Monday, October 10, 2022

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. 

Monday, August 22, 2022

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. 

Tuesday, April 12, 2022

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

 




Monday, March 28, 2022

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.

 

 

 

 

Monday, February 14, 2022

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!

 

Monday, February 7, 2022

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. 

Monday, January 31, 2022

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.