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