Wednesday, December 26, 2018

Antibiotics in 2019?

Antibiotic R&D has had a particularly bad year starting with The Medicines Company who abandoned their antibiotic R&D efforts and sold their antibiotic assets to Melinta late last year right after getting approval for vabomere.  This year both Sanofi and Novartis abandoned their antibiotic R&D efforts and divested their clinical and preclinical assets.  Allergan, holder of the North American rights to ceftaroline, dalbavancin and ceftazidime-avibactam, also announced that they would divest their antibiotic assets. I have not heard that they were successful.  Achaogen has now undergone two efforts at “restructuring” involving virtually eliminating all R&D and has essentially put up the “for sale” sign just after achieving approval for plazomicin. Finally, Melinta abandoned their antibiotic R&D efforts in the face of miserable sales of their recently launched antibiotics including delafloxacin and vabomere. 

For the last decade, we have seen the emergence of biotech as the primary antibiotic discovery and development engine replacing the large pharmaceutical companies that have continued to flee the area. Now, it seems, even biotech has hit the brick wall of the broken antibiotic market. 

Recently, Tetraphase gained approval for eravacycline, a new synthetic tetracycline with activity against resistant pathogens. They have priced the drug such that it will be easier for hospitals to put the drug on their formularies – but their limited label (only for intraabdominal infections) will still limit their sales prospects. Their current market cap is a miserable $58 million. Will Tetraphase achieve a successful launch in the face of all the other antibiotic launch failures? 2019 will provide the answer.

Nabriva recently submitted two NDAs for two antibiotics. IV fosfomycin for urinary tract infection is used throughout the world but was never approved in the US. Nabriva purchased Zavante Therapeutics to obtain this asset and filed an NDA for complicated urinary tract infection this year. Lefamulin was discovered and developed by Nabriva (I was involved in getting lefamulin through early development) and targets community acquired pneumonia. Nabriva’s second NDA this year is for lefamulin. Nabriva’s current market cap is $80 million. Once again, 2019 will be the critical year for this emerging biotech company attempting to launch important new antibiotics. 

What does 2019 have in store for the three large pharmaceutical companies that still maintain antibiotic R&D? This year a new biotech, Prokaryotics, licensed a number of preclinical antibiotic assets from Merck.  What antibiotic discovery activity still remains at Merck?  I am guessing that this is a minimal effort. At the same time, Merck continues to sell the antibiotics it acquired from Cubist, tedizolid and ceftolozane-tazobactam – but sales have been slow at best. Merck continues its development of imipenem-cilastatin-relebactam at a slow pace. Will Merck continue beyond 2019?

The antibiotic R&D effort at GSK has teetered on the edge of the precipice for years. A recent announcement that, with a new CEO, GSK will invest more in oncology and immuno-inflammation while continuing to focus on its top therapy areas: respiratory conditions, HIV and infectious diseases. Announcements like these in the past have not been harbingers of good news for antibiotics researchers. 

Roche, the third large pharmaceutical company still committed to antibiotics R&D, like Novartis, has its main research site in Basel, Switzerland. But most of the antibiotic interest in the company comes from its Genentech subsidiary in California. Will Roche follow the Novartis example in 2019 or will Genetech convince management to persevere?

Without large pharma and their deep pockets, investors are more hesitant to invest in R&D projects. Public-private partnerships like CARB-X and others have, to a certain extent, taken on some of the burden from venture capitalists for antibiotic discovery activity. But even well-funded efforts like CARB-X are likely to come crashing into the sharp rocks of the broken antibiotics market and the lack of big pharma interest. 

Given the events of the last year and the outlook for new antibiotic launches, I believe 2019 will be the most critical year since most of pharma abandoned antibiotics at the turn of the last century. I fear a catastrophic collapse of antibiotic R&D and commercialization in the absence of government efforts to bolster the broken marketplace for these essential medicines. 

Thursday, December 13, 2018

Why is this so hard?

The budget (FY 2017) for the Center for Medicare and Medicaid Services (CMS) was $1 trillion – with a T. In this budget, we pay top price for drugs including $100,00 cancer drugs. CMS would also pay for expensive antibiotics if hospitals would only stock them so they would be available to their physicians and patients. If this is true, why is it so hard to come up with a $2 billion dollar investment as a pull incentive to encourage antibiotic R&D? I don’t get it. 

Of course I see some minor issues here.  An incentive that is given as part of a contract with a pharmaceutical company might seem like a price negotiation – and that is forbidden by law (why???) at CMS. But FDA Commissioner Scott Gottlieb has proposed that CMS simply buy, upfront, a large supply of a new antibiotic fulfilling CDC’s priorities thus guaranteeing a market for any company succeeding in getting such a drug approved. This would work and seems within CMS’s authority.  Would they even need additional budget to cover this given their already existing budget figure? What is stopping this from happening?  I see no evidence of follow-up by CMS.

Other pull incentives would almost certainly require legislation. My current understanding is that the REVAMP bill proposing a transferable exclusivity voucher (conveyance) will not progress because of bipartisan agreement that exclusivity should not be commoditized. This is unfortunate since this would have been a valuable approach – although the bill would have required significant revision to put in place a few guardrails such that we were not spending many billions unnecessarily. 

A simple market entry award providing a payment of up to $2 billion over several years as part of a contractual arrangement with a company achieving approval of a priority antibiotic would work.  In one version of this model, the price the company could charge for the antibiotic would be capped throughout its marketed life.  In a second version (hybrid model) the price cap would be gradually lifted to provide incentive for the company to continue to be active in supporting the new antibiotic but also to encourage the entry of generics at the end of exclusivity for the new drug. I prefer the hybrid model here.  Again, these would require legislation with the HHS being the recipient of the funding. 

Since antibiotic sales are global, the cost of these pull incentives could be offset by similar incentives implemented by other countries. In any legislation or policy the secretary of HHS could be required to track such incentives offered around the world and use those to offset the US contribution.  So we’re talking about figure that will certainly be less than $2 billion per new and desperately needed antibiotic. In FY 2017 the US federal government spent almost $4 trillion (with a T). Discretionary spending was about $1.1 trillion.  So – again – why is this so hard?