(Correction in paragraph 3, regarding Targacept): The press coverage today was all about AZ’s decision to advance their BACEi for Alzheimer’s, AZD3293, into a Phase II/III trial that, if highly successful, could in theory serve as a single trial for NDA submission. The good news here is that AZ is making a large investment in a neuroscience program–not something that could be taken for granted in the wake of their transition to the neuro iMed virtual CNS format. Whether or not BACE inhibition is the optimal target for such a bet–no one really knows–but now Merck and AstraZeneca have both decided that their limited neuroscience budgets should focus significant resources on advanced testing for a BACE inhibitor.
The bad news was in the culling of multiple other programs, although none came as a surprise. NIR had noted the absence of news about the most recent PhII trial of IV AZD6765 and speculated that silence in this case meant the trial had failed. It turns out that was indeed the case, this product has fallen out of the race to develop the first rapid-acting antidepressant, the program terminated. Interestingly though, AZ has another IV NMDA antagonist, AZD6423, that they now have in Phase I, with the intention of pursuing suicidal ideation. This fits with a growing consensus that suicidality is a symptom-domain of its own that crosses multiple diagnostic boundaries, and is an endpoint worth pursuing in itself. No detail is available, we suspect that AZ may have observed changes in suicidal ideation with AZD6765, but the very narrow therapeutic window for that drug may have prevented its development in the suicidality context.
In the initial iteration of this post, we had commented on the nicotinic alpha4beta2 programs partnered with Targacept–who originated them. But we have been subsequently reminded that AZ had already relinquished rights to AZD3480 early in 2013, the Phase IIb trial in Alzheimer’s continues, but under Targacept’s auspices. AZD1446 has been dropped by AZ in Alzheimer’s, and is no longer publicly cited as in development at all, but they have not formally discontinued the program and are considering an alternative indication. It remains the case that it has been difficult to find any optimism about these programs anywhere for the past couple of years, and for at least the time being, we continue to believe that Targacept’s nearterm future rests primarily upon the effect of nicotinic modulation on bladder overactivity.
AstraZeneca also culled a H3 antagonist program for Alzheimer’s (AZD5213 continues in neuropathic pain and Tourette’s) and ended an IL-6 antibody program for pain. The only other clinical-stage program left standing is a myeloperoxidase inhibitor (AZD3241), in Phase II for Parkinson’s. There are several very early stage programs that have been inlicensed by the neuro iMed, but their longterm value has yet to be established. It is worth noting that the head of that iMed, Mike Poole, has just left AZ to take a position at the Gates Foundation.
All in all, it is a mixed bag of news: AZ has one very substantial bet in Alzheimer’s going into potentially pivotal testing, a number of inexpensive discovery and preclinical programs, and very little left in between. But given that AZ could have pulled out of neuroscience completely, the decision to ‘go for the gold’ in Alzheimer’s does speak to some resiliency and continued clout for the neuroscience constituency within AZ.