UPDATED: Cautiously optimistic, AC Immune delivers a mixed set of Alzheimer's data — but investors love it
Swiss biotech AC Immune is trading sharply higher Tuesday morning following the release of mixed topline Alzheimer’s data.
First, the good news: In a double-blinded and randomized Phase II study, AC Immune’s tau-targeting monoclonal antibody met a primary endpoint showing the candidate slowed cognitive decline at a statistically significant rate in mild-to-moderate Alzheimer’s patients compared to placebo. It’s the first time an anti-tau antibody has shown a therapeutic effect in Alzheimer’s, the company says, and the first-ever antibody to show an impact on cognition in this population.
But the Roche-partnered program whiffed on the co-primary endpoint measuring the rate of functional decline, and also missed on secondary endpoints looking at mental state and dementia effects. CEO Andrea Pfeifer is remaining cautiously optimistic about the topline data and hopes to learn more about the drug’s impact on function in a planned open-label extension.
“These data are solid, but we do not completely understand them,” Pfeifer told Endpoints News in an interview. “This is what we will be working on in November [at an upcoming conference] and should give us a little bit more clarity.”
Nevertheless, hitting one of the primaries was good enough for many investors, as AC Immune shares $ACIU were up more than 75% ahead of Tuesday’s morning bell.
As to why the drug passed the cognitive decline test but failed the functional decline endpoint, Pfeifer pointed to the study’s length, saying 12 months might have been too short a period to assess the function measure. She also faulted the endpoint itself, saying the cognitive endpoint is “much more objective” because it’s a patient-reported outcome, rather than the caregiver-reported functional measurement.
With patients continuing to receive treatment in the open-label extension, Pfeifer said she hopes to observe a positive trend on function here, but noted it’s still too early to say.
Tuesday’s results come from a Phase II study evaluating semorinemab, a monoclonal anti-tau antibody that targets the N-terminal portion of the tau protein. AC Immune enrolled 272 adults with mild-to-moderate Alzheimer’s, randomizing patients to either the semorinemab or placebo arms.
Researchers were aiming to clinch two co-primary endpoints — the change from baseline at week 49 in cognition, as measured by the Alzheimer’s Disease Assessment Scale, Cognitive Subscale, 11-Item Version (ADAS-Cog11); as well as the change from baseline in activities of daily living, as measured by the Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale.
In the cognition endpoint, AC Immune says semorinemab reduced cognitive decline by 43.6% compared to placebo. The biotech didn’t report an exact p-value, only saying it resulted in a p-value of p<0.0025 — stellar by any measure. On function, AC Immune reported no data at all, only saying the co-primary endpoint was not met. Pfeifer further declined to share these data when pressed.
The results mark a “surprising” turnaround for the program, Jefferies analyst Lucy Codrington wrote to investors Tuesday, though Codrington noted the lack of therapeutic effect on function left more to be desired. AC Immune’s data were particularly unexpected given the program had previously failed a trial last September looking at cognition and function in patients with earlier stages of Alzheimer’s, Codrington wrote.
SVB Leerink’s Marc Goodman agreed, writing investors “had minimal expectations” for this readout. Goodman now believes the data provide initial clinical validation of the anti-tau antibody approach, even though “the lack of consistency remains a significant issue that needs to be further analyzed.”
At the time AC Immune reported those data, the company said it was still waiting on further analyses from PET imaging to determine whether semorinemab reduced tau in the brain. Without that, there had been no way to know what specifically caused the trial failure, be it the particular drug, the antibody class, the patient population or the tau hypothesis itself.
In an email to Endpoints on Tuesday afternoon, Roche’s global head of neurodegeneration Rachelle Doody said the partners did not observe a benefit here in PET signaling. Like Pfeifer, Doody said Tuesday’s data represented a positive step forward, though much work remains.
“Although we are encouraged by the positive outcome for one co-primary endpoint measuring cognitive performance, we will continue our analyses of these data and continue the open label portion of the study to better understand why semorinemab didn’t show an effect on the co-primary endpoint measuring functional decline in activities of daily living, or on the secondary endpoints,” Doody wrote.
But with the positive results, Pfeifer — a longtime Alzheimer’s researcher — hypothesized that tau-targeting antibodies may produce different effects depending on how much tau has built up in the brain. One answer could be that rather than prevent tau from accruing, the antibodies simply slow the spread instead. It’s still far too early to draw any conclusions though, she said.
AC Immune is just another biotech partaking the wild Alzheimer’s drug ride of 2021. There’s been the controversial Aduhelm approval and its own ongoing saga over how much insurers will be willing to pay, as well as the back-and-forth between Cassava Sciences and some investors, which called for an audit after claims of manipulated data.
This article has been updated to include comments from Roche global head of neurodegeneration Rachelle Doody.