David's New Book

Wednesday, April 25, 2018

Education for Antibiotic Researchers

The Global Antibiotic Development Partnership (GARDP) has teamed up with CARB-Xto provide training to current and future antibiotic researchers and developers. I have been pushing this since 2004 when I recognized that the continued consolidation within industry and the abandonment of antibiotic research in industry was going to leave us without experienced antibiotic hunters in the near future.  That future has arrived! My experience in reviewing hundreds of grant requests from biotech and academia clearly demonstrates the lack of basic understanding of the fundamentals of drug discovery among today’s generation of would-be antibiotic researchers. A number of us experienced antibiotic researchers are retired, have been fired, or are now working on oncology or autoimmunity or in neurosciences or in diagnostics. Our expertise will be lost if we don’t do something to pass it on to a new generation. I have been trying to find a way forward for this for the last 15 years without success until now. GARDP and CARB-X are stepping up to the plate!

Before I get to the great work by GARDP and CARB-X, I ask – where is the National Institutes of Health here in the US on this? For more on this see one of my blogs from a few years ago. NIH (in spite of their “in kind” participation in CARB-X) is still very much on the sidelines in this educational effort as far as I can tell.

The GARDP-CARB-X effort kicked off last fall at the ASM-ESCMID meeting in Boston with three “bootcamps” for antibiotic researchers (entire talks via the links below). 

Antibiotic Bootcamp: What Makes a Good Hit? Why and How Do You Write a TPP? - https://www.youtube.com/watch?v=FwOtawrQjBs.


Antibiotic Bootcamp: Clinical Microbiology for a Development Program - https://www.youtube.com/watch?v=xfkuFhvOXsg.


Antibiotic Bootcamp: How Does a Molecule Become a Physical Medicine to be Given to a Human - https://www.youtube.com/watch?v=0IUan9LuDBQ.


GARDP and CARB-X just sponsored a symposium at the ECCMID meeting in Madrid, Spain (slides only).


Marco Cavaleri (EMA): EU regulatory tools for expedited antibacterial development programmes


Sumati Nambiar (FDA): US regulatory tools for expedited antibacterial development programmes

William Hope (Liverpool): PK-PD in support of accelerated programmes: how much is enough?

John Rex: Alternatives to (classical) antibiotics: what will it take to convincingly develop a virulence inhibitor or similar indirect agent?

GARDP has started providing a series of webinars. The first three webinars (presented by me) are on Clinical Development and they are specifically targeting scientists and others who are not clinical developers.  The idea is to provide an understanding to discovery researchers of the various development pathways available for new antibiotics and the risks that might be entailed for given types of products. The first webinar, focusing on traditional development pathways (Tiers A and B) has been prerecorded and is available here. A live version will take place on June 13, 2018.  You can preregister to listen and ask questions here.  Two additional webinars in this series will include one on the development of antibiotics targeting specific pathogens and another on enhancers and non-traditional approaches.  The dates for those have yet to be established, but both of them will include a panel of experts to provide information and answer questions. 

GARDP and CARB-X also plan symposia for the ASM Microbe in Atlanta and for the ASM-ESCMID meeting in Lisbon, Portugal later this year. 

I attended the first two bootcamps last year in Boston. I was incredibly impressed with the quality of the presentations, the speakers and the slides.  I am also extremely grateful that all of this is publicly available for anyone who wants to view the program now and in the future. I believe that all of the programs coming from GARDP and CARB-X will provide a similar high level of quality.  What I do not guarantee is that all of the experts will agree with each other on all topics. It’s going to be your problem to work your way through any controversies.  But at the very least, we will all start with a more advanced understanding of the subject.  

Many many thanks to GARDP and CARB-X for taking up this gauntlet and meeting the challenge head on!




Monday, April 16, 2018

Generic Antibiotics on the Edge

Many thanks to Lew Barrett for pointing me to this article

In the struggle to control drug prices, the rapid entry of new drugs into the generic marketplace is a key step.  This was emphasized by the National Academies of Science, Engineering and Medicine in their recent report on drug prices and shortages. 

Lets talk about generic medicines (even though I’m not an expert here). My understanding of the commercial aspect of selling generic drugs is basic. You work hard to identify the cheapest route to manufacture that you can. You set a price to maximize your margin.  You understand that as more manufacturers enter the field your sales volume will drop. So you keep working on that chemical synthesis and on your suppliers and supply chain to maximize efficiency.  This allows you drop your price while still maintaining enough margin to compensate for your decreased volume of sales. Is there a limit to this strategy? Apparently. 

A 10 day supply of trimethoprim-sulfamethoxazole (Bactrim, Septra, generic) costs from $.4.00 to $15.00 depending on your pharmacy.  That is $0.20-.75 per pill. A “Z-pack” of generic azithromycin runs $7.00-25.00 for the six tablets. According to the article by Cynthia Koons of Bloomberg Business, 90% of drug prescriptions in the US are filled with generic medicines. Generic drug prices are falling about 11% a year according to Koons. This is partly fueled by the domination of only a few giant drug purchasers in the US.  These large purchasers continue to pressure generic manufacturers on price. The generic manufacturers are, in turn, forced to compensate by selling drugs where margins are higher.  Antibiotics are apparently not among this group. Brendan O’Grady noted that Teva, where he is Executive VP for their North American business, still makes antibiotics – but Teva wonders why.

At the same time, drug pricing has become a hot-button political issue here in the US. The price gouging by Mylan for their Epi-Pen and, of course, that of the now infamous Mr. Shkreli and his $750 per pill price for the antiparasitic pyrimethamine used to treat opportunistic infections in immunocompromised patients, have inflamed public opinion.  Congress is not in the mood to support higher drug prices. Yet some reasonable strategy for drug pricing is required and this strategy might involve assuring some minimum value-based price for important drugs like, say, penicillin. This recommendation was, in fact, one of many from the National Academies.

Unfortunately, though, if Congress does not take this seemingly counter-intuitive step, we will continue to suffer more and more drug shortages. As the National Academies report notes, “drugs that are not affordable are of little value while drugs that do not exist are of no value.”  

It’s the triple whammy! Congress needs to provide financial support for new research and development of new antibiotics, money to fix the broken antibiotic marketplace, and support for pricing of generic antibiotics. Wow!  And Congress still seems unable to tie its own shoelaces . . . .

Thursday, April 5, 2018

Reflecting on Antibiotic R&D and Pull Incentives

Today I would like to reflect with you on what I have heard from investors, Pfizer, J&J and various biotech company executives concerning antibiotic R&D, the antibiotic marketplace and the potential role of pull incentives.  

One major problem is that pull incentives remain hypothetical.  Even in the hypothetical, the value of any potential incentive remains completely unknown.  Because of this, investors are essentially ignoring pull incentives, but are very focused on non-dilutive funding via push incentives. I am hearing that we are now experiencing another down cycle in antibiotic biotech investing in spite of the increasing opportunities for push incentives (CARB-X, Novo, Wellcome, BARDA). A recent survey of biotech investments shows that among the top ten life sciences investors, only Entasis, Spero and Nabriva among antibiotic R&D biotechs were recipients of their investments.  Most money pours into oncology and immunology biotech. A recent conversation with a top antibiotic investor confirms this current down cycle for me.

Biotech executives tell me that pull incentives play no role in their plans nor are they discussed in any serious way by their investors. Non-dilutive funding, however, plays an important role in their considerations. All agree that without more successful antibiotic launches, the investment future for antibiotic R&D will be bleak. Where they disagree is on what type of product will be required for a successful launch. Some say that the only way to go is with a relatively broad-spectrum antibiotic that can be used in empiric therapy.  Others say that a pathogen-specific antibiotic can garner a high price and also be successful. My personal opinion is that the high price strategy has, at least so far, been a dismal failure. (See my blog on price perversion). 
From large PhRMA, I have two opinions.  Actually, there is only one opinion and one obfuscation. Pfizer was quite clear. They look at antibiotic investing like any other potential portfolio opportunity. They are clear that they view the scientific risk of antibiotic discovery as simply to high to justify investment even with available push incentives at least given the current state of affairs. They are also clear that a substantial pull incentive will be required for them to invest in late stage antibiotic assets if the assets are to survive their portfolio review process. 

J&Jwas anything but clear. They start with their scientific expertise.  Although I know a number of antibiotic R&D experts who remain within J&J, I am not sure that they have the internal expertise to evaluate antibiotic opportunities.  They seem more interested in “global” needs such as treatment for resistant TB and gonorrhea. And they have demonstrated their commitment to TB with actual products from which they will gain no profits (their priority review voucher notwithstanding). Of course, this is nothing but laudable.  They would not really address any specific issues around what a pull incentive would need to look like for an antibiotic program targeting say resistant Gram negative pathogens to be adopted at J&J.  This makes me believe that such a program has little (but perhaps not zero) chance at J&J regardless of any pull incentive.

The events of the last several years leave me believing that we are standing on a cliff looking into the abyss. Astrazeneca’s spin-off of its antibiotic research assets into Entasis and its sale of marketed antibiotic assets to Pfizer was a beginning. This year we have seen the loss of another large PhRMA company from antibiotic R&D – Sanofi.  This is all the more ironic since they had reentered antibiotic R&D after having jettisoned their assets to form Novexel – the company that ultimately gave birth to avibactam. Once again, Sanofi spun out their assets (while retaining some rights) – this time to Evotec.  Nevertheless, every loss of a large PhRMA hurts because we lose their deep pocket support for the area.  The loss of the Medicines Company, a small pharma company, was especially discouraging since this occurred just after they had won approval for their meropenem-vaborbactam combination antibiotic. I firmly believe that the availability of substantial pull incentives would have altered at least some of these corporate decisions.

I have reason to believe that more losses are coming. Only the successful launch of a new antibiotic or the implementation of substantial pull incentives can keep us from the abyss.