Alnylam, the big name in RNAi therapeutics, had an awful day of it yesterday, and is having another one today. More may be on the way. Rivusiran, their Phase III candidate for transthyretin amyloidosis (ATTR), has been abruptly pulled from trials. This is particularly out of the blue, since the company had just completed enrollment this summer.
The reason was rather memorably given in the press release last night as an “imbalance of mortality”, which is exactly what you think it is: more people were dying in the treatment group than in the controls. The company appears to have no theories yet as to what led to this – the patients that have died during the trial have had their deaths ascribed largely to cardiac-related issues, but that’s not really unexpected, given that cardiac pathology is a distinguishing feature in ATTR itself (the patients in this trial were specifically selected with this pathology). The company had asked the data monitoring committee to look into the ongoing trial numbers because of some reports of worsening neuropathy (also a common problem in the disease). They reported back, after examining unblinded data, saying that the neuropathy issue was not the real problem, but that the trial still needed to be halted because of what was happening in the treatment arm.
This puts a major dent in Alnylam’s pipeline, and the big question is how it affects their other candidate in this area, patisiran, which is being studied in ATTR patients with polyneuropathy and other projects the company has coming up behind these. The uncertainty, for now, is hard to overstate: without any idea of why rivusiran failed, or even if it failed because of anything to do with rivusiran at all, there’s just no way of saying what might happen to patisiran. It might be a completely different story or it might run into the exact same problem, if there is a problem. Or it could be that rivusiran just wasn’t helping much at all, and these patient deaths were the normal course of events in these patients. Any of these are plausible, and that’s not what investors really want to hear: ALNY is down 47% as I write. Clarity, in the form of a good explanation for the rivusiran problems or solid clean data from the patisiran trial, is the only thing that’s going to resolve this, and that’s not going to be coming any time soon.