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. 

 

 

 

 

 

 

 

 

Empiric broad spectrum antimicrobial therapy is here to stay.

 Recent discussions on the economics of innovation in rapid diagnostic testing for bacterial infections in the hospital setting have inspired me to once again take pen (keyboard) in hand. In most of these discussions, the key variable in the utility of any diagnostic test has been ignored. I’m talking about basic aspects of physician thinking and behavior, 

 

The basic premise is that if accurate, bedside tests were available either in the hospital or in the physician’s office, we could avoid broad spectrum empiric antibacterial therapy and focus on the specific pathogen causing the infection. There are, though, a number of flaws that undermine this premise. The first is that antibacterials that are more specific for either pathogens or resistance mechanisms exist and can replace so-called broad-spectrum agents. In general, this is simply not true. Even amoxicillin, to which there is a high level of resistance among Gram-negatives, has a relatively broad spectrum.  The other assumption is that reducing the use of “broad-spectrum” antibacterials and increasing the use of pathogen-specific antibacterials will lead to a slower rate of rise of resistance.  While this may be a reasonable hypothesis, the quantitative effect remains to be determined and there will be other variables at play (eg – how long did it take for vancomycin resistance to emerge in the clinic?). 

 

The other part of the discussion is economic. It seems that the technology to provide rapid tests capable of identifying pathogens in primary specimens such as blood, sputum and urine exist today.  But the investment to bring them to market is much greater than the projected market since it is likely to be cheaper to use “broad-spectrum” empiric therapy than it would be to use the diagnostic tests to narrow therapy assuming such pathogen-specific therapy existed.  The implication is that broad-spectrum empiric therapy is “bad.” We need to understand that a  major reason for this lack of a market is based on well-justified physician hesitancy.

 

An additional issue relates to hospital and physician practice logistics. As I have noted in the past, if the diagnostic is not easily used (like a covid antigen test or a strep test for e.g.) and is designed to be carried out in a laboratory, there is the delay between obtaining the specimen, transportation to the lab, carrying out the test and reporting the result. In most cases, this delay would eliminate the potential advantage of the rapidity of the test. 

 

But let’s talk about physician behavior. Speaking as a physician who has spent time in the ICU caring for critically ill patients, I think I am qualified to address this issue. I admit that this experience is now quite dated. But in recent years I spent time working in a local hospital on antimicrobial stewardship and based on that experience, I don’t think things have changed that much since my own ICU attending days. 

 

Physicians see patients as individuals and the take their responsibility for each one extremely seriously. When a patient becomes acutely and severely ill in the hospital and where infection is a likely cause, I am not sure that even a reliable bedside test would be enough to prevent a physician from using additional or broad-spectrum antimicrobial therapy to be sure that all pathogens, likely and not so likely, will be attacked. 

 

Our best approach, in my view, will be to discontinue antibiotic therapy as soon as we can based on good clinical evidence.  Unfortunately, that evidence is still lacking for many infections.  It goes without saying that in the absence of further evidence of bacterial infection in the cold light of day, antibiotics should be discontinued in any case. 

 

This approach is validated by multiple clinical guidelines discussing appropriate empiric antibiotic therapy for various infections. I don’t see physicians changing their approach to empiric antimicrobial therapy of severely ill hospitalized patients regardless of the accuracy or rapidity of new diagnostic tests – and I’m not sure they should change.

 

 

Antibiotic Strategies for Success - A Bridge to Nowhere?

 This blog was inspired by a recent conversation with a CEO of a clinical phase antibiotic biotech. Among other things, we pursued a discussion of various strategies that companies developing antibiotics might pursue to avoid post-approval bankruptcy (the “no good deed shall go unpunished” avoidance strategy). 

 

Have a portfolio of antibiotics covering various groups of pathogens – all where there is medical need.  This could include an orally available drug active against resistant Gram positives, an oral plus IV drug active against resistant urinary pathogens, an IV only drug active against hospital acquired pneumonia, etc. The problem with this strategy is the existing, (relatively) inexpensive and diverse antibiotic armamentarium combined with the relatively small number of patients with high medical need.   Caveat - a large PhRMA that needs additional products for a limited hospital sales force might be interested in such a portfolio - post-launch (e.g. Pfizer and the AZ antibiotics).

 

Market your antibiotics as drugs for rare diseases and garner a very high price per course of therapy. This strategy will smack into the wall of hospital budgets, the history of antibiotic commercialization globally and the general under-valuation of antibiotics. 

 

What if you offered the possibility of empiric in-hospital IV therapy that included not only all other resistant Gram-negative pathogens (like metallo-B-lactamase producers and Pseudomonas) but also highly resistant Acinetobacter?  Would that be enough to provide a return on your investment?  I’m not sure given the low numbers of highly resistant Acinetobacter infections encountered by physicians. 

 

 How about if you balance your antibiotic portfolio with drugs targeting other diseases? But then what priority would your antibiotic projects garner? Why would you need an antibiotic portfolio at all? 

 

Sorry.  These strategies all seem to me like bridges to nowhere. . .

 

To all you antibiotic biotech CEOs out there, I only see a single strategy that will work. We must provide a market incentive for the approval and commercialization of needed new antibiotics that is of such size that large PhRMA will once again pursue these drugs and the small companies that develop them. I just don’t see any other choice that will incentivize private investment and provide a welcoming environment for antibiotic R&D once again. 

 

Not only that, but I only see a single choice in terms of a country or region that could provide such an incentive – the good old US of A! Europe has the resources as a region with a population of 500 million and a GDP of $19 trillion (in 2019).  But it has demonstrated that it does not have the competence to provide a unified strategy across all 27 national authorities. Not only that, but the judgement of the European Medicines Agency has also been brought into question with the decision of two antibiotic biotechs not to market their products in Europe because EMA’s regulatory requirements exceeded the market value of the projects under discussion. 

 

This leaves us with the US with its GDP or $21 trillion. Total spending on healthcare in the US is estimated to be $3.8 trillion (2019 numbers).  US government spending on healthcare approaches $2 trillion.  So, an incentive approaching $4 billion for up to 2 new and needed antibiotics per year would be a rounding error in our national budget. But, whether we like it or not, something like this is the only way forward to assure that we have an adequate antibiotic pipeline for today and for tomorrow. Without this, antibiotic biotechs are doomed to financial failure sometime in the several years following product launch.  As more antibiotic biotechs fail in this manner, the limited investment that still exists for antibiotic R&D will completely disappear. 

 

The AMR Action Fund, now over $1 billion, is dedicated to driving deserving antibiotic projects through late stage, expensive, clinical development to regulatory approval.  When the fund was announced, the sponsors warned that their effort was merely a holding strategy and that market incentives would be required to support a sustainable antibiotic pipeline. I can only laud their effort and echo their warning.  I don’t see any other viable strategy . . . .

 

 

 

 

 

 

 

 

Pull American - Why Not?

 In a sleepy moment I had an inspiration. Funding a pull incentive for antibiotic R&D in the US (like a market entry reward for example) would be more attractive to our representatives in congress if we required that all manufacturing and supply chains for the beneficiary product be physically located in the US. Great idea, right?  Not exactly.

 

I raised this with two biotech CEOs. Both, politely, told me I was out of my mind. The US currently does not have a sufficient small molecule manufacturing infrastructure to either provide for the entire manufacturing chain from API to finished product nor do we have sufficient availability of raw materials here. This is an especially acute problem for the manufacture of B-lactams (like penicillins and cephalosporins) which must be physically separate from all other drug manufacturing facilities because of concerns over allergic reactions.

 

This then leads to another thought. The US needs to invest in pharmaceutical manufacturing infrastructure. Now there’s a novel idea . . .. (??). The investment must include everything from provision of raw materials to manufacture of finished drug product, packaging and labeling. When I first started working in the industry in the 1990s, we were actually able to do this for some drugs, but rarely for B-lactams. My understanding is that today, as a result of competition from places like India, China and even the UK and Europe, US small molecule pharmaceutical manufacturing is nothing like it was 25 years ago. Of course, the problem is not just an antibiotics issue – this problem extends to all drug classes. And the US is not the only country that wants its drug supply chain to be domestic – India and China often insist on it. The global experience with the manufacture and distribution of vaccines for covid have emphasized the urgency of this problem. 

 

 This topic has been the subject of a number of articles (1,2,3) and of a report from the FDA.  Last year, the FDA released data on drug manufacturing. Only 28% of API (raw drug powder) for the US market is manufactured in the US while the EU, China and India account for most of the rest. I have not seen data on the global distribution of the supply of raw materials for API production – but I suspect that again there are few US suppliers. Forty-six percent of the final drug product (the pills or vials that are actually used) for the US market is made in the US.  I have not seen similar data specific for antibiotic manufacture, but I suspect the situation is no better and may be worse. 

 

Of course, adding US manufacturing capacity to bolster our domestic drug supply chain is a good idea.  All that is required is money.  In the case of antibiotic manufacture, the need may be even more critical. 

 

 

 

 

 

The Pew Trust Analysis of the Antibacterial Pipeline

 

The Pew Charitable Trust just posted their analysis of the antibacterial pipeline.  They provide two separate analyses, one for antibiotics and the other for non-traditional therapies. 

 

I will ignore entirely whether the pipeline products were considered to be innovative or not since I am focused solely on their potential clinical utility. 

 

Of 43 antibiotics in development, 17 are phase 2 and beyond. Of those, only five target resistant Gram-negative pathogens. One compound in phase 3 is solithromycin, an old and controversial ketolide antibiotic being investigated for treatment of gonorrhea.  Another more innovative compound in phase 3 for the treatment of gonorrhea is zoliflodacin.  (I was on the advisory board for GARDP, a co-developer of the compound). Of the six antibiotics in phase 2 development, five target C. difficile. 

 

For those antibiotics that target resistant Gram-negative pathogens, what will their ultimate market look like? Some have already suggested there is really only room for one such compound given the number of patients available for treatment. I can’t help but wonder what the investors in these companies and independent market analysts think about their chances of commercial success.  Or is everyone betting on a significant pull incentive for their product? 

 

The same comment might apply for all those phase 2 compounds targeting C. difficile.  Here the market probably revolves around efficacy in preventing recurrence following initial therapy. But how many products can this market support and at what price? Again, I am curious to understand the thinking of these companies, their investors, and market analysts.

 

The non-traditional therapies include 19 products in phase 2 or beyond. One is an interesting immunomodulator from AtoxBio for the treatment of sepsis and organ failure in patients suffering from necrotizing fasciitis. The company has filed an NDA based on somewhat mixed data.  To me, this is potentially the most interesting, novel and more importantly, useful of the late-stage non-traditional pipeline products. (I used to consult for them). Two compounds are lysins targeting S. aureus infections. Two are orally non-absorbable antibiotic inactivators to prevent C. diff or other resistant infections. A number of antibodies targeting bacterial virulence or toxins are on the list. Five compounds modulate the microbiome – but to what end? Of the 19 non-traditional products in late-stage development five target resistant Gram-negative infections. 

 

For the non-traditional therapies, we come down to two related issues.(See my previous blog on this here).   One revolves around clinical considerations in terms of how these products will be used by physicians to treat infected patients and whether the products offer clear clinical advantages.  This also becomes a regulatory question. Can these products be used as stand-alone therapy? If not, will sponsors need to provide superiority data? Then there is the issue of whether the non-traditional therapy offers clear advantages over other products with similar targets already marketed at a low price. This seems especially important in the case of products targeting C. diff and those targeting Gram-negative infections as noted above. 

 

While I have my own thoughts and biases regarding particular products in the antibacterial pipeline, I want to simply consider here whether this pipeline, given normal attrition rates, is adequate to our needs. If our unmet needs include, most importantly, resistant Pseudomonas and Acinetobacter infections, the answer is a resounding NO! There are only two late-stage antibiotics in the pipeline addressing these infections! Among late-stage non-traditional products, there are virulence inhibitors targeting Pseudomonas and bacteriophage capable of targeting these pathogens. But the use of such virulence inhibitors in clinical practice, for me, remains somewhat opaque.  Bacteriophage therapy seems promising, but so far seems limited to an almost case-by-case custom therapy approach similar to some cancer therapies. So, again, this pipeline, to address Paseudomonas and Acinetobacter, is NOT adequate.  But then,  neither is the market available to support such products without a significant pull incentive.  

 

Am I starting to sound like a broken record?  (You remember vinyl, right?) 

 

 

 

Pull Incentives and AMR - Is Europe up to the Task?

 I have been saying for years that for a pull incentive to actually function as an incentive, it must be large enough to motivate investors and large pharma to get back into antibiotic R&D. This will take a $2 (to $4) billion commitment for each priority drug approved regardless of how this goal is achieved. This could be a market entry reward, a transferable patent exclusivity reward (still my favorite), an antibiotic susceptibility bonus, a subscription payment regardless of use, etc. 

 

Years ago, DRIVE-AB, a European effort looking at potential incentives for antibiotic R&D suggested that countries “pilot” various models.  In fact, several countries are now doing just that.  France has had a DRG carve out for certain hospital antibiotics for years.  Germany just introduced such a carve out last year.  Has this increased the market for antibiotics in either country?  I don’t think so. Sweden is piloting a subscription model – but the money committed is not publicly available.  The UK (no longer part of Europe) is also piloting a subscription model committing up to  £10 million per year for up to 10 years per product.  It is claimed that this will constitute the UK’s fair share of the overall antibiotic market in terms of their commitment to a subscription type pull incentive. Of course – that is only meaningful if many other countries join since the UK accounts for something like 3% of the total market. But what does “pilot” mean exactly.  What is the endpoint?  How will we judge success or failure? Is success defined by the sponsor somehow in terms of market increase? And how would that be defined?  Is success defined by the national authority in terms of value of therapy?  What if the country has very few resistant infections like Sweden?  How will they define “value?” I admit that, at the time, sitting in the DRIVE-AB conference room in the Netherlands, I did not understand this concept – and I still don’t.

The other issue is that each country picks different antibiotics for its incentive. That just dilutes the market and makes no sense. 

In my view, the goal of a pull incentive is to provide a significant return on investment for companies who pursue antibiotic R&D and succeed. This, in turn, will motivate investors to invest in the area. No matter how I look at this problem, it seems like the only way that such a large pull incentive will come to pass is if a region or country takes a leadership position and provides an incentive that will work globally.  Once that occurs, we can work to bring other countries on board.  But until then, I think we are stuck in incentive purgatory. The Table below shows the 2017 (pre-Brexit, pre-Covid) GDPs of Western countries and Europe including the UK, Sweden and Germany. Clearly either Europe as Europe or the US are the best positioned to offer such an incentive just based on the size of their respective economies. 

 

 

GDP by country

 

Country/Region 2017 (Trillion USD) USA                19.5 Europe (pre Brexit) 13.0 UK                          2.6 Sweden                  0.5 Germany                  3.7

 

This brings me to a discussion of the possibility that Europe will take on this task. And every time I think about this, I go back to Flora Lewis’ book, Europe, A Tapestry of Nations. And there is no better example of the contemporary issues facing Europe’s ability to bring together its national authorities than their botched approach to providing covid vaccine for their population.  This problem has been analyzed in detail by Politico Europe and their analysis should be a wake-up call to all in Europe as to the continuing shortcomings of the alliance. According to the article, Europe was late coming to the table.  They even supplanted an alliance of four national authorities who had already begun negotiations for vaccines for their countries to restart negotiations for Europe. This resulted in further delay.  Then they negotiated a price well below what the US, Israel and others were paying – which may have dropped them further down the priority list for vaccine suppliers.  This is to say nothing of their clear preference for Europe-based vaccine companies like Sanofi that ultimately were unable to provide any supply in time. Then there were delays in approvals based on delayed applications to the European regulatory authority by sponsors (a frequent event since the US is a bigger market).  Even though Europe was quicker to approve than the US once having received the submissions, the delay based on delayed submssions was still present. Then there was continued bickering among the diverse national authorities in Europe.  Hungary, for example, recently approved and is administering Russia’s Sputnik and China’s Sinopharm vaccines. 

The recent experience of biotech attempting to market their new antibiotics in Europe is also cause for serious concern.  In at least two cases, the European regulators insisted on post-market commitments that would have been more costly than the total potential market in the region. Neither drug was ultimately marketed in the region. 

All this makes me less than optimistic about Europe’s ability to get a true pull incentive for antibiotic R&D together in any reasonable time frame. So – that brings us back to the US. The United States, in my view, is the only country capable of pulling this off. We have the PASTEUR Act on the table – which I think would work (given clarification around a number of questions). I think it is there where we need to focus our efforts.