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Sadly, it’s not really news when a biopharma company has an Alzheimer’s clinical trial failure. To a very good approximation, they all fail, or at least they have so far. Athira (NASDAQ:ATHA) announced just such an event on Wednesday, though, with some aspects that make the story interesting – although perhaps not in a good way. This reminds me of my wife saying to me (about various topics!) “Yeah, this is “interesting” in the way that you mean, not the way that a lot of other people mean“, and she’s got a point in this case, too!
First off, the drug under investigation. It’s called fosgonimeton, and it’s a different mechanism of action than you usually see. The compound is said to stimulate the hepatocyte growth factor/MET protein, which most of us have heard about as a target for inhibition in cancer therapy. MET itself is the tyrosine kinase receptor, and its only known ligand is the hepatocyte growth factor (HGF) protein. The first link in this paragraph will send you to several papers that suggest that MET receptor expression is diminished in Alzheimer’s, and that overexpression of HGF seems to have beneficial effects in rodent models. I will say that I applaud anyone who’s willing to try out modes of action in Alzheimer’s that don’t involve beta-amyloid, while simultaneously cautioning that if an apparently well-validated target like amyloid can fail over and over again, that the longer shots are probably going to be long indeed. The usual warnings also apply about rodent models of Alzheimer’s, because there really isn’t one that recapitulates the human disease (we humans are the only animals that actually get Alzheimer’s).
This was not a large trial – 77 patients, divided among two different doses of the drug and a placebo group. The primary endpoint was a measure of memory processing speed, with secondary endpoints of more traditional measure of cognition and function. The Phase I trial (also small) showed good safety and pharmcokinetics, and the clinicians also measured the processing speed and showed what looked like a significant effect for the drug. That unfortunately did not replicate in this latest Phase II study, not at all. Nothing showed significance – not the memory processing speed nor any of the secondary measures. It was a complete shutout. The company is of course talking about subgroup analysis and re-examining the data, but I honestly don’t see much hope for that. Objectively, fosgonimeton would appear to be done. The company has already been enrolling Phase III patients, though, so it’ll get another shot, but I would be very, very surprised to see positive results.
But there’s a backstory here. Athira’s CEO Leen Kawas had to step aside a year ago when question arose about a series of papers she had published during her doctoral work. PubPeer users had flagged these as apparently containing doctored Western blots – a distressingly common event – and that would be bad enough news on its own. The bands in the Westerns had (in many cases) faint lines around them that suggested cut-and-paste artifacts, and indeed, many of them appeared to be the same protein band that had been re-used multiple times. Worse, the papers were all about targeting the HGF/MET system, and that work was in fact one of the key things that caused Athira to be founded as a company in the first place (Kawas herself was a co-founder). These earlier papers didn’t involve fosgonimeton itself, but they most certainly did address HGF/Met as a target for cognitive disorders and neurodegeneration. Here’s Endpoints on that story, and here’s Stat, both by subscription. Athira had gone public in the fall of 2020 at $17/share and rose into the low 30-dollar range later in the year. It fell below the IPO price after the news about Kawas hit last summer, and today’s news has sent it down to about 3. As one might well imagine.
So we have a failed Alzheimer’s clinical candidate, and what may well be a failed target idea entirely. It’s cost a lot of people a lot of money and time and effort, and raised the hopes of some Alzheimer’s patients and their families, apparently for no good reason right from the beginning. Leen Kawas herself? She’s raising money for a biotech investment fund that she’s started. Some of Athira’s early investors are on board with her on that, and if you have sufficient funds and a taste for adventure, you can probably get in on it too. . .
Disclosure: None
Editor’s Note: The summary bullets for this article were chosen by Seeking Alpha editors.
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