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.