June 25, 2008

Acadia Gives Up On ADP-104-- Maybe It Shouldn't Have

The headline says almost everything:  Acadia shares plunge more than 50% on study data for schizophrenia drug.  Turns out the drug didn't work at either of the two doses tested.

They should have called me first: their study was flawed.

ADP-104 is an active metabolite of clozapine: N-desmethylclozapine.  The authors of a review write

High plasma levels of NDMC (ranging from 1200-4230 ng/ml), approaching those of clozapine itself, have been observed in humans given clozapine. Moreover, several investigators have shown that the degree to which clozapine is converted to NDMC predicts clinical outcome on multiple measures of cognition, negative and positive symptoms, as well as quality of life.  It is noteworthy that the ratio of NDMC to clozapine, rather than absolute levels of either clozapine or NDMC, was found to be the best predictor of a positive clinical outcome. This observation suggests that certain pharmacological properties of clozapine may actually counteract beneficial pharmacology of NDMC.

That's the premise.  But the premise is wrong, the blood levels and the ratio of NDMC to clozapine are coincidences, they have nothing whatsoever to do with clinical outcome.

The authors try also to make a case that D4 blockade may be involved, or at least cause an "atypical" profile (e.g. low EPs, etc), but Thorazine and Haldol are potent D4 blockers, so there.

I am also aware of the considerable ink and paper spent describing the contributions of serotonergic pathways, but it is categorically true that there does not exist a drug that is a pure 5HT antagonist-- take your pick of subtype-- that works as an antipsychotic.

It is so far without exception that every efficacious antipsychotic has power of significant D2 blockade.  Or, said another way, there does not exist any antipsychotic that lacks significant power for D2 blockade.  Whatever the contribution of other receptors, it is overwhelmed by the presence, or absence of D2 blockade.

Going from there, the single most important question that can be asked of any antipsychotic is: at what dose does this drug cause significant D2 blockade?  Whatever the answer is, it is again certain that at a dose less than that, it will fail to provide any efficacy.

The article shows nearly equal D2 antagonist activity for clozapine and for NDMC, and one can conclude dosing will be similar, e.g. 300-500mg/d.

Unfortuantely, NDMC is also a partial agonist at low doses; so the dose needed for D2 blockade will be higher.

Acadia, the drug company, tested NDMC at 100mg/d and 200mg/d.  It failed.  This is a lot like saying one tested clozapine at 100mg, found significant side effects but no reliable efficacy, and canned it.

Acadia should try again.  I am sure they worry that the side effects will get worse, but they won't.