZxBA_l58d_WoFLbGv7vNOfxWOR8VDFyVCm1d190RvQaMIv-02Zp5mu4_QSK9lCNVJ9HHN_VoZJ_fU7XW4hhfNDUPBk/s276/EU+flag.jpg" style="margin-left: 1em; margin-right: 1em;"><span style="font-family: helvetica; font-size: large;"><img border="0" data-original-height="183" data-original-width="276" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEipov8q2BqdvbO2RN795ubr4J8Spyrtz8DfjEQ0JWE2N84qWBo1wZxBA_l58d_WoFLbGv7vNOfxWOR8VDFyVCm1d190RvQaMIv-02Zp5mu4_QSK9lCNVJ9HHN_VoZJ_fU7XW4hhfNDUPBk/s0/EU+flag.jpg" /></span></a></div><span style="font-family: helvetica; font-size: large;"><br /><span><br /></span></span><p></p><p><span style="font-family: helvetica; font-size: large;"> <span face="Calibri, sans-serif">I have been saying for years that for a pull incentive to actually function as an incentive, it must be large enough to motivate investors and large pharma to get back into antibiotic R&D. This will take a $2 (to $4) billion commitment for each priority drug approved regardless of how this goal is achieved. This could be a market entry reward, a transferable patent exclusivity reward (still my favorite), an antibiotic susceptibility bonus, a subscription payment regardless of use, etc.</span><span face="Calibri, sans-serif"> </span></span></p><p class="MsoNormal" style="margin: 0in;"><span face="Calibri, sans-serif"><span style="font-family: helvetica; font-size: large;"> </span></span></p><p class="MsoNormal" style="margin: 0in;"><span style="font-family: helvetica; font-size: large;"><span face="Calibri, sans-serif"><span></span></span></span></p><div class="separator" style="clear: both; text-align: center;"><span style="font-family: helvetica; font-size: large;"><span face="Calibri, sans-serif"><span><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiNg-qTBu01jYnUi3HgBcRuSGSocq2Wbs-K1ggW0-mt-7_ClRtvppJ6Hy7pkD2a-7o0GYvyaJSfYryT6GE1S8f_OUzPfG-G9VI2Uxzr7wflVRikFPQuUXEhPUOf65cZfRpg3LJW1Rlep5I/s244/drive+ab.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="148" data-original-width="244" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiNg-qTBu01jYnUi3HgBcRuSGSocq2Wbs-K1ggW0-mt-7_ClRtvppJ6Hy7pkD2a-7o0GYvyaJSfYryT6GE1S8f_OUzPfG-G9VI2Uxzr7wflVRikFPQuUXEhPUOf65cZfRpg3LJW1Rlep5I/s0/drive+ab.jpg" /></a></span></span></span></div><span style="font-family: helvetica; font-size: large;"><span face="Calibri, sans-serif"><span>Years ago, DRIVE-AB, a European effort looking at potential incentives for antibiotic R&D suggested that countries “pilot” various models. In fact, several countries are now doing just that. France has had a DRG carve out for certain hospital antibiotics for years. Germany just introduced such a carve out last year. Has this increased the market for antibiotics in either country? I don’t think so. <a href="https://www.folkhalsomyndigheten.se/the-public-health-agency-of-sweden/communicable-disease-control/antibiotics-and-antimicrobial-resistance/availability-of-antibiotics/"><span style="color: red;">Sweden</span></a> is piloting a subscription model – but the money committed is not publicly available. The UK (no longer part of Europe) is also piloting a subscription model committing up to </span></span><span face="Calibri, sans-serif"> </span><span face="Calibri, sans-serif"><span>£</span></span><span>10 million per year for up to 10 years per product. It is </span><a href="https://amr.solutions/2020/03/29/uk-antibiotic-subscription-pilot-implies-pull-incentive-of-up-to-4b-across-the-g20/"><span style="color: red;">claimed</span></a><span> that this will constitute the UK’s fair share of the overall antibiotic market in terms of their commitment to a subscription type pull incentive. Of course – that is only meaningful if many other countries join since the UK accounts for something like 3% of the total market. But what does “pilot” mean exactly. What is the endpoint? How will we judge success or failure? Is success defined by the sponsor somehow in terms of market increase? And how would that be defined? Is success defined by the national authority in terms of value of therapy? What if the country has very few resistant infections like Sweden? How will they define “value?” I admit that, at the time, sitting in the DRIVE-AB conference room in the Netherlands, I did not understand this concept – and I still don’t.</span></span><p></p><p class="MsoNormal" style="margin: 0in;"><span style="font-size: large;"><span style="font-family: helvetica;"><br /></span></span></p><p class="MsoNormal" style="margin: 0in;"><span style="font-size: large;"><span style="font-family: helvetica;">The other issue is that each country picks different antibiotics for its incentive. That just dilutes the market and makes no sense. </span></span></p><p class="MsoNormal" style="margin: 0in;"><span style="font-size: large;"><span style="font-family: helvetica;"><br /></span></span></p><p class="MsoNormal" style="margin: 0in;"><span face="Calibri, sans-serif"><span style="font-family: helvetica; font-size: large;">In my view, the goal of a pull incentive is to provide a significant return on investment for companies who pursue antibiotic R&D and succeed. This, in turn, will motivate investors to invest in the area. No matter how I look at this problem, it seems like the only way that such a large pull incentive will come to pass is if a region or country takes a leadership position and provides an incentive that will work globally. Once that occurs, we can work to bring other countries on board. But until then, I think we are stuck in incentive purgatory. The Table below shows the 2017 (pre-Brexit, pre-Covid) GDPs of Western countries and Europe including the UK, Sweden and Germany. Clearly either Europe as Europe or the US are the best positioned to offer such an incentive just based on the size of their respective economies. <o:p></o:p></span></span></p><p class="MsoNormal" style="margin: 0in;"><span face="Calibri, sans-serif"><span style="font-family: helvetica; font-size: large;"> </span></span></p><p class="MsoNormal" style="margin: 0in;"><span face="Calibri, sans-serif"><span style="font-family: helvetica; font-size: large;"> </span></span></p><p class="MsoNormal" style="margin: 0in;"><span face="Calibri, sans-serif"><span style="font-family: helvetica; font-size: large;">GDP by country<o:p></o:p></span></span></p><p class="MsoNormal" style="margin: 0in;"><span face="Calibri, sans-serif"><span style="font-family: helvetica; font-size: large;"> </span></span></p><table border="0" cellpadding="0" cellspacing="0" class="MsoNormalTable" style="border-collapse: collapse; color: black; width: 520px;"><tbody><tr style="height: 26pt;"><td colspan="6" nowrap="" style="height: 26pt; padding: 0in 5.4pt; width: 390pt;" valign="bottom" width="520"><p class="MsoNormal" style="margin: 0in;"><span style="font-family: helvetica;"><span face="Calibri, sans-serif"><span style="font-size: large;"> </span></span><span style="font-size: large;"> Country/Region 2017 (Trillion USD)<span class="Apple-tab-span" style="white-space: pre;"> </span></span></span></p><p class="MsoNormal" style="margin: 0in;"><span style="font-family: helvetica; font-size: large;">USA<span class="Apple-tab-span" style="white-space: pre;"> </span> 19.5</span></p><p class="MsoNormal" style="margin: 0in;"><span style="font-family: helvetica; font-size: large;">Europe (pre Brexit)<span class="Apple-tab-span" style="white-space: pre;"> </span>13.0</span></p><p class="MsoNormal" style="margin: 0in;"><span style="font-family: helvetica; font-size: large;">UK<span class="Apple-tab-span" style="white-space: pre;"> </span> 2.6</span></p><p class="MsoNormal" style="margin: 0in;"><span style="font-family: helvetica; font-size: large;">Sweden<span class="Apple-tab-span" style="white-space: pre;"> </span> 0.5</span></p><p class="MsoNormal" style="margin: 0in;"><span style="font-family: helvetica; font-size: large;">Germany<span class="Apple-tab-span" style="white-space: pre;"> </span> 3.7</span></p></td></tr></tbody></table><p class="MsoNormal" style="margin: 0in;"><span face="Calibri, sans-serif"><span style="font-family: helvetica; font-size: large;"> </span></span></p><p class="MsoNormal" style="margin: 0in;"><span face="Calibri, sans-serif"><span style="font-family: helvetica; font-size: large;"></span></span></p><div class="separator" style="clear: both; text-align: center;"><span style="font-family: helvetica; font-size: large;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjIy_bHPdeBSFsvDDNNDsXrsgQGXGvcfCKks2kpwjlLuvFFnNfkNXm2JPmtdOWlf9EUcnaKt74nN7PiEr9eSYrIR2nwy0NFnuuUyLgLzP7TO9pYLAzNrdNWdxWNG374EBKJajH2FT6b3kY/s1000/tapestry.jpg" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img border="0" data-original-height="1000" data-original-width="640" height="320" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjIy_bHPdeBSFsvDDNNDsXrsgQGXGvcfCKks2kpwjlLuvFFnNfkNXm2JPmtdOWlf9EUcnaKt74nN7PiEr9eSYrIR2nwy0NFnuuUyLgLzP7TO9pYLAzNrdNWdxWNG374EBKJajH2FT6b3kY/s320/tapestry.jpg" /></a></span></div><span style="font-family: helvetica; font-size: large;"><br />This brings me to a discussion of the possibility that Europe will take on this task. And every time I think about this, I go back to Flora Lewis’ book, Europe, A Tapestry of Nations. And there is no better example of the contemporary issues facing Europe’s ability to bring together its national authorities than their botched approach to providing covid vaccine for their population. This problem has been analyzed in detail by Politico Europe and their <a href="https://www.politico.eu/article/europe-coronavirus-vaccine-struggle-pfizer-biontech-astrazeneca/"><span style="color: red;">analysis</span></a> should be a wake-up call to all in Europe as to the continuing shortcomings of the alliance. According to the article, Europe was late coming to the table. They even supplanted an alliance of four national authorities who had already begun negotiations for vaccines for their countries to restart negotiations for Europe. This resulted in further delay. Then they negotiated a price well below what the US, Israel and others were paying – which may have dropped them further down the priority list for vaccine suppliers. This is to say nothing of their clear preference for Europe-based vaccine companies like Sanofi that ultimately were unable to provide any supply in time. Then there were delays in approvals based on delayed applications to the European regulatory authority by sponsors (a frequent event since the US is a bigger market). Even though Europe was quicker to approve than the US once having received the submissions, the delay based on delayed submssions was still present. Then there was continued bickering among the diverse national authorities in Europe. <a href="https://www.euronews.com/2021/02/12/hungary-to-begin-using-russia-s-sputnik-v-vaccine-today"><span style="color: red;">Hungary</span></a>, for example, recently approved and is administering Russia’s Sputnik and China’s Sinopharm vaccines. </span><div><span style="font-size: x-large;"><span style="font-family: helvetica;"><br /></span></span></div><div><span style="font-family: helvetica; font-size: large;">The recent experience of biotech attempting to market their new antibiotics in Europe is also cause for serious concern. In at least two <a href="https://antibiotics-theperfectstorm.blogspot.com/2020/09/amr-and-europe-what-happened.html"><span style="color: red;">cases</span></a>, the European regulators insisted on post-market commitments that would have been more costly than the total potential market in the region. Neither drug was ultimately marketed in the region. </span></div><div><span style="font-family: helvetica; font-size: large;"><br /></span></div><div><span style="font-family: helvetica; font-size: large;">All this makes me less than optimistic about Europe’s ability to get a true pull incentive for antibiotic R&D together in any reasonable time frame. So – that brings us back to the US. The United States, in my view, is the only country capable of pulling this off. We have the PASTEUR Act on the table – which I think would work (given clarification around a number of <a href="https://antibiotics-theperfectstorm.blogspot.com/2020/10/the-pasteur-act-view-from-industry.html"><span style="color: red;">questions</span></a>). I think it is there where we need to focus our efforts. </span><p class="MsoNormal" style="margin: 0in;"><span face="Calibri, sans-serif"><span style="font-family: helvetica; font-size: large;"> </span></span></p><p class="MsoNormal" style="margin: 0in;"><span face="Calibri, sans-serif"><span style="font-family: helvetica; font-size: large;"> </span></span></p></div>David Shlaeshttp://www.blogger.com/profile/00228776693058791618noreply@blogger.com0tag:blogger.com,1999:blog-4287560491211025099.post-91450872992417152152021-02-08T09:01:00.005-05:002021-02-12T10:44:12.780-05:00Covid vaccines compared to AMR<p><span style="font-size: large;"> </span></p><p><span style="font-size: large;"></span></p><div class="separator" style="clear: both; text-align: center;"><span style="font-size: large;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgOVSbS7yKBnOmwaAAdXIlzFoMv-fT8q95di-ktU5mLhh8BmXk1QkZfsR5iPhSbWCc9VANzohTiF0LoKoQ0j0F6GbFa92kx5fVzzbzGyy98cv3BcGJYBssrq8R69X4cV8HsVf6qXsS1HAk/s1024/AMR+2050.png" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img border="0" data-original-height="512" data-original-width="1024" height="221" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgOVSbS7yKBnOmwaAAdXIlzFoMv-fT8q95di-ktU5mLhh8BmXk1QkZfsR5iPhSbWCc9VANzohTiF0LoKoQ0j0F6GbFa92kx5fVzzbzGyy98cv3BcGJYBssrq8R69X4cV8HsVf6qXsS1HAk/w396-h221/AMR+2050.png" width="396" /></a></span></div><span style="font-size: large;"><br /><br /><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgyo3f8kNE9SdHTwTll5b0Nm_v1NhQEjQI_DJBrg-FYdjBZi7mNHW2qLLretukTQp7BZGkcagv-cqEwsz33YR1SmuF5Tv5tpu9kOmKE3tm5d6X8yj3_wH5g5WfrcduuOh4iJpCT3zRoU5w/s300/coronavirus.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="168" data-original-width="300" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgyo3f8kNE9SdHTwTll5b0Nm_v1NhQEjQI_DJBrg-FYdjBZi7mNHW2qLLretukTQp7BZGkcagv-cqEwsz33YR1SmuF5Tv5tpu9kOmKE3tm5d6X8yj3_wH5g5WfrcduuOh4iJpCT3zRoU5w/s0/coronavirus.jpg" /></a><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEihANgYsi_Uhz7bsZv9g9-oXPvElSC4JnznZakT96aZloTDhsby78QwicpOMeim5SWYlw8yf9XOh13kLnGdBH9PpN1iYFrJbeJ3LkeDMO_zXMVrxFo2YuXayXXSed6PV1cp7KkD8F2DRas/s300/corona+warps+speed.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="168" data-original-width="300" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEihANgYsi_Uhz7bsZv9g9-oXPvElSC4JnznZakT96aZloTDhsby78QwicpOMeim5SWYlw8yf9XOh13kLnGdBH9PpN1iYFrJbeJ3LkeDMO_zXMVrxFo2YuXayXXSed6PV1cp7KkD8F2DRas/s0/corona+warps+speed.jpg" /></a></div></div><br /><span face="Calibri, sans-serif"><br /></span></span><p></p><p><span style="font-size: large;"><span face="Calibri, sans-serif"><br /></span></span></p><p><span style="font-size: large;"><span face="Calibri, sans-serif">I never dreamed this would be possible. Of course, so many things are possible today that I thought were impossible that I’m almost embarrassed to admit it (but I have no pride). Twenty-five years ago I thought that an immunologic approach to cancer would never work because cancer cells are, after all, self. My excuse is that I am neither an immunologist nor an oncologist and many of my oncologist friends agreed with me. But to think that one could go from the SARS-COV-2 viral nucleic acid sequence to a marketed vaccine in less than a year – I’m sorry – but that was science fiction, Star Wars, warp speed. Plus – mRNA instead of a killed virus or protein or conjugate antigen?</span><span face="Calibri, sans-serif"> </span><span face="Calibri, sans-serif"> </span><span face="Calibri, sans-serif">mRNA – the epitome of instability? Come on!</span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span face="Calibri, sans-serif"><span style="font-size: large;"> </span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span face="Calibri, sans-serif"><span style="font-size: large;">Beyond the technology though, there was the desire, based on a lethal danger to the population posed by a pandemic virus, to get to this goal of a vaccine that is safe and effective and that can be distributed in record time. To accomplish this required an enormous investment in manufacturing – at risk. This investment came either from government (us taxpayers), from private industry (large and small) or from both. And, at the end, governments are paying for the final product – although some vaccines are being sold at cost (not for profit). This plan required a strong will, a strength of steel, and an organization and expertise that we have rarely seen anywhere before. It’s almost enough to give one confidence in government again – since without government intervention, this could not have happened. The plan also should make us stand in awe and gratitude for the extraordinary efforts of the pharmaceutical industry and their scientists and clinicians and their partners and stakeholders without whom this would never have happened. The industry should no longer be viewed as evil incarnate!<o:p></o:p></span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span face="Calibri, sans-serif"><span style="font-size: large;"> </span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span face="Calibri, sans-serif"><span style="font-size: large;">Compare and contrast. Antibiotic resistant infections have been killing people since the dawn of the antibiotic era. According to the CDC, the use of seat belts saved 13,000 lives in 2009. Compared to the 460,000 Americans killed by covid in this past year, 13,000 seems like a small number. Does that mean we should forget about wearing seat belts? Again, according to the CDC, antibiotic resistant infections and C. difficile kill 48,000 Americans every year. And most of us think this is a significant underestimate. Should we now relax since this number is almost 10- fold lower than the covid losses to date? Should any sense of urgency to save these lives be somehow lessened because of covid? Or should we rather look at this lesson from covid and apply it to lethal antibiotic resistant infections? How would we do that?<o:p></o:p></span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span face="Calibri, sans-serif"><span style="font-size: large;"> </span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span face="Calibri, sans-serif"><span style="font-size: large;">First, although a vaccine approach to the prevention of resistant bacterial infections is a great idea, and one that has worked for a few selected bacterial infections, I don’t think that we are at the same place with this problem as we were for certain viruses and mRNA technology. We will need other approaches focusing on therapy. It takes us 10-20 years to go from an idea to a new antibiotic. We could shorten that time by doing more at risk as we did for covid. We could also do a better job of delaying the increase in resistance by doing a better job of restricting antibiotic use to cases where it is really necessary both in humans, plants, fish and other animals. But because even appropriate antibiotic use will ultimately lead to resistance, we still must find new approaches to the treatment of resistant infections. My personal opinion is that this will most likely involve new antibiotics or new inhibitors of resistance (like B-lactamase inhibitors). But right now, our pipeline is in a disastrous state and any companies still working in the space are facing economic oblivion. One risk we must take is the use of financial incentives to make up for the broken marketplace that is driving investors out of the antibacterial space. Compared to the cost of warp speed for covid at $18 billion, the fix for the antibiotic marketplace would probably be more like $2 billion per new product. If we awarded one or two new products per year, we’re talking $20 billion over five years maximum. In any case, I don’t think our current pipeline would get us to 10 approved products in five years at least in terms of our</span></span><span style="font-size: x-large;"> key</span><span style="font-size: x-large;"> priorities. So, new antibiotics for resistant infections – a fire sale! Why can’t we see this?</span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span face="Calibri, sans-serif"><span style="font-size: large;"> <o:p></o:p></span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span face="Calibri, sans-serif"><span style="font-size: large;">Let’s talk about Europe for just a minute. Will Europe and its disparate national authorities have learned the lesson of pricing for new products from its experience with covid vaccines? Will they have learned that their regulatory approach leaves something to be desired when it comes to considerations of feasibility in their demands for new data? Will Europe be left behind again as they have been for covid vaccines if (my lips to God’s ear) the US establishes a market incentive for new antibacterial products? <o:p></o:p></span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span face="Calibri, sans-serif"><span style="font-size: large;"> </span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span face="Calibri, sans-serif"><span style="font-size: large;">We need to learn from this pandemic and apply these lessons to our approach to fighting antibiotic resistant infections – and we need to do it urgently!<o:p></o:p></span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span face="Calibri, sans-serif"><span style="font-size: large;"> </span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span face="Calibri, sans-serif"><span style="font-size: large;"> </span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span face="Calibri, sans-serif"><span style="font-size: large;"> </span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span face="Calibri, sans-serif"><span style="font-size: large;"> </span></span></p>David Shlaeshttp://www.blogger.com/profile/00228776693058791618noreply@blogger.com0tag:blogger.com,1999:blog-4287560491211025099.post-11063774081002780212021-02-05T09:33:00.000-05:002021-02-05T09:33:29.787-05:00AMR - a Holistic Approach<p><span style="font-size: large;"> </span></p><div class="separator" style="clear: both; text-align: center;"><span style="font-size: large;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgdMjLWW3cTtyHE47s9yMx4CBDVGZSKhyphenhyphen8IQsrex7UZQBo66SLyvDt2UPrj-S5enuz0azs_UY3N5pi3SwABVp5XKG87lZOhbQt4j3jBHSYa53XJdMv7KEjjtb1ENcLEI9GiuyMF0dwBhW4/s385/CDDEP.png" imageanchor="1" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img border="0" data-original-height="131" data-original-width="385" height="152" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgdMjLWW3cTtyHE47s9yMx4CBDVGZSKhyphenhyphen8IQsrex7UZQBo66SLyvDt2UPrj-S5enuz0azs_UY3N5pi3SwABVp5XKG87lZOhbQt4j3jBHSYa53XJdMv7KEjjtb1ENcLEI9GiuyMF0dwBhW4/w446-h152/CDDEP.png" width="446" /></a></span></div><span style="font-size: large;"><br /></span><p></p><p><span style="font-size: large;"><span style="font-family: Calibri, sans-serif;"><br /></span></span></p><p><span style="font-size: large;"><span style="font-family: Calibri, sans-serif;">A very important</span><span style="font-family: Calibri, sans-serif;"> </span><a href="https://cddep.org/wp-content/uploads/2021/02/The-State-of-the-Worlds-Antibiotics-2021.pdf" style="font-family: Calibri, sans-serif;"><span style="color: red;">report</span></a><span style="font-family: Calibri, sans-serif;"> </span><span style="font-family: Calibri, sans-serif;">on the state of antibiotic use and resistance globally has just been release by The Center for Disease Dynamics, Economics & Policy (CDDEP).</span><span style="font-family: Calibri, sans-serif;"> </span><span style="font-family: Calibri, sans-serif;"> </span><span style="font-family: Calibri, sans-serif;">Before delving into this topic, I want to explain my long absence from my blog.</span><span style="font-family: Calibri, sans-serif;"> </span><span style="font-family: Calibri, sans-serif;"> </span><span style="font-family: Calibri, sans-serif;">I have been ill but am rapidly recovering and am now ready to continue thinking and writing about AMR.</span><span style="font-family: Calibri, sans-serif;"> </span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> The report focuses on the relationship between antibiotic use and resistance with a tool that provides an index or score for a given country. A number of countries are included as examples in a digital dashboard. This tool and dashboard will be helpful for national and international agencies to evaluate and develop policies to address problems of resistance. The report also notes that among some LMICs, there is a clear issue of access such that patients suffer and die from simple lack of antimicrobial therapy or vaccines more than from resistant infections. A <a href="https://www.facebook.com/pg/cddep/videos/?ref=page_internal"><span style="color: red;">webinar</span></a> by CDDEP with Ramanan Laxminarayan and Dame Sally Davies and others discussing the report is also available. <o:p></o:p></span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;">While I cannot agree more wholeheartedly that a greater understanding of the “you use it, you lose it” law of antimicrobial resistance is important, it is not the whole story. As implied, even carefully monitored and appropriate use of antibiotics will still select for resistant variants within microbial populations. There are many examples of this from our experience in hospitals with strong antimicrobial stewardship policies, even given the fact that these hospitals exist within a larger global community. What this means is that, even if we alter our policies and focus our antimicrobial use in animals and in humans to only what is needed, we will still face the problem of resistance. It is likely that under those circumstances resistance will evolve and grow more slowly – but it is still going to be inevitable. <o:p></o:p></span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;">Therefore, in a holistic approach to resistance, we have to anticipate resistance even to our last line antibiotics. This means that our current antibiotics will yield to resistance over time and that we will need new antibiotics (or possibly other approaches) to deal with these resistant infections. And today, we are nowhere near ready for that eventuality given the perilous state of our antimicrobial pipeline. <o:p></o:p></span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;">Our pipeline depends on the ability of sponsors (for profit or not) to discover, develop, manufacture and distribute new, effective drugs for the treatment of resistant infections. While there is more and more support for discovery and early development, and even some new support for late-stage development, without an ability to manufacture and distribute these putative new products globally, the entire endeavor collapses like a house of cards. And that is exactly what has been happening over the last decade. The clear evidence for this is in the bankruptcy of multiple small companies who engaged in the commercialization of new antibiotics active against resistant infections. To compound this, a number of sponsors have been unable to market their new antibiotics in Europe given burdensome and expensive regulatory requirements or inadequate national pricing proposals. Even if, as some argue, that these products deserved their fate, private investment in antibiotics is getting more and more difficult. <o:p></o:p></span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;">Recent economic analyses by John Rex and Kevin Krause at a meeting of the National Academies (see links <a href="https://amr.solutions/2021/01/09/all-in-cost-of-a-new-antibiotic-from-discovery-to-10-years-on-market/"><span style="color: red;">here</span></a>) shed some light on the costs of commercialization – and they are considerable. The problem is that we know what we must do to address the problem. We have to pay! While some countries (e.g. UK) are trying this by an effort to “pay their share” – this is clearly insufficient by itself. Either we need a more global approach, or some country or region must take a leadership position and provide much more than their “share.” I’m looking at you US and EU! <o:p></o:p></span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;">Without addressing this other end of the AMR problem, our inadequate pipeline, stewardship will only delay the inevitable. <o:p></o:p></span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p>David Shlaeshttp://www.blogger.com/profile/00228776693058791618noreply@blogger.com0tag:blogger.com,1999:blog-4287560491211025099.post-16761500237841847622020-10-26T08:26:00.000-04:002020-10-26T08:26:12.097-04:00The Pasteur Act - A View from Industry<p><span style="font-size: large;"></span></p><div class="separator" style="clear: both; text-align: center;"><span style="font-size: large;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh0efqdwq4GDYCh2ZDIWKitTsGR3_WKA3-o2kcj2paHB8oXNt3hdi2QdoW2ss592hyphenhyphena82ScVgMhP6CdxR0AOUrfTk_lQNF3_syWNFRGiWdcZn5yQf52mPeCyQWAZ7SiHYC1iuv65mu3Ic0/s380/venatorx.png" imageanchor="1" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img border="0" data-original-height="133" data-original-width="380" height="70" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh0efqdwq4GDYCh2ZDIWKitTsGR3_WKA3-o2kcj2paHB8oXNt3hdi2QdoW2ss592hyphenhyphena82ScVgMhP6CdxR0AOUrfTk_lQNF3_syWNFRGiWdcZn5yQf52mPeCyQWAZ7SiHYC1iuv65mu3Ic0/w200-h70/venatorx.png" width="200" /></a></span></div><div class="separator" style="clear: both; text-align: center;"><table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto;"><tbody><tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiA_J72DSU4KJW00ie0MxlOzFtkhGS_5O-dvVem1081CnVHkDecXKT882u3gsG4w9vkUg-_QnhrlcNles4xE8tSGbKwb5a-rjIwVw_8vEEBPxa3Sm6nKFv3GLtYjy7LSnfOfP2vockAu4g/s225/chris+burns.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="225" data-original-width="225" height="200" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiA_J72DSU4KJW00ie0MxlOzFtkhGS_5O-dvVem1081CnVHkDecXKT882u3gsG4w9vkUg-_QnhrlcNles4xE8tSGbKwb5a-rjIwVw_8vEEBPxa3Sm6nKFv3GLtYjy7LSnfOfP2vockAu4g/w200-h200/chris+burns.jpg" width="200" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;">Chris Burns<br /><br /></td></tr></tbody></table><div class="separator" style="clear: both; text-align: center;"><span style="font-size: large;"></span></div><span style="font-size: large;"><br /><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjsoplwKHgxneMj5jZ9UJEym9Zn3-37zo4AnIdp07TlDPPxBrPgspnmhTXyJmMCrYc7k3simTxmaVpNMkxMgXNLos8ZG6SAIFiNO5oPGZTD5fUxzy1DBFy3vhsjT-M-FcgXdGdGe0LDZRc/s275/paratek+logo.png" imageanchor="1" style="clear: right; float: right; margin-bottom: 1em; margin-left: 1em;"><img border="0" data-original-height="183" data-original-width="275" height="133" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjsoplwKHgxneMj5jZ9UJEym9Zn3-37zo4AnIdp07TlDPPxBrPgspnmhTXyJmMCrYc7k3simTxmaVpNMkxMgXNLos8ZG6SAIFiNO5oPGZTD5fUxzy1DBFy3vhsjT-M-FcgXdGdGe0LDZRc/w200-h133/paratek+logo.png" width="200" /></a></span></div><span style="font-size: large;"> <br /><br /><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhDotzBESIxMUQpxBCrqoCOe3qjj9FxkJlRXWS-pZqZohxCkWuhOeO7Ws95WF8z7bKDV2smc6z_ofqeN5xPPZQGDYV_LpHP2f3OI9glCbv1MfJadcwNFpPwCCBRPNWtUYv9xGtQUwwhhKY/s1080/evanloh.jpg" imageanchor="1" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><br /></a><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhDotzBESIxMUQpxBCrqoCOe3qjj9FxkJlRXWS-pZqZohxCkWuhOeO7Ws95WF8z7bKDV2smc6z_ofqeN5xPPZQGDYV_LpHP2f3OI9glCbv1MfJadcwNFpPwCCBRPNWtUYv9xGtQUwwhhKY/s1080/evanloh.jpg" imageanchor="1" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><br /></a></div><br /><br /></span><p></p><p><span style="font-size: large;"><span style="font-family: Calibri, sans-serif;"><br /></span></span></p><table cellpadding="0" cellspacing="0" class="tr-caption-container" style="float: left;"><tbody><tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhDotzBESIxMUQpxBCrqoCOe3qjj9FxkJlRXWS-pZqZohxCkWuhOeO7Ws95WF8z7bKDV2smc6z_ofqeN5xPPZQGDYV_LpHP2f3OI9glCbv1MfJadcwNFpPwCCBRPNWtUYv9xGtQUwwhhKY/s1080/evanloh.jpg" imageanchor="1" style="clear: left; margin-bottom: 1em; margin-left: auto; margin-right: auto;"><img border="0" data-original-height="721" data-original-width="1080" height="134" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhDotzBESIxMUQpxBCrqoCOe3qjj9FxkJlRXWS-pZqZohxCkWuhOeO7Ws95WF8z7bKDV2smc6z_ofqeN5xPPZQGDYV_LpHP2f3OI9glCbv1MfJadcwNFpPwCCBRPNWtUYv9xGtQUwwhhKY/w200-h134/evanloh.jpg" width="200" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;">Evan Loh<br /></td></tr></tbody></table><p><br /></p><p><span style="font-size: large;"><span style="font-family: Calibri, sans-serif;"><br /></span></span></p><p><span style="font-size: large;"><span style="font-family: Calibri, sans-serif;"><br /></span></span></p><p><span style="font-size: large;"><span style="font-family: Calibri, sans-serif;"><br /></span></span></p><p><span style="font-size: large;"><span style="font-family: Calibri, sans-serif;"><br /></span></span></p><p><span style="font-size: large;"><span style="font-family: Calibri, sans-serif;"><br /></span></span></p><p><span style="font-size: large;"><span style="font-family: Calibri, sans-serif;">We will continue our discussion of the Pasteur Act as proposed by Senators Bennet and Young. Today I discuss the bill with two biotech CEOs, Chris Burns of Venatorx and Evan Loh of Paratek. Venatorx has a new antibiotic in phase 3 trials and Paratek won approval of their Nuzyra in 2018. Both expressed their appreciation to the Senators for bringing Pasteur forward.</span><span style="font-family: Calibri, sans-serif;"> </span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;">To remind you, a summary of the bill is <a href="https://amr.solutions/wp-content/uploads/2020/09/PASTEUR-Act-30-Sep-2020-One-Pager.pdf"><span style="color: red;">here</span></a> and the full bill (as it stands) is <a href="https://amr.solutions/wp-content/uploads/2020/09/PASTEUR-Act-30-Sep-2020-draft.pdf"><span style="color: red;">here</span></a>. As I noted in the last blog, the Pasteur Act proposes a subscription plan not dissimilar to what is being implemented in the UK and Sweden. The plan will purchase a specified number of doses (or the rights to such) at some price over a multi-year period. The total commitment proposed over up to 10 years is not less than $750 million and not more than $3 billion! The proposal only covers federally funded programs such as Medicare, Medicaid, VA, etc. There is a statement that encourages HHS to encourage participation by private payers . . .The bill is planned to assure sponsors that they will have guaranteed income in the absence of marketing – a delinkage between sales volume and revenues.<o:p></o:p></span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;">Everyone agrees with Chris Burns that waiting for market forces to increase investment and antibiotic R&D is futile. Both CEOs agreed (as do I) that Pasteur does not provide enough specifics for industry to judge how it will affect commercialization of their new antibiotics. They both offered a number of key questions and concerns. <o:p></o:p></span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;">Pasteur does not address the need for hospitals to place the new drugs on formulary and to stock at least a small number of doses. Recognizing that the majority of US hospitals are under 200 beds and that these hospitals are often in dire financial straits, the payment required to stock drug may be too much of a burden. (The same would be true for the DISARM Act by the way). <o:p></o:p></span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;">Chris Burns noted that since the entire subscription contract is with the sponsor, the list of pharmaceutical middlemen with their various price mark-ups is not affected. Evan Loh noted that in DISARM, by contrast, pricing is defined by the drug’s Average Sale Price or ASP. <o:p></o:p></span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-size: large;"><span style="font-family: Calibri, sans-serif;">Chris Burns is looking for more clarity as to whether the subscription is for an actual number of courses of therapy (per year or per award period) or is more for a guarantee that the drug will be commercially and federally available in the distribution chain. He believes it is the latter. In that case, he accepts that if the government makes the annual subscription payments, it wants a “credit” back when it effectively pays a second time through normal distribution (e.g. through Medicare or Medicaid reimbursement).</span><o:p></o:p></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;">He also pointed out that DISARM might work better IF one can achieve reasonable peak year sales because of the proposed reimbursement. He also notes that DISARM will work better (obviously) for those sponsors whose products might not qualify for the Pasteur subscription based on the proposed committee or panel to make these choices. Evan Loh suggested that this committee plan was, in fact, too opaque and would prefer that all QIDP products approved over the last five years be offered such a subscription automatically. I agree with both CEOs that the panel who makes this decision as to which products are deserving is too vague and will not encourage investors. We need a much more transparent process such as designating top CDC and/or WHO priorities that are already well defined as criteria which might obviate the need for a panel. FDA could make this determination. <o:p></o:p></span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;">Evan Loh, as one might guess, strongly prefers DISARM. His company has carried out interviews with key pharmacists who suggest that a promise of reimbursement would lead to a clear increase in positive formulary decisions for Nuzyra. <o:p></o:p></span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;">Evan views Pasteur as complementary to DISARM depending on eligibility and process. The bill proposes transition measures that might be attractive but more clarity required. For example, according to Evan, Pasteur should provide for a transition contract for all recent QIDPs in the range of $250 million. This will immediately help save small biotechs from bankruptcy at the moment of commercialization. Evan suggests excluding big pharma (that we would need to define) from these transition grants. He further suggests that there be a post-acceptance review at some point such as is proposed in DISARM. Above all, Pasteur must avoid the creation of impossible hurdles. It is clear to both CEOs that investors still lack confidence and it is not clear to them that either of these Acts, should they become law, will provide that confidence until data shows that they can provide for successful commercialization of needed new antibiotics.<o:p></o:p></span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;">I asked both CEOs about alternatives to DISARM and Pasteur. Both agreed that contracts for addition to the US strategic stockpile would be viable IF there were enough funds to make a large purchase comparable to the sums anticipated by Pasteur – something that does not appear to be the case currently. <o:p></o:p></span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;">I specifically proposed a Hybrid Market Entry Award of ~$2 billion provided over the first five years post approval of a new antibiotic addressing CDC’s high priority pathogens. In this case the sponsor would be limited to charging a low (to be defined) price during those first five years. After that period, the sponsor would be allowed to gradually increase the price over the life of exclusivity of the product. The idea would be to provide a motivation for generic manufacturers to enter the marketplace after the end of branded exclusivity. Chris Burns thought that this would work much better than Pasteur, but noted that it is much less politically palatable. Evan Loh was skeptical that a sponsor would be able to increase prices enough to achieve the stated goal. <o:p></o:p></span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;">Evan suggested a small, initial government investment that would be enough to get the sponsor to profitability after 2-3 years. At that point the government could charge the sponsor a royalty such that the originating fund could become evergreen. Personally, I am skeptical that this would work in the absence of many more patients with resistant infections.<o:p></o:p></span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-size: large;"><span style="font-family: Calibri, sans-serif;">Conclusions: There are too many questions around key aspects of Pasteur for industry to have confidence that it would work as intended according to both the CEOs I interviewed. </span><span style="font-family: Calibri, sans-serif;">However, both CEOs look forward to more development of the concept.</span><o:p></o:p></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;"> </span></span></p><p class="MsoNormal" style="font-family: "Times New Roman", serif; margin: 0in;"><span style="font-family: Calibri, sans-serif;"><span style="font-size: large;">I am grateful to both Evan Loh and Chris Burns for spending the time with me to help clarify industry concerns around recently proposed government aid for the suffering antibiotic R&D community. </span><o:p></o:p></span></p>David Shlaeshttp://www.blogger.com/profile/00228776693058791618noreply@blogger.com0tag:blogger.com,1999:blog-4287560491211025099.post-67997866056563406372020-10-13T17:06:00.000-04:002020-10-13T17:06:07.943-04:00Introducing the Pasteur Act for AMR<p><span style="font-size: large;"> </span>
</p><p class="MsoNormal"><span style="font-size: large;"></span></p><div class="separator" style="clear: both; text-align: center;"><span style="font-size: large;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEic-PWUWix_BWRRh_r03QJnHodQOJ93jfrArnjxRLipYULk08oQbeKDEt2oYN5sEoOqt5pIa39_YNwND56vO7HBvF6McQVqVt2vlKlNJbqXgQZlsZCHMfH1DZXSaSJPVF7ETFfMG5be19U/s225/US+Senate+Seal.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="225" data-original-width="225" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEic-PWUWix_BWRRh_r03QJnHodQOJ93jfrArnjxRLipYULk08oQbeKDEt2oYN5sEoOqt5pIa39_YNwND56vO7HBvF6McQVqVt2vlKlNJbqXgQZlsZCHMfH1DZXSaSJPVF7ETFfMG5be19U/s0/US+Senate+Seal.png" /></a></span></div><span style="font-size: large;"><br />WARNING - This is long! <br /></span><p></p><p class="MsoNormal"><span style="font-size: large;"> </span></p><p class="MsoNormal"><span style="font-size: large;">Today, I discuss the Pasteur Act, a new bill proposed in the
US Senate by senators Bennet and Young, with Ryan Cirz. You can find a summary
of the bill <span style="color: red;"><a href="https://amr.solutions/wp-content/uploads/2020/09/PASTEUR-Act-30-Sep-2020-One-Pager.pdf">here</a></span>
and the full bill (as it stands) <a href="https://amr.solutions/wp-content/uploads/2020/09/PASTEUR-Act-30-Sep-2020-draft.pdf">here</a>.
The Pasteur Act proposes a subscription plan not dissimilar to what is being
implemented in the UK and Sweden.<span> </span>The
plan will purchase a specified number of doses (or the rights to such) at some
price over a multi-year period.<span> </span>The
total commitment proposed over up to 10 years is not less than $750 million and
not more than $3 billion! The proposal only covers federally funded programs
such as Medicare, Medicaid, VA, etc. There is a statement that encourages HHS
to encourage participation by private payers . . .The bill is planned to assure
sponsors that they will have guaranteed income in the absence of marketing – a
delinkage between sales volume and revenues. But, will it actually work that
way?</span></p><span style="font-size: large;">
</span><p class="MsoNormal"><span style="font-size: large;"> </span></p><span style="font-size: large;">
</span><p class="MsoNormal" style="background: white;"><span style="font-size: large;"><span style="color: black; mso-color-alt: windowtext;">Ryan Cirz:<span> </span></span><i><span style="color: black; font-family: "Arial",sans-serif; mso-fareast-font-family: "Times New Roman"; mso-themecolor: text1;">We have a math problem in the field.<span> </span>Revenues are limited by price x volume.<span> </span>Durations of therapy are generally short, so
volume is ~ number of patients.<span> </span>Either price
or number of patients must go up for products to be sustainable in the marketplace.</span></i></span></p><span style="font-size: large;">
</span><p class="MsoNormal" style="background: white;"><span style="font-size: large;"><i><span style="color: black; font-family: "Arial",sans-serif; mso-fareast-font-family: "Times New Roman"; mso-themecolor: text1;"> </span></i></span></p><span style="font-size: large;">
</span><p class="MsoNormal" style="background: white;"><span style="font-size: large;"><i><span style="color: black; font-family: "Arial",sans-serif; mso-fareast-font-family: "Times New Roman"; mso-themecolor: text1;">Enabling
higher pricing is the focus of the DISARM act (an Act I believe is needed to
make the PASTEUR act function properly and drive optimum behavior).<span> </span>The low number of patients can be solved two
ways:<span> </span>just wait until there are more
patients, or artificially bolster the economics by ‘buying’ access to more drug
than you need at that moment in time – the latter is what I perceive PASTEUR as
attempting to do.<span> </span></span></i></span></p><span style="font-size: large;">
</span><p class="MsoNormal" style="background: white;"><span style="font-size: large;"><i><span style="color: black; font-family: "Arial",sans-serif; mso-fareast-font-family: "Times New Roman"; mso-themecolor: text1;"> </span></i></span></p><span style="font-size: large;">
</span><p class="MsoNormal" style="background: white;"><span style="font-size: large;"><i><span style="color: black; font-family: "Arial",sans-serif; mso-fareast-font-family: "Times New Roman"; mso-themecolor: text1;">I’m
sure some readers are thinking ‘if there aren’t that many patients, maybe
there’s no need and we shouldn’t spend taxpayer money on this!’ – hey, maybe
that’s correct.<span> </span>I will say 37 years ago
we decided <200,000 patients/year didn’t make a market, but we didn’t want
to leave those patients without treatments – hence the Orphan Drug Act.<span> </span>Here we are talking about a current market
size where there are only 10,000 or 50,000 patients – and antibiotics cure
people fast (unlike most orphan drugs) – so it’s no wonder the market is
breaking.</span></i></span></p><span style="font-size: large;">
</span><p class="MsoNormal" style="background: white;"><span style="font-size: large;"><i><span style="color: black; font-family: "Arial",sans-serif; mso-fareast-font-family: "Times New Roman"; mso-themecolor: text1;"> </span></i></span></p><span style="font-size: large;">
</span><p class="MsoNormal" style="background: white;"><span style="font-size: large;"><i><span style="color: black; font-family: "Arial",sans-serif; mso-fareast-font-family: "Times New Roman"; mso-themecolor: text1;">If
you are in the camp that you’d rather just wait until there are sufficient
patients for the market to solve itself, it’s important to remember the vast
majority of patients’ experience with an antibiotic is during its much longer
lifespan as an inexpensive generic.<span> </span>If
you want those generics to exist in the future, there must be a way to reward
the innovator companies (more importantly, their investors) during the short,
branded years after launch – then 10-15 years later, when the market is big,
society gets cheap access ad libitum.</span></i></span></p><span style="font-size: large;">
</span><p class="MsoNormal"><span style="font-size: large;"> </span></p><span style="font-size: large;">
</span><p class="MsoNormal"><span style="font-size: large;">There are other examples of this in the US.<span> </span>One is the State of Louisiana’s <a href="https://www.npr.org/sections/health-shots/2019/06/26/736312262/louisianas-novel-subscription-model-for-pricey-hepatitis-c-drugs-gains-approval">subscription</a>
for HCV therapeutics for their Medicaid population. In that case, Louisiana
guarantees a purchase of a specific number of doses of these drugs at a
negotiated price (lower than the usual retail price). The company is guaranteed
revenues upfront. The State saves money over the number of patients treated and
– therefore – can treat more patients.<span>
</span>This is a win-win for taxpayers, patients and Louisiana. </span></p><span style="font-size: large;">
</span><p class="MsoNormal"><span style="font-size: large;"> </span></p><span style="font-size: large;">
</span><p class="MsoListParagraph" style="mso-list: l0 level1 lfo1; text-indent: -.25in;"><span style="font-size: large;"><span><span>1.<span style="font-family: "Times New Roman"; font-feature-settings: normal; font-kerning: auto; font-language-override: normal; font-optical-sizing: auto; font-size-adjust: none; font-stretch: normal; font-style: normal; font-variant: normal; font-variation-settings: normal; font-weight: normal; line-height: normal;">
</span></span></span>The subscription is for government payers
only.<span> </span>While this is a large number of
very key payers (VA, Medicare, Medicaid etc), it does not include private
insurers. The bill encourages HHS to encourage private payers to participate,
but how will this work exactly in your opinion?</span></p><span style="font-size: large;">
</span><p class="MsoNormal" style="background: white; margin-left: .25in; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto;"><span style="font-size: large;"><i><span style="color: black; font-family: "Arial",sans-serif; mso-fareast-font-family: "Times New Roman"; mso-themecolor: text1;">Full
disclosure:<span> </span>I have no idea how this will
work – related though - I prefer a system with a de-linked incentive and a
natural competitive market. My fear is, without some sort of competitive
market, there will be regression to minimum standards to be eligible for a
subscription contract.<span> </span>There are infinite
parameters that can be dialed when designing and developing a drug and without
market forces, the pressure to strive for the very best you can achieve will be
absent.<span> </span>So I’m open-minded as we start
to really experiment and get specific with these pieces of legislation but
hoping we have a stabilized base of revenue from a PASTEUR-type system and
perhaps leave the private payer market separate so there’s reason to compete to
make the very best product – even within the subscription tiers – TBD as things
unfold</span></i></span></p><span style="font-size: large;">
</span><p class="MsoListParagraphCxSpFirst"><span style="font-size: large;"> </span></p><span style="font-size: large;">
</span><p class="MsoListParagraphCxSpMiddle" style="mso-list: l0 level1 lfo1; text-indent: -.25in;"><span style="font-size: large;"><span><span>2.<span style="font-family: "Times New Roman"; font-feature-settings: normal; font-kerning: auto; font-language-override: normal; font-optical-sizing: auto; font-size-adjust: none; font-stretch: normal; font-style: normal; font-variant: normal; font-variation-settings: normal; font-weight: normal; line-height: normal;">
</span></span></span>If I am a hospital pharmacist, when I order an
antibiotic covered by Pasteur, will I need to pay the upfront price to stock
the drug before being reimbursed by a payer one patient at a time?<span> </span>I don’t know the answer to this and neither
does Ryan (apparently). But I suspect that hospitals will have to pay upfront
to stock the new drug. </span></p><span style="font-size: large;">
</span><p class="MsoListParagraphCxSpMiddle"><span style="font-size: large;"> </span></p><span style="font-size: large;">
</span><p class="MsoListParagraphCxSpMiddle" style="mso-list: l0 level1 lfo1; text-indent: -.25in;"><span style="font-size: large;"><span><span>3.<span style="font-family: "Times New Roman"; font-feature-settings: normal; font-kerning: auto; font-language-override: normal; font-optical-sizing: auto; font-size-adjust: none; font-stretch: normal; font-style: normal; font-variant: normal; font-variation-settings: normal; font-weight: normal; line-height: normal;"> </span></span></span>If I am a sponsor, will I need to work to get my
product on the formulary (assuming I have to pay to stock the drug)? How much
will this interfere with the presumed delinkage of the model?</span></p><span style="font-size: large;">
</span><p class="MsoListParagraphCxSpLast"><span style="font-size: large;"> </span><span style="font-size: large;"><i><span style="color: black; font-family: "Arial",sans-serif; mso-fareast-font-family: "Times New Roman"; mso-themecolor: text1;">This is a great question
because it costs a lot of money to support formulary review.<span> </span>Pharmacists often depend on the sponsor to
generate additional data beyond what’s in the approval package – sometimes even
assembling the information for the hospitals. </span></i></span><span style="font-size: large;">
</span></p><p class="MsoNormal" style="background-attachment: scroll; background-clip: border-box; background-image: none; background-origin: padding-box; background-position: 0% 0%; background-repeat: repeat; background-size: auto;"><span style="background-color: white;"><span style="font-size: large;"><span style="color: black; font-family: "Arial",sans-serif; mso-fareast-font-family: "Times New Roman"; mso-themecolor: text1;">DS here – In my view, Pasteur
will have to have a contractual mechanism obligating sponsors to support
formulary decisions in hospitals. </span></span></span></p><span style="font-size: large;">
</span><p class="MsoListParagraph" style="mso-list: l0 level1 lfo1; text-indent: -.25in;"><span style="font-size: large;"><span><span>4.<span style="font-family: "Times New Roman"; font-feature-settings: normal; font-kerning: auto; font-language-override: normal; font-optical-sizing: auto; font-size-adjust: none; font-stretch: normal; font-style: normal; font-variant: normal; font-variation-settings: normal; font-weight: normal; line-height: normal;">
</span></span></span>If I am HHS, how will I determine how many doses
to order and how do you see price negotiations progressing? </span></p><span style="font-size: large;">
</span><p class="MsoNormal" style="background: white; margin-left: .25in; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto;"><span style="font-size: large;"><i><span style="color: black; font-family: "Arial",sans-serif; mso-fareast-font-family: "Times New Roman"; mso-themecolor: text1;">This
is an open question I have – and where I could see things breaking down if
there isn’t a normal competitive market to supplement the subscription.<span> </span>The only super clear number to me is there
will be an annual payment and the totals for all payments will range from $750M
- $3B.<span> </span>Also, revenues from federally
insured will be subtracted, but at what unit price?<span> </span>The only information is a price floor, which
I assume is there to avoid enticing use over expensive generics like
carbapenems.<span> </span></span></i></span></p><span style="font-size: large;">
</span><p class="MsoNormal" style="background: white; margin-left: .25in; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto;"><span style="font-size: large;"><i><span style="color: black; font-family: "Arial",sans-serif; mso-fareast-font-family: "Times New Roman"; mso-themecolor: text1;">If
there is a set number of doses that must be available, that imputes a price per
course.<span> </span>If the number of doses that must
be available is determined based on disease prevalence, then could that entice
people to go for the rarest condition as long as it qualifies for the highest
reward? – why? - if I only have to supply super small numbers – I don’t have to
worry about cost of goods, re-stocking, or frequent pharmacovigilance
reporting…</span></i></span></p><span style="font-size: large;">
</span><p class="MsoNormal" style="background: white; margin-left: .25in; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto;"><span style="font-size: large;"><i><span style="color: black; font-family: "Arial",sans-serif; mso-fareast-font-family: "Times New Roman"; mso-themecolor: text1;">It
would be important to see just a bit more detail on the proposed mechanics here.<span> </span>For a number of scenarios I can picture,
having some component of a normal competitive market may help counteract some
behaviors I could see going awry in a subscription-only incentive world.</span></i></span></p><span style="font-size: large;">
</span><p class="MsoNormal" style="background: white; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto;"><span style="font-size: large;"><span style="color: #222222; font-family: "Arial",sans-serif; mso-fareast-font-family: "Times New Roman";">6. If I am a sponsor, how will this
effect my development, post-approval development and marketing plans?</span></span></p><span style="font-size: large;">
</span><p class="MsoNormal"><span style="font-size: large;"><i><span style="color: black; font-family: "Arial",sans-serif; mso-fareast-font-family: "Times New Roman"; mso-themecolor: text1;">If PASTEUR passed tomorrow,
for me at least - I’d say no change right away to the pipeline focus.<span> </span>It will take quite a bit of time to spin up
the committees and see how the different tiers are defined.<span> </span>There’s even some funding to bridge that
initial period – Pandemic stockpile purchases and contracts that could provide
post-market development support.</span></i></span></p><span style="font-size: large;">
</span><p class="MsoNormal"><span style="font-size: large;"><i><span style="color: black; font-family: "Arial",sans-serif; mso-fareast-font-family: "Times New Roman"; mso-themecolor: text1;"> </span></i></span><span style="font-size: large;"><i><span style="color: black; font-family: "Arial",sans-serif; mso-fareast-font-family: "Times New Roman"; mso-themecolor: text1;">We need to see how this
committee values different attributes – of course we can all predict the types
of things that would drive value of an award.<span>
</span>HABP/VABP label > cUTI/cIAI; including non-fermenters is a higher
value tier. </span></i><span style="color: black; font-family: "Arial",sans-serif; mso-fareast-font-family: "Times New Roman"; mso-themecolor: text1;">(From DS – an oral cUTI drug
active against high priority pathogens would also be1st tier I would think).<i>
<span> </span>But nuances around narrow vs. broad
spectrum (do I just need 1 non-fermenter or many?), what discounts apply to the
almost infinite spectrum of safety considerations, and my fear novel mode of
action, and not novel spectrum of activity will be the definition of novel
could swing the incentive structure quite dramatically.</i></span></span><span style="font-size: large;">
</span></p><p class="MsoNormal"><span style="font-size: large;"><i><span style="color: black; font-family: "Arial",sans-serif; mso-fareast-font-family: "Times New Roman"; mso-themecolor: text1;"> </span></i></span><span style="font-size: large;"><i><span style="color: black; font-family: "Arial",sans-serif; mso-fareast-font-family: "Times New Roman"; mso-themecolor: text1;">So I’d do what I’ve always
done – keep a diverse pipeline of assets at different stages of maturity so you
can pivot as the rules change.<span> </span>Perhaps
some pipeline programs that clearly have no hope in the current reimbursement
environment (say a narrow-spectrum inpatient only program) you might push a
little further along at risk if legislation passes – but otherwise no immediate
change until we see how value is defined.</span></i></span><span style="font-size: large;">
</span></p><p class="MsoNormal"><span style="font-size: large;"><i><span style="color: black; font-family: "Arial",sans-serif; mso-fareast-font-family: "Times New Roman"; mso-themecolor: text1;"> </span></i></span><span style="font-size: large;"><i><span style="color: black; font-family: "Arial",sans-serif; mso-fareast-font-family: "Times New Roman"; mso-themecolor: text1;">Post-approval plans – it
seems obvious that one of the goals of PASTEUR would be to provide some
incentive for label expansion.<span> </span>While
it’s not explicitly stated, there is language around ‘upgrading’ your
subscription tier at a later date.<span> </span>So
for example if I come up with a drug active against CRE/CRAB/CRPA and initially
develop it in cUTI, say that gets me the middle tier – but if I get a HABP/VABP
indication later, I get the higher tier.<span>
</span>I do like that it creates incentives to keep studying the drug post
approval – I know physicians want this.<span>
</span>It will be interesting to see if that could incentivize any adverse
behaviors – for example delays to market:<span>
</span>HABP/VABP labels typically come several years after initial approval –
so is it better to delay approval 5 years for 5 more years of top tier payments
or get my 5 years of cUTI payments and then take 5 of the top tier?</span></i></span><span style="font-size: large;">
</span></p><p class="MsoNormal"><span style="font-size: large;"><i><span style="color: black; font-family: "Arial",sans-serif; mso-fareast-font-family: "Times New Roman"; mso-themecolor: text1;"> </span></i></span><span style="font-size: large;"><i><span style="color: black; font-family: "Arial",sans-serif; mso-fareast-font-family: "Times New Roman"; mso-themecolor: text1;">Again in the immediate
term, it looks like there will be PBS-style contracts to bridge those companies
that are nearing approval now – so I’d focus on making sure I’m in position for
those as the idea is they’d cover the post-approval costs and purchase some
drug to bolster initial revenues while we sort the rest of this out!</span></i></span><span style="font-size: large;">
</span></p><p class="MsoNormal"><span style="font-size: large;"> </span></p><span style="font-size: large;">
</span><p><style><font size="5">
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{margin-bottom:0in;}</font></style></p>David Shlaeshttp://www.blogger.com/profile/00228776693058791618noreply@blogger.com0tag:blogger.com,1999:blog-4287560491211025099.post-52208816062145499972020-09-10T09:59:00.000-04:002020-09-10T09:59:57.626-04:00AMR and Europe - What Happened?<p><span style="font-size: large;"></span></p><div class="separator" style="clear: both; text-align: center;"><span style="font-size: large;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEidHZzSZkoLY4vVfRhK6eKQhnq4TWOh87kmArnuPy1Vut6K4xv-Aw5N9pTvjHB6B2kKlAIXNklaT2VZB2miti5HKrEQ1xgVqi87Am8ggUdjupka81117arZvnZdMj0OU47WtVZXaNNqQno/s408/amr+solutions.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="123" data-original-width="408" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEidHZzSZkoLY4vVfRhK6eKQhnq4TWOh87kmArnuPy1Vut6K4xv-Aw5N9pTvjHB6B2kKlAIXNklaT2VZB2miti5HKrEQ1xgVqi87Am8ggUdjupka81117arZvnZdMj0OU47WtVZXaNNqQno/s320/amr+solutions.jpg" width="320" /></a></span></div><span style="font-size: large;"><br /><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjk5xrEpLUu4L8EHVZhtblP5AtyodtuXCmaSbY-RtFrhwFZJRAp6rDpiMGJUJCF6ApspzlHGtTFfnklhwyQhWTDyerfNmnTKu0Z9s4OhfYzrLhsDXUeopDIzFT5ez9SKP3yVzHZ8DNbuFI/s428/EMA_European_Medicines_Agency_logo.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="147" data-original-width="428" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjk5xrEpLUu4L8EHVZhtblP5AtyodtuXCmaSbY-RtFrhwFZJRAp6rDpiMGJUJCF6ApspzlHGtTFfnklhwyQhWTDyerfNmnTKu0Z9s4OhfYzrLhsDXUeopDIzFT5ez9SKP3yVzHZ8DNbuFI/s320/EMA_European_Medicines_Agency_logo.jpg" width="320" /></a></div><br /><br /> <span style="font-family: Cambria, serif;">Like many of you, I recently received a</span><span style="font-family: Cambria, serif;"> </span><a href="https://amr.solutions/2020/09/07/new-antibiotics-are-not-being-registered-or-sold-in-europe-in-a-timely-manner/" style="font-family: Cambria, serif;"><span style="color: red;">notification</span></a><span style="font-family: Cambria, serif;"> </span><span style="font-family: Cambria, serif;">from John Rex and Kevin Outterson regarding the fact that many recently approved antibiotics will not be marketed in Europe. At first glance, I assumed that these products were simply unable to obtain a price that would provide for a return on investment leading the companies to abandon the European marketplace. But, based on the information provided by Rex and Outterson, its more complicated and more discouraging than that.</span></span><p></p><p class="MsoListParagraphCxSpFirst" style="font-family: Cambria, serif; margin: 0in 0in 0in 0.5in;"><span style="font-size: large;"><o:p></o:p></span></p><p class="MsoListParagraphCxSpMiddle" style="font-family: Cambria, serif; margin: 0in 0in 0in 0.5in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoListParagraphCxSpMiddle" style="font-family: Cambria, serif; margin: 0in 0in 0in 0.5in;"><span style="font-size: large;">To go back in time, during the struggles at the FDA starting around 2000, Europe almost seemed like a haven of regulatory bliss for antibiotic developers. Many of you will remember how antibiotics almost always were approved in Europe one or more years after their approval in the US during the last part of the last century. We viewed Europe as slow, cumbersome and driven by inconsistent and often academic concerns. But these perceived faults were clearly overcome when Europe became a regulatory haven as an alternative to an FDA that had lost its way. <o:p></o:p></span></p><p class="MsoListParagraphCxSpMiddle" style="font-family: Cambria, serif; margin: 0in 0in 0in 0.5in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoListParagraphCxSpMiddle" style="font-family: Cambria, serif; margin: 0in 0in 0in 0.5in;"><span style="font-size: large;">During my consulting years, that covered the worst of the FDA antibiotic crisis, I often advised my clients to work through European regulators primarily and put the FDA aside or at least on a lower priority in terms of trying to negotiate clinical trial designs that could lead to approval. My clients, perhaps correctly, noted that they would have a difficult time obtaining a return on their investment without the US market and as such, the FDA became a key hurdle for them to overcome. Unfortunately, years were lost in that struggle as were several of my clients. <o:p></o:p></span></p><p class="MsoListParagraphCxSpMiddle" style="font-family: Cambria, serif; margin: 0in 0in 0in 0.5in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoListParagraphCxSpMiddle" style="font-family: Cambria, serif; margin: 0in 0in 0in 0.5in;"><span style="font-size: large;">Then, in 2012, the FDA awoke from their state of hibernation realizing that the antibiotic pipeline had all but disappeared under their regulatory restrictions – especially for antibiotics targeting pneumonia and other serious infections. They quickly established new regulatory pathways that are more efficient and rapid for new antibiotics addressing resistant infections. <o:p></o:p></span></p><p class="MsoListParagraphCxSpMiddle" style="font-family: Cambria, serif; margin: 0in 0in 0in 0.5in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoListParagraphCxSpMiddle" style="font-family: Cambria, serif; margin: 0in 0in 0in 0.5in;"><span style="font-size: large;">And here we are in 2020. Our antibiotic pipeline remains in shambles mainly due to a lack of a sufficient marketplace. But we must remember that “sufficient” depends on costs to get there and stay there. And costs, often, still depend greatly on the regulators. <o:p></o:p></span></p><p class="MsoListParagraphCxSpMiddle" style="font-family: Cambria, serif; margin: 0in 0in 0in 0.5in;"><o:p><span style="font-size: large;"> </span></o:p><img border="0" data-original-height="97" data-original-width="250" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhKNR0uhJkLXVYpz5ceCK9PMxbo8cgIx__L35uw4ioNiI8zBteNw861T9h7Qy-oZRE22DHOVjIr5K3RxGXi9D6V-3ihFdnhBdjKFz_mfO_tDmK31NcxVeFqf9-6gKkAeSc64cpL3CHppVA/s0/nabriva.png" /></p><p class="MsoListParagraphCxSpMiddle" style="font-family: Cambria, serif; margin: 0in 0in 0in 0.5in;"><span style="font-size: large;">Nabriva will not market Lefamulin in Europe partly because it is unable to find a commercial partner to drive sales. But more ominous in their recent <a href="https://www.sec.gov/ix?doc=/Archives/edgar/data/1641640/000155837020009653/nbrv-20200630x10q.htm"><span style="color: red;">SEC</span></a> filing is the statement that they may not be able to continue to survive at all given marketing restrictions associated with covid plus outstanding obligations and debt. <o:p></o:p></span></p><p class="MsoListParagraphCxSpMiddle" style="font-family: Cambria, serif; margin: 0in 0in 0in 0.5in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoListParagraphCxSpMiddle" style="font-family: Cambria, serif; margin: 0in 0in 0in 0.5in;"><span style="font-size: large;">Plazomicin has been withdrawn from Europe apparently because the costs of the pediatric trials required in Europe “exceed all estimates of potential sales” in the region. <o:p></o:p></span></p><p class="MsoListParagraphCxSpMiddle" style="font-family: Cambria, serif; margin: 0in 0in 0in 0.5in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoListParagraphCxSpMiddle" style="font-family: Cambria, serif; margin: 0in 0in 0in 0.5in;"><span style="font-size: large;">Eravacycline is the victim of the financial difficulties of its parent company, Tetraphase, its limited indication and its relatively poor advantages compared to competing products. <o:p></o:p></span></p><p class="MsoListParagraphCxSpMiddle" style="font-family: Cambria, serif; margin: 0in 0in 0in 0.5in;"><o:p><span style="font-size: large;"> </span></o:p><img border="0" data-original-height="183" data-original-width="275" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiHYG9ZPwM2mPqz2Dhk1tmgEcSqeJWU728PVR_vpJbhwM3jDsnRU5vzq9fIE5D7g6cwsdRvO1gzMbpFuP3pKc1kcpz-9XfnZNEtVmhDvkofchC6cz-vNybjpoSpCHMrFuSq29pX4WqSirM/s0/paratek+logo.png" /></p><p class="MsoListParagraphCxSpMiddle" style="font-family: Cambria, serif; margin: 0in 0in 0in 0.5in;"><span style="font-size: large;">Paratek's omadacycline was withdrawn from consideration in Europe because the EMA <a href="https://www.ema.europa.eu/en/medicines/human/withdrawn-applications/nuzyra"><span style="color: red;">insisted</span></a> on a second trial in community-acquired pneumonia. Omadacycline was approved in the US based on two successful trials in skin infection and a single trial in pneumonia consistent with FDA guidelines for approval in both indications. FDA <a href="https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2018/209816Orig1s000,209817Orig1s000Ltr.pdf"><span style="color: red;">approved</span></a> omadacycline for both indications but requested a second pneumonia study as a post-approval obligation. <o:p></o:p></span></p><p class="MsoListParagraphCxSpMiddle" style="font-family: Cambria, serif; margin: 0in 0in 0in 0.5in;"><o:p><span style="font-size: large;"> </span></o:p></p><p class="MsoListParagraphCxSpLast" style="font-family: Cambria, serif; margin: 0in 0in 0in 0.5in;"><span style="font-size: large;">In the case of both omadacycline and plazomicin, the regulators have doomed the products for the European market. Some may argue that these products do not deserve to be marketed given the availability of other agents. In fact, for omadacycline, that almost seems to be what the EMA is saying. On the other hand, the regulatory hurdles to the marketplace in Europe now become yet another nail in the coffin of new antibiotic investment in research and development. After placing so much hope in European regulators, I find I am profoundly disappointed in their actions. </span><o:p></o:p></p>David Shlaeshttp://www.blogger.com/profile/00228776693058791618noreply@blogger.com0