I am moving my blog

 You can find archived articles and new blogs on davidshlaes.substack.com.  Blogger has just become too restrictive. I apologize for any inconvenience. 

Antibiotic Biotech Execs Share Their Concerns

 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.  My original question rapidly became irrelevant. (Since some executives asked to remain nameless, I am keeping everyone anonymous). 

 

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.” 

 

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 successful asset that the market is literally valuing at $20M at best?”

 

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.”

 

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!”

 

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. 

 

 

The Fate of Another Antibiotic Biotech - Nabriva

 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?  Whatever the cause, this is another blow to the world of antibiotic R&D.

 

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. 

 

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. 

 

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.

 

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. 

The Grinch Stole PASTEUR

 Antibiotic resistant infections are rising.  Deaths from these infections are rising.  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. 

 

The perfect storm has intensified since I wrote my book (Antibiotics – the Perfect Storm) back in 2010. 

 

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. 

 

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. 

 

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. 

 

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. 

 

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.

 

PASTEUR, Do or . . .

 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.  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.  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.  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.  You’ve got to be kidding, right?  This does not even amount to a rounding error. 

 

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. 

 

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. 

 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.

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. 

Why Antibiotics Don't Work - Implications for Clinical Trial Design

 

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. 

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 . . .

 

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. 

 

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. 

 

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. 

 

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?

 

Let’s look at one example - serious infections caused by Staphylococcus aureus.  Disseminated infections withS.aureus 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. 

 

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. 

 

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. 

 

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. 

ASM Microbe - Antimicrobial Agents and Resistance

 Guest Blogger

Krisztina M. Papp-Wallace

 

Introducing the ASM Microbe 2022 Antimicrobial Agents and Resistance Program

 

Dear AAR community,

 

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.!

 

Please register today: https://asm.org/Events/ASM-Microbe/Registration

 

Pull Incentives for Antibiotic R&D and Private Investment

 John Rex (thank you) just sent out an email highlighting a paper 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.  They are not new.  They are not surprising.  And I think I understand what I’m thinking . . .

 

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?

 

As I’ve noted previously, 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. 

 

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. 

 

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 trouble. 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 imminent.  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.  

 

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. 

 

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.

 

 

 

 

The Future of Antibiotics

 Spoiler alert – get out the anti-depressants.

 

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 post, 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 . . .

 

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.  

 

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 some other more secure field. Those expert consultants who were approaching or had passed retirement age back in 2022 are no longer available to help. 

 

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. 

 

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 expertise.  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. 

 

What about public-private partnerships?  Sure.  But you must have the funding for the private part . . .I rest my case. 

 

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. 

This is urgent.  This needs to change now!

 

Entasis, Antibiotics and the Dodo

 

And again! Entasis Therapeutics has been 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. 

 

Entasis 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 pipeline 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. 

 

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).  

 

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. 

 

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 1.7 million deaths per year globally with most coming from lower respiratory infections. Our antibiotic pipeline to deal with the problem of resistance remains pathetic. 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.  

 

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. 

 

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.” 

 

The US dithers, Europe ponders and the extinction of life-saving antibiotics continues apace. 

To have functioning public health in the US, we must first have national healthcare.

 

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) (1,2). 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.

 

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.)

 

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. 

 

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, 

A recent viewpoint article 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 conclusions.

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. 

 

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. 

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. 

 

 

Covid - Thank you to industry - Please do the same for AMR.

 

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! 

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!

The Pasteur Act, 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.  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.  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. 

 

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. 

 

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.

 

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. 

 

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. 

 

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.  

 

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. 

 

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.  

 

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. 

 

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!

 

 

Pull Incentives for AMR - Where is Biden?

 This will be a short note . . .

We are about to dedicate an entire ASM/ESCMID 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?

 

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 summary 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. 

 

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 comments 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.

 

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. 

Pull Incentives at ASM/ESCMID

 

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. 

 

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 Pasteur Act and the 21^stCentury Cures Act 2.0. Europe has requested public comments on a proposal to provide pull incentives of some sort as well. 

This year, the ASM/ESCMID 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.  

The experts presenting the morning of December 8 include, 

Christine Ardal (Institute of Public Health, Norway),

Louise Norton-Smith, M.A., (Head of Global AMR Strategy, U.K. Department of Health and Social Care), 

Kevin Outterson, J.D., (Boston University, School of Law, Boston, Mass), 

Beth Woods, MSc., (Centre for Health Economics, University of York, U.K.),

Colm Leonard, M.D., (National Institute for Health and Care Excellence UK), 

Nick Crabb Ph.D., (National Institute for Health and Care Excellence UK),

Emily Wheeler, (Biotechnology Innovation Organization), 

Helen Boucher, M.D., FACP, FIDSA, (Interim Dean Tufts School of Medicine, IDSA Officer).

 

Clearly the speakers and panel could hardly be of greater quality.  

 

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. 

 

Since any pull incentive, to be effective, must be large ($2-4 billion), who should bear the financial burden of such pull incentives? 

 

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?

 

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. 

 

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? 

 

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. 

 

 

 

Europe, Antibacterials, Pull Incentives and Access

  

 

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. [Sweden - Zerbaxa (ceftolozan-tazobactam), Recarbrio (imipenem-cilastatin-relebactam), Fetcroja (cefiderocol), Vaborem (meropenem-vaborbactam) and Fosfomycin infectopharm (fosfomycin).  UK - cefiderocol (Fetcroja) manufactured by Shionogi, and ceftazidime with avibactam (Zavicefta)]. This is also a good argument for a European approach (Brexit notwithstanding). 

 

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.  

 

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. 

 

Innovation vs. Clinical Utility

 

Many have proposed that innovation be a key criterion for awarding a significant pull incentive to a sponsor. How could that be defined?

 

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. 

 

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. 

 

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 (diazabicyclooctane) or boron chemistry (see Entasis, VenatoRx and Qpex). 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. 

 

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, Entasis).  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.

 

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?

 

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. 

 

Access and EMA

 

In thinking about Europe, I must turn to the new European Medicines Agency. In brief, the US FDA learned 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 requirement 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.