David's New Book

Monday, April 26, 2021

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 . . . .

 

 

 

 

 

 

 

 

Monday, April 5, 2021

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. 

 

 

 

 

 

Friday, March 12, 2021

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?) 

 

 

 

Monday, February 15, 2021

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. 

 

 

Monday, February 8, 2021

Covid vaccines compared to AMR

 






I never dreamed this would be possible. Of course, so many things are possible today that I thought were impossible that I’m almost embarrassed to admit it (but I have no pride). Twenty-five years ago I thought that an immunologic approach to cancer would never work because cancer cells are, after all, self. My excuse is that I am neither an immunologist nor an oncologist and many of my oncologist friends agreed with me. But to think that one could go from the SARS-COV-2 viral nucleic acid sequence to a marketed vaccine in less than a year – I’m sorry – but that was science fiction, Star Wars, warp speed. Plus – mRNA instead of a killed virus or protein or conjugate antigen?  mRNA – the epitome of instability? Come on!

 

Beyond the technology though, there was the desire, based on a lethal danger to the population posed by a pandemic virus, to get to this goal of a vaccine that is safe and effective and that can be distributed in record time. To accomplish this required an enormous investment in manufacturing – at risk. This investment came either from government (us taxpayers), from private industry (large and small) or from both.  And, at the end, governments are paying for the final product – although some vaccines are being sold at cost (not for profit). This plan required a strong will, a strength of steel, and an organization and expertise that we have rarely seen anywhere before. It’s almost enough to give one confidence in government again – since without government intervention, this could not have happened.  The plan also should make us stand in awe and gratitude for the extraordinary efforts of the pharmaceutical industry and their scientists and clinicians and their partners and stakeholders without whom this would never have happened. The industry should no longer be viewed as evil incarnate!

 

Compare and contrast. Antibiotic resistant infections have been killing people since the dawn of the antibiotic era. According to the CDC, the use of seat belts saved 13,000 lives in 2009. Compared to the 460,000 Americans killed by covid in this past year, 13,000 seems like a small number.  Does that mean we should forget about wearing seat belts? Again, according to the CDC, antibiotic resistant infections and C. difficile kill 48,000 Americans every year. And most of us think this is a significant underestimate. Should we now relax since this number is almost 10- fold lower than the covid losses to date? Should any sense of urgency to save these lives be somehow lessened because of covid?  Or should we rather look at this lesson from covid and apply it to lethal antibiotic resistant infections? How would we do that?

 

First, although a vaccine approach to the prevention of resistant bacterial infections is a great idea, and one that has worked for a few selected bacterial infections, I don’t think that we are at the same place with this problem as we were for certain viruses and mRNA technology. We will need other approaches focusing on therapy. It takes us 10-20 years to go from an idea to a new antibiotic.  We could shorten that time by doing more at risk as we did for covid. We could also do a better job of delaying the increase in resistance by doing a better job of restricting antibiotic use to cases where it is really necessary both in humans, plants, fish and other animals. But because even appropriate antibiotic use will ultimately lead to resistance, we still must find new approaches to the treatment of resistant infections.  My personal opinion is that this will most likely involve new antibiotics or new inhibitors of resistance (like B-lactamase inhibitors). But right now, our pipeline is in a disastrous state and any companies still working in the space are facing economic oblivion. One risk we must take is the use of financial incentives to make up for the broken marketplace that is driving investors out of the antibacterial space. Compared to the cost of warp speed for covid at $18 billion, the fix for the antibiotic marketplace would probably be more like $2 billion per new product.  If we awarded one or two new products per year, we’re talking $20 billion over five years maximum.  In any case, I don’t think our current pipeline would get us to 10 approved products in five years at least in terms of our key priorities.  So, new antibiotics for resistant infections – a fire sale! Why can’t we see this?

 

Let’s talk about Europe for just a minute.  Will Europe and its disparate national authorities have learned the lesson of pricing for new products from its experience with covid vaccines?  Will they have learned that their regulatory approach leaves something to be desired when it comes to considerations of feasibility in their demands for new data? Will Europe be left behind again as they have been for covid vaccines if (my lips to God’s ear) the US establishes a market incentive for new antibacterial products? 

 

We need to learn from this pandemic and apply these lessons to our approach to fighting antibiotic resistant infections – and we need to do it urgently!

 

 

 

 

Friday, February 5, 2021

AMR - a Holistic Approach

 



A very important report on the state of antibiotic use and resistance globally has just been release by The Center for Disease Dynamics, Economics & Policy (CDDEP).  Before delving into this topic, I want to explain my long absence from my blog.  I have been ill but am rapidly recovering and am now ready to continue thinking and writing about AMR. 

 

 The report focuses on the relationship between antibiotic use and resistance with a tool that provides an index or score for a given country.  A number of countries are included as examples in a digital dashboard. This tool and dashboard will be helpful for national and international agencies to evaluate and develop policies to address problems of resistance.  The report also notes that among some LMICs, there is a clear issue of access such that patients suffer and die from simple lack of antimicrobial therapy or vaccines more than from resistant infections. A webinar by CDDEP with Ramanan Laxminarayan and Dame Sally Davies and others discussing the report is also available. 

 

While I cannot agree more wholeheartedly that a greater understanding of the “you use it, you lose it” law of antimicrobial resistance is important, it is not the whole story.  As implied, even carefully monitored and appropriate use of antibiotics will still select for resistant variants within microbial populations. There are many examples of this from our experience in hospitals with strong antimicrobial stewardship policies, even given the fact that these hospitals exist within a larger global community. What this means is that, even if we alter our policies and focus our antimicrobial use in animals and in humans to only what is needed, we will still face the problem of resistance.  It is likely that under those circumstances resistance will evolve and grow more slowly – but it is still going to be inevitable. 

 

Therefore, in a holistic approach to resistance, we have to anticipate resistance even to our last line antibiotics. This means that our current antibiotics will yield to resistance over time and that we will need new antibiotics (or possibly other approaches) to deal with these resistant infections. And today, we are nowhere near ready for that eventuality given the perilous state of our antimicrobial pipeline. 

 

Our pipeline depends on the ability of sponsors (for profit or not) to discover, develop, manufacture and distribute new, effective drugs for the treatment of resistant infections. While there is more and more support for discovery and early development, and even some new support for late-stage development, without an ability to manufacture and distribute these putative new products globally, the entire endeavor collapses like a house of cards. And that is exactly what has been happening over the last decade. The clear evidence for this is in the bankruptcy of multiple small companies who engaged in the commercialization of new antibiotics active against resistant infections. To compound this, a number of sponsors have been unable to market their new antibiotics in Europe given burdensome and expensive regulatory requirements or inadequate national pricing proposals. Even if, as some argue, that these products deserved their fate, private investment in antibiotics is getting more and more difficult. 

 

Recent economic analyses by John Rex and Kevin Krause at a meeting of the National Academies (see links here) shed some light on the costs of commercialization – and they are considerable. The problem is that we know what we must do to address the problem.  We have to pay! While some countries (e.g. UK) are trying this by an effort to “pay their share” – this is clearly insufficient by itself. Either we need a more global approach, or some country or region must take a leadership position and provide much more than their “share.” I’m looking at you US and EU! 

 

Without addressing this other end of the AMR problem, our inadequate pipeline, stewardship will only delay the inevitable.