12 Jul 2019

The Alzheimer’s field was dealt another body blow yesterday with the announcement of a premature end to testing of Novartis/Amgen’s BACE inhibitor CNP520, aka umibecestat, in two Phase 2/3 trials. Part of the Alzheimer’s Prevention Initiative’s Generation program, the trials evaluated the ability of this BACE inhibitor to prevent Alzheimer’s dementia in cognitively unimpaired people who are at high risk for the disease. As a reason for the decision, announced on July 11, the sponsors cited worsening of cognitive function in the treatment groups as measured during a preplanned interim analysis.

Apparently, participants taking umibecestat declined on the RBANS cognitive composite, had more brain atrophy, and lost more weight than did people on placebo. The results appear broadly similar to those of Merck’s verubecestat, Janssen’s atabecestat, and Lilly’s lanabecestat (April 2019 news; Nov 2018 conference news; May 2019 conference news).

“We were extremely disappointed to learn about the early worsening of some cognitive measures in our research participants, and the need to discontinue testing of the BACE1 inhibitor CNP520 (umibecestat) in our API Generation Program,” wrote Banner Alzheimer’s Institute directors Pierre Tariot, Eric Reiman, and Jessica Langbaum in a statement to Alzforum. “Our research participants are pioneers in Alzheimer’s prevention research, and their participation in these studies has already had a positive impact on how to conduct prevention trials. Trial data and biological samples from these studies will provide vitally important new information to help us better understand how to treat or even prevent AD.”

Other site leaders were equally dismayed at having to cut back another big Alzheimer’s program, noting that enthusiasm and compliance for the CNP520 trials had been high. Both Phase 2/3 trials included at least one treatment group that received CNP520 (Lopez et al., 2017). The Generation Study 1 had been on track to enroll 1,340 homozygous ApoE4 carriers aged 60 to 75. It included one group taking 50 mg CNP520 daily, one group treated with the active anti-Aβ vaccine CAD106, and a placebo group. The trial was slated to run for 60 to 96 months, with change on the Alzheimer's Prevention Initiative Composite Cognitive or time to diagnosis of mild cognitive impairment or AD as dual primary endpoints. The CAD106 portion of the API program will continue.

The Generation Study 2 aimed to enroll 2,000 people who either carried two copies of ApoE4, or who carried one copy and had evidence of amyloid deposition. This trial tested two daily doses—15mg and 50mg—of CNP520 compared with placebo.

The decision to end these two CNP520 studies leaves the field with only one large BACE inhibitor program, Eisai/Biogen’s two Phase 3 Mission trials of elenbecestat.

Eisai announced in May 2019 that the NIA-funded Alzheimer’s Clinical Trials Consortium had chosen elenbecestat for the upcoming A3 prevention trial. Whether Eisai and ACTC will stick with this decision in light of umibecestat’s failure is now in question. The announcement of a cognitive liability with this reportedly more BACE1-selective compound also complicates the choice of drug for the DIAN primary prevention trial. That said, Randy Bateman of Washington University noted that while BACE inhibitors do seem to have a class problem, each drug is different. Other indications also went through crisis periods where most investigational drugs in a given class failed—until one succeeded.

Umibecestat’s downfall raises pressure on the field to develop a greater variety of new treatments. Attention is shifting toward tau-based drugs, ASOs, and other genetic approaches.—Jessica Shugart and Gabrielle Strobel