Genentech-AC Immune's Alzheimer's drug failed, but what have they learned from crenezumab?

Roche’s Genentech and AC Immune know they have a failed trial on their hands for the Alzheimer’s disease drug crenezumab. But the partners are still parsing through the data, trying to find signals that could inform the next wave of development in the neurodegenerative disease.

Now, they think they have a couple clues as to what happened and how they can improve if—and that if is still very iffy—they decide to move the therapy forward.

AC Immune CEO Andrea Pfeifer
Andrea Pfeifer, Ph.D. (AC Immune)

Further data from the phase 2 Alzheimer’s Prevention Initiative Autosomal Dominant Alzheimer's Disease, or API ADAD, trial will be presented at the Alzheimer’s Association International Conference (AAIC) today. The results will tell the world more about why the monoclonal antibody crenezumab failed in a group of patients with a genetically caused type of early-onset Alzheimer’s.

There’s no change to the underlying result: Crenezumab was not successful. But AC Immune and Genentech are pointing to safety data showing no instances of amyloid-related imaging abnormalities, or ARIA, as a beacon of light, as well as a few “consistent trends” that favored the study drug over placebo.

“I think the picture we are giving is clearly showing that the molecule seems to do something,” said AC Immune CEO Andrea Pfeifer, Ph.D., in an interview.

Crenezumab failed to improve outcomes in cognitively unimpaired individuals who had a high imminent risk of developing Alzheimer’s symptoms. Genentech was hoping to see a slowing of the rate of change in cognitive abilities or episodic memory function, which were the two co-primary endpoints. It also failed on a number of secondary endpoints.

The AAIC data show a slightly clearer picture of what the companies mean when they say the data favored crenezumab but was not statistically significant. On a measure of cognitive abilities, patients taking the therapy scored about 22% better than placebo and on a measure of time to dementia due to Alzheimer’s, crenezumab-treated patients bested placebo by about 21%.

On safety, Pfeifer said there was not a single event of ARIA in the nine years of the study.

“The safety of the molecule is just really incredible,” Pfeifer said. “I have to say this is really even above our expectations.”

These adverse events, which can hint to brain damage, have cropped up in clinical studies of other amyloid therapies, such as Biogen’s Aduhelm. In a world where Alzheimer’s treatments rarely make the grade in clinical trials, having a drug that doesn’t cause ARIA is important, because it could allow a broad range of testing without risks to patients.

What AC Immune has taken from the safety data is the opportunity to up the dose. In the last two years of the API ADAD trial, they did exactly that—and patients seemed to show a slight improvement in those years, compared to previous years on the lower dose.

One intriguing finding is that the study population was on average younger and at an earlier preclinical stage in their disease than expected. The average age was 37 years old at enrollment, which is four years younger than what had been expected in the planning of the study. Only half of the patients had detectable amyloid.  The average age at diagnosis for this specific genetic cause of Alzheimer’s is 44. This may have been one of the factors that rendered API ADAD underpowered to show clinical effect, according to Pfeifer. 

Because of the young age, the placebo group declined at a much slower rate than expected, which reduced the sensitivity of the statistical analysis, Pfeifer said.

When asked if this suggests crenezumab might need the presence of amyloid plaques in order to work rather than being able to prevent the formation of plaques in the first place, Pfeiffer was thoughtful.

“It's a very good question … and I'm sort of debating this myself too,” she said, suggesting that what the study could be revealing is crenezumab’s two mechanisms of action—prevention and clearing of existing plaques—are being applied.

Another finding is that crenezumab seemed to lead to a 51% reduction in the build up of tau, which is a separate theory in Alzheimer’s that suggests a tangle of proteins leads to cognitive decline. Testing for this measure was only introduced into the study in 2019.

The API ADAD trial continues in an open-label extension with patients receiving the higher dose of crenezumab. The companies have not yet released some key biomarker data that Pfeifer is looking forward to. But she is already checking off ways to improve the next study, if it ever happens: higher dosing, more stringent enrollment criteria for those with and without presence of beta plaques, being among the key learnings.

So that brings us to the question on everyone’s minds: is Genentech going to keep moving forward with crenezumab? The company remains mum on exactly what comes next, besides saying they are still sorting through the data. Pfeifer, for her part, said the same. But if it were up to her, things would keep moving.

“To have a drug like this available, one should not drop it. One should make it work, in my view,” she said.