Future Investigation and Use of Amyloid-Targeted Agents in AD

Jeffrey L. Cummings, MD, ScD: Maybe, Elaine, I could turn to you. I know that elenbecestat and BAN2401 have both been chosen by the Alzheimer’s Clinical Trial Consortium, funded by the NIA [National Institute on Aging], to be tested in that consortium. Could you tell us a little bit about that decision process and how you see that going ahead?

Elaine R. Peskind, MD: Yes. Richard touched on this in the session we saw yesterday afternoon talking about all the BACE [beta secretase] inhibitors in testing. To some degree, elenbecestat is the last man standing. A handful of them have been shown to either have been stopped for futility or to actually cause worsening of cognition, so cognitive decline and 1 showing hepatic toxicity. So for elenbecestat, still we have no negatives. We have some positives, the phase 2 study is showing, and they’ve all shown, robust target engagement. They all robustly reduce the production of new Abeta-42.

Elenbecestat in the phase 2 study showed robust target engagement, reduction of amyloid positivity on amyloid PET [positron emission tomography], and some clinical benefit with respect to a modest reduction of decline, of 35% at 12 months and 30% at 18 months. So there are still some positives. There are no negatives for cognition. And in the phase 3 study, at least the first DSMB, the Data and Safety Monitoring Board meeting, shows no concern about safety.

Let me talk a little bit about the A3 and A45 studies. The A45 study is a planned study for secondary prevention of Alzheimer disease in the preclinical setting, so these are people who are cognitively normal and have the amyloid PET signal of having amyloid in their brain. And it’s a sequential strategy of first removing amyloid using the monoclonal antibody BAN2401. Then following that, reducing the production of new amyloid using elenbecestat. The A3 study even shoots a little earlier. It’s the same strategy but now in pre-preclinical Alzheimer disease. That includes people who are cognitively normal who have a little bit of amyloid in their brain but don’t meet that threshold for saying this an amyloid-positive scan. So that’s the strategy.

But to return to Richard’s point, robust advocacy for amyloid therapies, I think I’m going to play a little bit of the devil’s advocate. There have been a lot of strategies for removing or reducing amyloid: monoclonal antibodies, a large number of them, gamma-secretase inhibitors, BACE inhibitors, and amyloid aggregation prevention strategies. And still they have not borne the fruit we would have liked them to have seen. But I think the A3 and A45 studies will give a definitive answer to whether anti-amyloid therapies are the way to go for Alzheimer disease.

Jeffrey L. Cummings, MD, ScD: Thank you. Both of these drugs are being used in both A3 and A45, is that correct?

Elaine R. Peskind, MD: Yes, in the sequential strategy.