Tuesday, June 21, 2016

Infinity's Sad RUD

Almost five years ago, I wrote of voluntarily leaving Infinity Pharmaceuticals.  Particularly due to the novelty (for me) of the voluntary part, at times I've wondered how long I would have stayed there.  Indeed, the offspring asked just that question just over a week ago. I do know now when I couldn't have stayed any longer, as to my great dismay Infinity announced last week it was discontinuing its Discovery operations due to a disappointing drug trial result.

Derek Lowe wrote a neat summary of much of Infinity's bad luck in the clinic, to which I will add a bit of personal flavor. Infinity never shied away from novel drugs targeted new pathways, which meant at times a hard road.  When I left, I was very optimistic about the hedgehog pathway inhibitor and cautiously optimistic about the HSP90 inhibitor program,  I had spent quite a bit of my two years working on these programs, and hoped to see them make real differences.  I also was disappointed to leave a very interesting discovery program which I was deeply involved with.  Infinity had another program which it had in-licensed, inhibitors of gamma and delta PI3 kinase isoforms.  My sole contribution to the PI3K program was to craft about two sentences that went into the inlicensing contract, defining contractually what constituted at the sequence level gamma and delta isoforms.

So it was a very great shock to many, including myself, when the big trial (pancreatic adenocarcinoma) for the hedgehog program was stopped after interim analysis showed that not only was it not going to succeed, but mortality was worse in the treatment arm.  I ran into the head of biology at a networking event just after the trial halt, and he was still in complete shock.  Unsurprising, as the pre-clinical data was excellent, including engineered mouse models.  The trial designed to provide early market approval for that compound, in chondrosarcoma, followed soon after, stopped after an interim analysis showed success was unlikely.  A third trial was soon dropped.  The HSP90 inhibitor failed to impress, and was also dropped.

Going into clinical science, one should have no illusions.  Certainly any I had were dispelled before I was even officially employed by Infinity.  I had just sent in an email to the hiring manager saying I'd take the position, when he called me back.  Yes, I still had a job.  WHAAATTTT?  I hadn't seen the news that Infinity had halted their Phase III trial for the HSP90 inhibitor in gastrointestinal stromal tumor (GIST), which had been a path to marketing a drug soon.  Infinity survived that setback, as did my employment (a friend in the clinical space would have to wait longer).  Infinity then spent a lot of effort showing that the deaths in the GIST trial were probably due to liver toxicity -- this is a major issue with HSP90 inhibition and many of these patients had extensively resected livers due to metastases.  So Infinity pushed on with other trials for HSP90 inhibition.

Infinity also just couldn't catch a break on some.  That's not a whine; this is the real world, but one could easily see routes that just didn't quite work out.  For example, HSP90 inhibition did show great promise in a genetically-defined subset of tumors.  The problem was the subset was EML4-ALK fusions, which Pfizer already was hot on the trail of with a direct ALK inhibitor.  Similarly, Genentech was just ahead of Infinity in their hedgehog program, which meant they captured what has turned out to be the only clear indication for hedgehog inhibitors: the rare tumors which are driven by activating lesions in hedgehog pathway genes.  

The last program, the PI3K program I wrote the tiny bit of text for, that is what cratered most recently.  Sadly, it didn't actually fail in the clinic -- the results were positive, but not sufficiently positive for a crowded indication (indolent non-Hodgkin's lymphoma).

And so Infinity is shedding its excellent discovery operation.  It is sobering to think that such an organization, which I can attest is full of very dedicated, very talented individuals, could not succeed even when led by someone (Julian Adams) who had notched two successful drugs to his belt already.  And these weren't boring me-too compounds either; before Julian drove the boronic acid Velcade to market there was apparently a saying ined chem that "boron is for morons (full disclosure: Julian sits on my company's board -- but I'd say the same nice things regardless).  Infinity was not a platform-touting company or a hype engine; it simply tried to be the best at prosecuting drug discovery.  

Infinity also had a lot of focus on company culture, due in large part to founding CEO Steve Holtzman.  He wanted a company which attracted and retained talented people by doing extremely good science, but which also functioned by being a community of colleagues who supported each other and had fun.  Open offices are a controversial topic, but at Infinity everyone had one -- there was no bubble of upper management excluded.  Cynics might look askance at the Infinity terminology, such as we were not employees but "Citizen-Owners", but this was part of Holtzman's vision.  Owners had a stake in the success of the company, but Citizens have responsibilities that go far beyond simple pecuniary benefit.  Infinity had a strong emphasis on charitable events, and while some were chosen to enhance the company's presence in targeted disease areas (Miss Amanda and I proudly did a three mile Pancreatic Cancer Walk one fall), many were simply to give back and to have fun.  I really did feel like it was a place in which one could work very hard on very important and difficult problems, yet there was far more than lip service paid to the idea of "work-life balance".  Periodic long hours were put in not due to threats or bribes, but because employee loyalty had been earned.

With Discovery lost to a Rapid Unscheduled Disassembly (RUD), can the rest of the company survive?  Apparently management is waiting to discuss matters with their partner AbVie, but it is hard to be optimistic.  Wall Street values the company no better than cash.  Some companies have traversed the valley of the shadow of death successfully (Alnylam comes to mind) and truly rebounded; others (such as Ariad) seem more like wounded zombies waiting a buy-out.  Infinity had been starting to pitch some PI3K assets in the uber-hot immunoncology direction, but without a discovery organization such an early stage program can't go anywhere.  

At the moment, beyond mourning a quality organization that has crumbled, one can do little more than try to help the affected -- my network is your network.  If you are looking for biology or chemistry talent in the Cambridge area, a whole bunch just became available.  The ideals and skills of Infinity will likely continue to influence biotech, long after the Moebius strip is no longer seen on Memorial Drive.

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