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. 

 

 

Monday, December 13, 2021

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!

 

 

Thursday, December 2, 2021

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.