Another knock back for amyloid: Roche's approach to presymptomatic Alzheimer's ends in failure

Roche’s long-running attempt to show its anti-amyloid-beta antibody works very early in the Alzheimer’s disease pathway has ended in defeat. The AC Immune-discovered candidate failed to improve outcomes in cognitively unimpaired individuals at high imminent risk for developing Alzheimer’s symptoms.

As trial after trial failed in symptomatic patients, some researchers argued anti-amyloid-beta antibodies were potentially effective therapies being used too late in the Alzheimer’s pathway to make a dent on the condition. That line of thinking led to attempts to identify and enroll patients earlier. For Roche, that meant finding a healthy population of patients genetically predisposed to Alzheimer’s.

The resulting trial, which got underway in 2013, enrolled 252 people from the world’s largest extended family with autosomal dominant Alzheimer's disease (ADAD) in Colombia. Two-thirds of participants had the presenilin 1 E280A mutation, which typically causes Alzheimer’s-related cognitive impairment around 44 years of age. 

By randomizing people in that high-risk population to receive crenezumab or placebo for up to eight years, Roche sought to show whether its antibody could slow the rate of change in cognitive abilities or episodic memory function. Crenezumab failed to statistically improve on placebo against either measure, causing the trial to miss its co-primary endpoints. The trial also missed its secondary endpoints.

Roche said crenezumab achieved “small” numerical improvements on the co-primary endpoints and multiple secondary and exploratory measures. However, the lack of any statistically significant results is the key takeaway. Roche will share initial data from the trial at the Alzheimer's Association International Conference in early August.

The failure follows two flops in a more traditional Alzheimer’s patient population in 2019. Roche stopped the two phase 3 trials of crenezumab in people with prodromal to mild sporadic Alzheimer’s early that year after coming up short at an interim analysis. The newly failed ADAD trial was the last active study of crenezumab.

As hopes for crenezumab have fallen away, Roche has continued to advance another anti-amyloid-beta antibody, gantenerumab. Readouts from phase 3 clinical trials of that candidate in early Alzheimer’s are slated for the fourth quarter. Roche walked away from gantenerumab after earlier clinical failures, only to resurrect the candidate in 2017 and establish it as one of the molecules that could come to market in the wake of the FDA’s controversial approval of Biogen’s Aduhelm.