Acadia Pharmaceuticals: Commentary

(from July/August 2008 NI; added 7/9/08)

It was not a completely unexpected event, given earlier animal data but Acadia was hit hard late 2Q when ACP-104 came up with all zeroes in its Phase II trial in schizophrenia. This leaves ACP-103, developed by Acadia as a potential adjunct for the atypicals, perhaps (this has yet to be proven) reducing olanzapine/Zyprexa's awful metabolic profile by reducing the necessary dosing (it has only been tested with Risperdal thus far). No doubt Acadia now has second thoughts about having rejected some previous offers, ACP-103 as an adjunct, even with a possible role in Parkinsonian psychosis, is a less compelling partnership opportunity than the 103/104 combination seemed to be. Acadia continues to be in a solid cash position, and has a productive relationship with Allergan. However, we have doubts as to the fundamental worth of their sleep maintenance and Parkinsonian psychosis programs. The question is: Will Acadia rely upon their inhouse assets or will they broaden their pipeline via licensing? Hopefully, it will be the latter, because in spite of their strong science, their mechanisms-of-choice have not panned out as hoped. With schizophrenia now much diminished as a valuation driver, 2H:08 is likely to be pretty grim at Acadia Pharmaceuticals.

(from January 2008 NI)

Acadia had a strong first half, though 2H silence led to some anxiety amongst observers. ACP-103 sufficiently enhanced Risperdal's efficacy (and hence reduced side effects) in Phase IIa that they see it as a potential adjunct for the atypicals, perhaps (this has yet to be proven) reducing olanzapine/Zyprexa's awful metabolic profile. The hope is that ACP-103 may permit a reduction of 2/3 for any antipsychotic with which it is combined, ACP-103 is now moving into PhIII for Parkinson's psychosis as well, data in 2009. With ACP-104, the clozaril metabolite, now moving into Phase IIb, billed as possibly emulating the parent's thus far unequaled effect upon cognitive/negative symptoms (also not yet proven), Acadia has assembled a one-two antipsychotic combination that we thought would attract a Big Pharma partner (for ACP-103, if not both) by the end of 2007. It did not happen, and some have begun to doubt the partnership potential. This does not present any nearterm problem for Acadia; they wisely raised cash at the price peak. We still look for a partnership during 1Q.

Acadia Pharmaceuticals : (ACP-103 comment, 3/20/07)

Acadia's valuation more than doubled the day they announced positive result for their 5HT-2a inverse agonist as an adjunct to risperidone or haloperidol in schizophrenia. The most important findings were: ACP-103 allowed a 67% decrease in the dose of risperidone, with no loss of efficacy on the overall PANSS score; the ACP-103 adjunct group showed faster stabilization; the ACP-103 group showed a strong trend (p=.078) towards decreased weight gain, gaining 50% less than those on risperidone. Being able to use the lower dose of risperidone also appeared to ameliorate (at least partly) the hyperprolactinemia which is problematic for risperidone. The CC was vague about eps (extrapyramidal symptoms) which are higher with risperidone than any other 'atypical' antipsychotic--the inference was that none of the groups showed much in the way of eps, which, given haloperidol's high propensity for eps, and risperidone's modest risk, is not entirely reassuring. We are also not totally convinced about the acceleration of benefit comparison--there is great variability in the speed of response to antipsychotic meds (Raedler & Schreiner, 2007), and while the fact that the ACP-103 group responded more quickly than any of the other groups carries weight, we think this needs further validation.

But it appears that we had underappreciated ACP-103's possibilities, focused as we were on ACP-104. IF eps risk is also reduced, and IF the potentiation of low dose efficacy is similar across other antipsychotics (especially olanzapine/Zyprexa, and our underinformed guess is that it will be) and IF it has a similarly robust effect upon weight gain vis-a-vis Zyprexa, ACP-103 would have a compelling case for being utilized as an adjunct--particularly with patients at greater metabolic risk. Managed care will have to be convinced that they should pay for two drugs instead of one--though one good pharmacoeconomic study showing what they'd save on diabetes treatments and other medical costs might make that an easy sell.

The main question left open has to do with those pesky cognitive and negative symptoms. Based on what Acadia has disclosed thus far, it sounds like ACP-103 allows low-dose risperidone to function like high-dose risperidone in all symptom domains. That's good, but risperidone is not the panacea for negative/cognitive symptoms, it falls short of both olanzapine and clozapine--neither of which constitutes a panacea either. As was reviewed in the March issue of NeuroInvestment, there are numerous drugs being evaluated for their impact upon schizophreniform cognition. Not only does it remain to be which ones will work in that domain, that does not necessarily mean that a broad spectrum of effect could be expected, allowing control of positive symptoms with a lower antipsychotic dose. But if one of these competitors does allow dose-lowering, hence reduced side effects, while also improving on the atypical effect upon negative/cognitive symptoms, that would be a problem for ACP-103. The bottom line is that this is very good news or Acadia Pharmaceuticals--but this is still a Phase IIb drug with a lot of varied competition in the wings.