Forum and CIAS

Forum Pharmaceuticals (formerly EnVivo) announced today that their two Phase III trials of FRM-6124 in CIAS (Cognitive Impairment Associated with Schizophrenia) failed to hit their co-primary endpoints.   No details were provided, but there apparently are signs of a treatment effect on subgroups and secondary endpoints–but the placebo effect was apparently outsized and had a devastating impact on the ability to demonstrate a signal. This was the major nicotinic alpha7 drug ‘still standing’, with several competitors having demised over the years, and Merck/Bionomics and Sunovion much earlier stage in their development programs. Having had their Alzheimer’s Phase III trials torpedoed by an unexpected GI adverse event in a small number of patients, FRM-6124’s prospects were completely dependent on the CIAS trials, and these results are a profound disappointment from a program NIR has long seen as one of the more promising late-stage CNS projects, particularly given the success shown in Phase II.
One key question yet to be answered is whether the trial failed, or the drug failed. A very high placebo rate could constitute a trial failure, and Forum’s post-mortem assessment will have to include a review of their 200+ trial sites, to see if there were any high-enrollers with particularly elevated rates of placebo responders. Sites that choose to accentuate speed over enrollee quality have been known to sabotage studies, we are curious as to whether that may have occurred here.
The bottom-line question now is whether there is a future for FRM-6124, and indeed, for Forum. Forum/EnVivo has enjoyed the luxury of being funded solely, and generously, by Fidelity. But Abigail Johnson does not have the loyalty to neuroscience that her father did, and over $850 million later, we strongly doubt that Fidelity will put any more resources into Forum. Indeed, Forum’s CEO Deborah Dunsire, in the FRM-6124 press release, made reference to Forum’s need to “evaluate a potential path forward, if any.”  Trying to sort out how to reduce the placebo response rate and identify potential responder populations for the CIAS program will be time-consuming, expensive, and far from guaranteed to pay off. Developing an algorithm predictive of GI vulnerability in the Alzheimer’s indication will have a tough time of passing FDA scrutiny. We do not think Fidelity will have any appetite for funding either of these processes, and the question is begged as to whether anyone will. Forum had already laid off most of its R&D staff, and the betting was that, had the CIAS trial succeeded, Fidelity would have sold Forum. Now, the prospects for a sale are greatly diminished, though perhaps not completely absent. Might there be a company willing to acquire FRM-6124 in a backend-loaded deal where Fidelity would receive significant payments only if there was eventual success? That unlikely scenario would be completely dependent on what is seen in the data-mining now starting–whether a case can be made for a signal in a major subgroup that would be likely to manifest if the placebo effect were better controlled. In the meantime, the kind of vital treatment paradigm shift that neuroscience must begin to produce remains elusive.

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One Response to Forum and CIAS

  1. PorkPieHat says:

    I think the “unexpectedly high” placebo response shouldn’t have been unexpected given the failures (or clinical pauses) of companies like Targacept , Novartis, Abbvie, and now Forum. The application of this mechanism for direct cognitive or psychiatric benefit in CIAS/AD indications appears to be very difficult. A major cause of this difficulty appears to be the exceedingly high placebo response in these types of studies, one which seems to grown more powerful over the past couple of decades. But here’s a question: Will we ever be able to affordably power clinical studies of cognitive benefit in Schizophrenia/Alzheimer’s to show separation which demonstrates a drug effect? Don’t know, but at least Forum’s results (and the results of many others in the clinic) seem to demonstrate the safety and tolerability of a7 agonists. But companies don’t get bought based on safe, ineffective phase 3 drugs…what else does Forum have that makes it a compelling buy?

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