Antibiotics - the Perfect Storm - A Retrospective
This is both the end and the beginning of an era. I started writing a book, Antibiotics – The Perfect Storm, in 2009 (it was published in 2010). I began writing the blog at the same time. I made the decision to leave Blogger after almost 14 years because Google persisted in deleting my blogs for violation of their community guidelines. I could never understand which guidelines I had violated, and, upon appeal, my blogs were always re-posted. But – I’m getting too old for this nonsense. I am hoping that Substack will be a more welcoming place for my writings and my audience. With this change in venue, I thought that you, my readers, might appreciate a little retrospective look at the perfect storm and its evolution over the last 14 years.
What is the perfect storm that afflicts the world of antibiotics?
1. Antibiotic resistance is an ever-growing problem that requires a constant pipeline of new antibiotics active against resistant pathogens.
2. Antibiotic discovery is hard. That was a lesson learned during the heyday of bacterial genomics research when we thought that we could discover new antibacterial targets by mining the bacterial genome.
3. The antibiotic market has gone from bad to worse. Antibiotics are administered for days, other treatments are required for months, years or for the life of the patient.
4. Starting around the year 2000, the regulatory climate, especially here in the US (thanks to our FDA), began to become more restrictive. This required longer, more expensive trials to get approval to market antibiotics in an ever-decreasing marketplace.
For me, the years between 2006 and 2009 were the bottom for antibiotics – or so I thought. I couldn’t imagine that anything could be worse. It began when a new antibiotic, Ketek or telithromycin, was approved by the FDA (through an unusual and controversial mechanism) and marketed and led to rare but serious liver toxicity. This led to an over-the-top scandal that in turn led to the FDA essentially halting almost all antibiotic development for almost six years.
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The European regulatory agency, after years of trailing behind FDA in many ways, became a regulatory sanctuary for antibiotic development.
The problem was that companies needed access to global markets especially the US market. And, at the time, the US accounted for more than 50% of antibiotic sales globally. The absence of a functioning FDA caused a wave of investor flight from antibiotic R&D that has never really recovered.
In 2012, Janet Woodcock and Rachel Sherman at the FDA realized that no new antibiotics (almost) were under development. The staff at the antibiotics division had little to do other than obstruct new projects. Drs. Woodcock and Sherman initiated a reboot of the FDA approach to the regulation of antibiotic development that led, finally, to a markedly improved environment for antibiotic development at FDA.
But all this came at a cost. Starting in 1999, but accelerating during the FDA’s dark years, the vast majority of large pharmaceutical companies engaging in antibiotic R&D abandoned the field for all of the reasons cited above.
While large pharma abandoned the field, antibiotic resistance progressed apace. Entrepreneurs and investors perceived an opportunity. Over the last two decades, a number of small biotechs appeared and began to attempt to find and develop new antibiotics for resistant infections. 80% of the current antibiotic pipeline comes from biotech. Like all biotech, the overall success of antibiotic biotechs has been poor.
Investors realized that their preferred exit strategy, outright purchase by a large pharma company, was unlikely to occur since most large pharma companies were no longer interested in antibiotics. The alternative, turning to the public marketplace for investment, was a distant second choice.
Physicians feared using new antibiotics unless they were truly needed – a laudable and appropriate position that delays as long as possible the emergence of resistance to the new agents. The number of resistant infections, while climbing, remains relatively small in terms of the number of treatment courses of a new antibiotic that would be needed. Thus, the market for these new antibiotics remains dismal. As a consequence, most of the biotechs that managed to obtain regulatory approval for a new antibiotic over the last decade went bankrupt or sold for pennies on the dollar. Even for “successful” biotechs, investors were doomed by the time they had an approved product. Investor flight has, if anything, accelerated in recent years. My last blog discusses the situation from the point of view of executives at surviving antibiotic biotechs – and its not pretty.
That discussion brings me to the question of how we fix this problem. We have to strengthen the marketplace to make antibiotic R&D profitable again. If we do that, large pharma might once again become interested in the area. Even if they do not establish their own R&D programs, they can once again license products from biotech or even purchase biotech companies outright (the investors’ preferred exit). This could then become a virtuous cycle. But it won’t happen until we address the dead antibiotic marketplace.
As we all know, the US has a plan – the PASTEUR Act – an antibiotic subscription plan that failed to pass during the last congress but that is once again on the table.
We know that such an investment will provide at least a 20x return on investment. Europe is still debating how to address the failed antibiotic market as Europe as opposed to country by country – the current approach.
Without an important ($2-4 billion) investment in the antibiotic market, we are all doomed. The antibiotic pipeline will wither and die. Private and ultimately public and non-profit investment will follow. Us older folks, and more importantly our children and grandchildren will face a very different medical world where the miracle of antibiotic therapy will just not be what it once was.