Feb. 3, 2011
A Boston Biotech Watch Book Review
By Steve Dickman, CEO, CBT Advisors
The rise of super-resistant bacteria and the inadequate attempts to combat them: Who but David Shlaes could give us such an entertaining and wide-ranging book, Antibiotics: The Perfect Storm, on such a gloomy topic? Shlaes, a top consultant working on the discovery and development of antibiotics, brings an encyclopedic and wry perspective to a field that, for pharma anyway, has mostly fallen between the cracks.
The broad outlines of the antibiotics tragedy-in-the-making are familiar: overuse and misuse of antibiotics has combined with a slowdown in new drug research to create what Shlaes aptly calls a “perfect storm:” more powerful and versatile bugs are morphing into existence daily, it seems, but the drugs to combat them have ceased to reach the market, felled by irrational regulators and markets not huge enough for Big Pharma. Consequently, we overuse those antibiotics that are still effective, which elicits resistance and then leads to disaster: the spread of multiply resistant superbugs and no way to stop them.
Just two new classes of antibiotics have reached the market in forty-two years, writes Shlaes: linezolid (Zyvox, Pfizer), belonging to the oxazolidinone class, and daptomycin (Cubicin, Cubist), a cyclic lipopeptide. Meantime, the “perfect” bug, equipped with resistance to every known antibiotic, creeps ever closer. In August of last year, reports surfaced about Enterobacteriaceae (gut bacteria) sporting a gene that codes for a penicillin-busting enzyme called NDM-1. The bacteria were found in Pakistan, India and the United States and only a single, old-school, kidney-toxic antibiotic, colistin, showed activity against it.
This sad state of affairs was predicted by Shlaes, who has long been on a crusade to loosen the logjam of unhelpful regulations, especially in the United States. The man is ideally suited to lead the charge. He started out in academia, realized after sixteen years that if he wanted to change the world he had to move into the pharmaceutical industry and then embarked on a successful career as an executive with Wyeth, where he was vice president in charge of infectious disease. From that lofty post, he dove into biotech and worked for Cambridge, MA-based Idenix Pharmaceuticals and joined the board of Novexel in France. He is now a Connecticut-based consultant.
Plenty of industry consultants are on their game; few write books. Shlaes became one of this select group because he is deeply passionate on the dual subjects of improving antibiotics R&D and increasing new drug approvals, and he wants to let his passion move others to action.
The major culprit in Shlaes’ mind – and in the views of some antibiotics-savvy venture capitalists interviewed for this article – is the Food and Drug Administration (FDA). FDA has, according to Shlaes, thoroughly messed up its mandate. Shlaes sees three main issues that have plagued the agency for most of the antibiotics drought of the last two decades:
- FDA has increased clinical trial design stringency to the point where trials become so large that they no longer pay. At the same time, FDA adheres, despite recent progress in some hearings at which Shlaes has presented, to outdated standards for approval. For instance, these include mortality endpoints in community-acquired pneumonia that date from the 1930s and have long since been superseded by other, more up-to-date and realistic measures.
- Because these drugs work so well when they work, there is a double standard for anti-infectives compared to other drug classes. “Tylenol,” Shlaes writes on page 40, “is one of the most widely used drugs in the world … and causes more cases of acute liver failure requiring liver transplant than any other drug. It is still sold without prescription worldwide.” By contrast, antibiotics such as Ketek in sinusitis and bronchitis, which have much lower complication rates, have nonetheless had their marketing approval withdrawn.
- Most troublingly, FDA continues to “move the goal posts” in mandating one set of endpoints early in a new antibiotic’s development and then increasing the requirements as the antibiotic moves closer to approval. Shlaes experienced this firsthand in his years at Wyeth and it has clearly left a bitter taste. One hopes we all benefit from the crusader’s zeal he brings to improving this unhappy state of affairs.
Pharma is a second culprit. Pharma consolidation has gone so far that the revenues from even a top-selling antibiotic barely move the needle. The largest-selling antibiotic in history, Augmentin, peaked at just under $2 billion. By contrast, Shlaes points out, Pfizer and Wyeth had combined 2008 revenues of $71.1 billion. So the economic incentive to try to bring forward new antibiotics is not as strong as Shlaes would like. At the moment, there is a shift occurring in pharma’s thinking, of course, away from blockbusters and toward smaller-market opportunities such as orphan drugs. I imagine that there could be good reason to expect pharma to become more interested in moving back into antibiotics after abandoning them; Shlaes writes that there is no evidence of this.
Shlaes is too heavy-handed in his critique of the biotech response to the antibiotics crisi. It would be nice to have a couple of case studies of biotechs that succeeded (such as Vicuron, acquired in 2005 by Pfizer for $1.9 billion) instead of (1) a blanket statement like “some experts predict that only 10% of biotech companies will succeed” in antibiotics development; and (2) a single case study of one such failure, a Colorado company called Replidyne, that was killed off in large part by FDA moving the goal posts.
A closer look at Achaogen and Tetraphase (in Watertown, Massachusetts), mentioned briefly, would have yielded a rich vein of hope. Both companies have managed to raise large amounts of venture capital money despite all the challenges. Achaogen, based in South San Francisco, has even succeeded at raising as much non-dilutive capital as any private biotech I’ve ever heard of, well over $100 million, from sources such as the U.S. military and the Wellcome Trust. The forces arrayed against successful marketing of new antibiotics can be overcome, these companies’ investors believe, through conducting clever clinical trial strategies (Achaogen) and inventing unique chemistries (Tetraphase). That is a story worth hearing and it would be interesting to hear Shlaes tell it.
In addition to the role of these biotechs, other areas I wish Shlaes had touched on include:
- The epidemic of hand-washing with “anti-bacterial” soaps and its implications for the rise of resistant bacteria
- The role for improved, genomics-based diagnostics in the clinical care of infected persons or those at risk
- The role of genetics-based susceptibility on the part of some of us to certain subsets of the bacteria out there
- Potential contributions by academic consortia in filling the gaps left by the vanished big pharma research and development programs
- A view of antibiotics development through the prism of healthcare costs – stays in sealed intensive care wards can’t be cheap, so it must be in the interests of the healthcare system to have more impactful tools to fight those nasty hospital-acquired infections, especially now that Medicare is slashing reimbursement to hospitals that do not report them …
It is hard to know what to do next when reading such a persuasive argument for societal action. Found a non-profit? Jawbone a regulator? Invest in more biotech companies that pursue anti-infectives? But one thing is for sure: if Big Pharma and FDA manage to pull themselves out of the current morass, it will be due to Shlaes and his allies in industry and academia exerting their maximally persuasive powers to bring about the unending supply of new antibiotics that society desperately needs.
# # #