Nicotinic alpha 7 update

In the January issue of NeuroPerspective, NIR speculated about the failure of Targacept’s TC-5619 Phase IIb trial in schizophrenia: ” This  trial was dosed at 5mg and 50mg levels, compared to .3 and 1mg dosing for EnVivo’s EVP-6124 in the same population, thus Targacept may have overshot the mark considerably…given the success of EnVivo’s nicotinic alpha 7 entrant, we do believe that this was more likely a failure of the trial than of the molecule.”

Since then, we have heard bits and pieces of information from a number of sources, none from Targacept itself. Today, we heard AbbVie report that their nicotinic alpha7 drug, AB-126, dosed at 10mg and 25mg, had performed well in a Schizophrenia/CIAS trial that enrolled 207pts. Both doses produced improvement on the MATRICS battery–more so in specific subpopulations that will be disclosed later. They are in additional trials that go up to 75mg dosing. This program will go into Phase III. Their Alzheimer’s data showed minor cognitive improvement, but apparently not better than produced by donepezil; they are discontinuing the AD program because of the availability of generics accomplishing a similar  magnitude of effect.

So we have EnVivo moving ahead with both schizophrenia and AD, using very small doses of EVP-6124; AbbVie moving ahead with ABT-126 in sz, using doses that were between Targacept’s, but now assessing even higher doses; and Targacept ceasing CNS development for TC-5619. Three very different outcomes, which do not suggest any simplistic association of dosing with outcome.

Possible factors include duration of binding (leading to receptor desensitization), brain penetrance (higher dosing not necessarily reaching the brain due to characteristics of a molecule), or some other issue, it does appear that the problem with TC-5619’s data is more complicated than that of simply overshooting the mark. The broad range of doses used by Targacept (5mg and 50mg) does suggest that they were far from certain as to the optimal dosing-window.

The bottom line is: we really do not know whether the Phase IIb trial failure was a failure of the molecule, trial, or both. Perhaps no one yet does know the answer to that question, and whether TC-5619 is an asset worth further exploration in CNS.



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1 Response to Nicotinic alpha 7 update

  1. PorkPieHat says:

    In the wake of the uniform failure (excepting encinicline) of alpha7 agonists and PAMs in schizophrenia, one has to wonder if there is a fundamental problem with the alpha7 rationale for this indication.

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