Monday, January 16, 2023

The Fate of Another Antibiotic Biotech - Nabriva

 Last week, a small, publicly held antibiotic biotech, Nabriva, announced that they would wind down their operations. Everyone still there lost their jobs. This occurred just a few years after getting approval for Lefamulin, an antibiotic available both orally and by injection that was active against MRSA and, mostly, shared no cross resistance with other antibiotics. Was this the inevitable result of a biotech with another drug that did not meet medical needs, or one that followed a deluded strategy, or is this just another tale of a broken antibiotic market?  Whatever the cause, this is another blow to the world of antibiotic R&D.


I have personal history with Nabriva that I would like to share with you. When I left Idenix (an antiviral biotech) in 2005, had no idea what I would be doing next. We sold our house in the Boston area and moved to France while I tried to formulate a plan. Shortly after our move, I received a call from a member of the board of Idenix asking if I could look at a plan to spin out an antibiotic biotech from Sandoz in Vienna. I agreed and my consulting business was born. This small group within Sandoz was mainly working on trying to identify a pleuromutilin compound that would be safe and effective for use in humans.  These compounds had been used in animals for decades, but always remained too toxic for human use. The Sandoz group had made hundreds of compounds some of which even had drug-like properties and were potent antimicrobials. I helped this group spin out.  The company was named Nabriva and remained located in Vienna. 


During the discovery process, we learned that these compounds suffered from problems of solubility, bioavailability, cardiotoxicity (prolonged QT) and spectrum. The first compound that went into development was BC3205. It was active against community respiratory pathogens and staphylococci including MRSA. The problem was that it had highly variable oral bioavailability and caused prolongation of QT (cardiotox).  That was not a good combination. The team quickly searched through their database of compounds and identified BC3781 that had even better antimicrobial potency, was more soluble and had a lower propensity for cardiotoxicity. This backup compound became Lefamulin. 


During my later consulting years, Nabriva debated their development strategy for Lefamulin. They were comparing it to linezolid. Linezolid, an oxazolidinone, was famous for its anti-MRSA activity and oral bioavailability – that filled a huge unmet medical need at the time. But Nabriva noted, surprisingly, that linezolid was used mostly for patients with pneumonia.  They also observed that there were many many more pneumonia patients treated with antibiotics than those with typical staphylococcal infections. They decided that they would go after that population rather than the staph infection market.  As I saw it, the problem was that the pneumonia market was satisfied and saturated with existing compounds and that any new entry would struggle for market share. I was almost alone in opposing this strategy and was overruled.


So, yes, I still think Nabriva was misguided in their strategy. I still think Lefamulin could be a useful alternative to other anti-staphylococcal treatments – but its really too late now to go back. A recent conversation with an old friend in the infectious diseases world reminded me that some of these biotechs deserve their fate. If that is the case for Nabriva, its still sad and it still will provide another nail in the coffin of antibiotic R&D funding. Many will see this as more evidence that no good deed shall go unpunished and that antibiotic R&D is to be avoided at all costs even if this may not really be correct in the case of Nabriva.