On the surface, Biogen’s decision to pay $75m up front for a Pfizer cast-off looks like a relatively expensive bet on a field of research that in recent years has struggled to progress. PF-04958242 is described as an Ampa receptor potentiator, and it follows several similarly acting compounds that have failed to prove particularly useful in neurological conditions.
Still, although Pfizer stopped work on the asset a few years ago, it was interested enough at the time to test ’242 in 10 phase I studies, and the breadth of clinical data amassed across more than 300 subjects has apparently tempted Biogen to push on. And, while the US biotech has stated that cognitive impairment associated with schizophrenia is its primary focus, the potential for utility in Alzheimer’s disease might also have piqued its interest.
This is not a novel leap to make – work with previous projects targeting the Ampa receptor encompassed Alzheimer’s patients, although unsuccessfully. In 2015 Servier abandoned work on S47445/CX1632 in depressive patients with the degenerative disease on efficacy grounds, after running a 520-patient trial.
S47445 came from Respirerx’s (formerly Cortex’s) Ampakine portfolio, the source of a large proportion of the Ampa-targeting agents to make it into the clinic in recent years. Another major researcher was Lilly, which developed a class of drug known as biarylpropylsulfonamides, though again no compound progressed very far.
Unwanted side effects and/or lack of a therapeutic window largely derailed these projects. Servier was also testing S47445 in major depressive disorder, but looks to have scrapped all work.
Takeda also had an Ampa receptor potentiator, TAK-653, in the clinic as recently as last year in depressive disorder, but this no longer features in its pipeline and has also presumably been abandoned. The Japanese company discontinued work on a previous asset, TAK-137, in 2015 for safety reasons.
|Standing alone in the Ampa pipeline?|
|Biogen||PF-04958242||Phase IIb in cognitive impairment to start in H2 2018||Pfizer|
|Takeda||TAK-653||Presumed abandoned in depressive disorder||Takeda|
|Servier||S47445/CX1632||Abandoned in Alzheimer’s depression in 2015, presumed abandoned in major depressive disorder||Respirerx (Cortex)|
|Respirerx||CX516 (SPD420)||Abandoned by Shire in 2002 and Cortex in 2006; completed phase II in ADHD, schizophrenia and cognitive impairment||Respirerx (Cortex)|
|Takeda||TAK-137||Abandoned in 2015 on safety grounds; completed phase I in healthy volunteers||Takeda|
|Lilly||LY451395||Abandoned ~2011; completed two phase II trials in Alzheimer’s and Alzheimer’s agitation||Lilly|
|Note: Selected projects only. Source: EvaluatePharma.|
Presumably Biogen can argue that ’242 is different enough that it might produce better results than these predecessors. It has described the molecule as “first in class” so presumably it is structurally different, though the compound has also been described as a biarylpropylsulfonamide.
Still, there are good reasons why past efforts have failed. Ampa receptors play a very dominant role throughout the brain, which causes problems of selectivity, while many Ampa receptor subtypes exists, upon which experimental compounds can act differently.
Some researchers believe that other therapy target sites need to be found to modulate Ampa receptors, which is perhaps what Biogen has uncovered with PF-04958242.
But, with confirmatory data still some way off, ’242 looks set to remain a wild card in Biogen's pipeline for some time.