Merck halts Alzheimer’s phase 3 after interim data analysis

Merck has halted a phase 2/3 Alzheimer’s disease trial after an interim analysis found it was destined to fail. The failure of the BACE inhibitor to move the needle in the trial of 2,000 patients with mild-to-moderate Alzheimer’s dented Merck’s stock price after hours and dealt another blow to the amyloid hypothesis.

Executives at Merck pulled the plug on the study of verubecestat after an interim review by an external data group found it had “virtually no chance of finding a positive clinical effect.” Shares in Merck traded down 2% after hours on news of the setback.

Merck is pushing ahead with an ongoing trial of verubecestat in patients with earlier forms of the disease. But the failure of verubecestat in the other phase 3 ratchets up the risk the BACE inhibitor will join the ever-growing list of assets that swung and missed at Alzheimer’s in late-stage trials.

The data deal another blow to the amyloid hypothesis. Verubecestat, like other BACE inhibitors, was designed to improve outcomes in Alzheimer's patients by disrupting the production of the amyloid beta protein. The approach was seen as offering a lifeline to the amyloid hypothesis after drugs designed to clear away existing amyloid proteins failed in the clinic.

Back in 2013, Merck VP of Neuroscience Darryle Schoepp framed the verubecestat phase 3 trials as putting the question of whether the amyloid approach is effective to bed once and for all.

“Now we can get an answer on the amyloid hypothesis,” Schoepp told Bloomberg. “We will have the data that will tell one way or the other [whether slashing amyloid levels will slow the disease itself].”

Schoepp’s bullishness about the definitive nature of the phase 3 program was supported by data showing verubecestat cut amyloid by up to 90%. The failure of this effect to translate into success in phase 3 suggests the amyloid hypothesis is on its last legs, although, for those who still believe in the idea, the question of whether treating patients in earlier stages of the disease would yield better outcomes remains unanswered.

The second, ongoing phase 3 trial of verubecestat is looking at the effect of the BACE inhibitor in patients with an early form of the disease, known as prodromal Alzheimer’s. These patients have memory impairment and accumulations of the amyloid protein, but are yet to meet criteria for diagnosis with full-blown Alzheimer's.

Merck is one of several companies seeking to buck the odds and bring a BACE inhibitor through a phase 3 successfully. AstraZeneca and Eli Lilly are working toward a 2019 readout on their BACE inhibitor. Biogen and Eisai moved their contender into phase 3 last year. And Amgen and Novartis are in the middle of testing their BACE inhibitor and amyloid immunotherapy as monotherapies and in combination. Amgen and Novartis are enrolling healthy patients at risk of developing clinical symptoms of Alzheimer’s in their phase 2, making it the study that goes furthest back into disease progression.

Before those studies readout, Axovant is set to drop data from a phase 3 trial of its 5-HT6 therapy. With Lundbeck having recently called time on its 5-HT6 drug after three phase 3 failures, a setback for Axovant could deal a terminal blow to hopes that mechanism of action offers a way forward in Alzheimer's.