Janssen drops the BACE as Alzheimer’s candidate joins fail list

Johnson & Johnson’s Janssen unit has joined the far-from-exclusive Alzheimer's disease failure club after deciding to terminate trials of its BACE inhibitor atabacestat.

This time the decision hasn’t been made because the amyloid-targeting drug failed to show efficacy in clinical trials. Janssen says the drug has liver safety issues, which means “the benefit-risk ratio is no longer favorable to continue development of atabecestat for people who have late-onset preclinical stage Alzheimer’s disease.”

The decision means the drugmaker is halting the EARLY phase 2b/3 trial of atabecestat (also known as JNJ-54861911) in preclinical Alzheimer’s disease, as well as a phase 2 long-term safety study. EARLY got underway in 2015 and was due to complete in 2024.

Janssen said it “continues to maintain a strong commitment to discovering and developing new treatments for this devastating disease.”

It’s not the first time a BACE inhibitor has been dropped because of safety issues. It is well established that selectively targeting the BACE1 form of the enzyme, which is involved in the generation of beta-amyloid peptide that clumps together in the plaques that characterize the disease, can be tricky. Off-target side effects led to the demise of Eli Lilly’s LY2811376 and LY2886721—the latter because of liver toxicity—and Roche’s RG7129.

Of course, after dozens of failed programs, Janssen’s decision doesn’t add anything to the debate about whether targeting BACE specifically and beta-amyloid in general is still a viable strategy efficacy-wise in Alzheimer’s disease.

The news comes just a few weeks after Merck & Co. abandoned a second phase 3 trial of its BACE inhibitor candidate verubecestat after seeing lackluster efficacy data. The study was in "prodromal" Alzheimer’s—involving patients in the earliest stages of cognitive impairment—and came after verubecestat failed to improve cognition in patients with mild-to-moderate forms of the disease.

The prodromal data with verubecestat sent a shockwave through other developers of BACE drugs, particularly as the prevailing trend among Alzheimer’s drug developers for years has been to test candidates earlier in the course of the disease in the hope of interrupting the processes leading to cognitive decline.

Other BACE inhibitors still in mid- to late-stage testing include Biogen and Eisai’s elenbecestat (E2609), as well as Lilly’s LY3202626 and AstraZeneca-partnered lanabecestat.

Analysts at Bernstein quizzed Merck’s R&D chief Roger Perlmutter on the company’s Alzheimer’s portfolio earlier this month, and he confirmed the pharma company isn’t giving up on Alzheimer’s nor BACE, with a candidate in early clinical development.

According to the analysts, Perlmutter said one of the imperatives is to gain a better understanding of the natural disease process so as to identify people early on who are at risk of developing Alzheimer's. It’s also important to understand the nature of that progression and subset people into those that will progress early versus late, and then direct the right therapies to the right patients.

Verubecestat is an “excellent” BACE inhibitor, said Perlmutter, but while there is evidence that intervening early enough in the disease process could have an impact on dementia, it’s not feasible to run trials that—for instance—would enroll post-adolescent subjects and follow them for 50 years or more.

There are other targets beyond BACE, according to Perlmutter, including tau protein and “many other mechanisms.” Merck has an active anti-tau program in play.

Senior editor's note: For the Friday, 18th May newsletter, we incorrectly stated:

While some keep the faith, Lilly drops the BACE—it was of course Janssen who had dropped the BACE, not Eli Lilly, for which we apologize. 

Editor's note: The ninth paragraph originally identified Biogen and Eisai's

elenbecestat (E2609) as a BACE inhibitor that had flunked an early trial readout. It was actually the companies' other Alzheimer's candidate, the amyloid-beta drug BAN2401, that put up disappointing early results.