Alzheimer’s Researchers Delve Into Data From Failed Crenezumab Trial

Nearly 2 months after it was first reported that investigational crenezumab missed its primary endpoints in an Alzheimer’s disease prevention trial, researchers released details about the findings.

In the Alzheimer’s Prevention Initiative Autosomal Dominant Alzheimer’s Disease (API ADAD) trial, crenezumab failed to slow or prevent decline over 5 to 8 years in cognitively healthy Colombian people who carried PSEN1 E280A, a rare genetic mutation that causes early-onset Alzheimer’s disease.

The anti-amyloid agent did not demonstrate a significant benefit in either of the trial’s primary endpoints, which assessed changes in cognitive abilities and episodic memory function.

Even so, “there were small numerical differences favoring crenezumab over placebo in every outcome,” said Pierre Tariot, MD, of the Banner Alzheimer’s Institute in Phoenix, in a presentation at the 2022 Alzheimer’s Association International Conference.

The phase II trial evaluated three groups of participants: 85 mutation carriers who received crenezumab, 84 carriers who received placebo, and 83 non-carriers who received placebo. Participants were 30 to 60 years old. Nearly half of the mutation carriers had a negative amyloid PET scan.

On the first primary outcome — the API ADAD composite, a measure of cognitive decline (range 1-100) — mutation carriers reached an annual rate of change of -1.10 in the crenezumab group and -1.43 in the placebo group (P=0.43).

On the second primary outcome — the Free and Cued Selective Reminding Test (FCSRT) Cueing Index, an assessment of episodic memory impairment (range 0-1) — annual change among mutation carriers was -0.03 in the crenezumab group and -0.04 in the placebo group (P=0.16).

Biomarker endpoints for amyloid and tau, assessed on PET and in cerebrospinal fluid, showed no significant differences. There also was no difference in time to mild cognitive impairment or dementia due to Alzheimer’s disease among mutation carriers in the crenezumab versus placebo groups (P=0.48).

Fewer than three people in each group had treatment-related serious adverse events, with “very little drug-placebo difference,” Tariot said.

The study may have been limited by insufficient statistical power, “or perhaps the exposure was insufficient, or the drug doesn’t work in this population, or there was a combination of factors,” he noted.

The findings don’t offer any insight about the amyloid hypothesis or the value of anti-amyloid therapies, said trial co-leader Eric Reiman, MD, also of the Banner Alzheimer’s Institute, who spoke at the presentation and at a press conference.

Crenezumab preferentially targets amyloid oligomers and was designed to minimize an inflammatory brain cell response, Reiman noted. In this trial, participants were on the highest dose for only about 2 years.

“Due to the limited number of participants at an unusually early stage of the disease and a limited duration of treatment at the highest dose, we cannot tell you for sure whether or not the treatment at the highest dose might have a clinical benefit,” he said. Former trial participants are continuing to receive crenezumab, he noted.

Reiman also focused on the wider influence of the study. “This trial introduced ways to accelerate the evaluation and approval of prevention therapies,” he said, adding that “it introduced the first agreement to share data and samples with the field after the trial was over to have the greatest impact, which has been embraced and improved … by leaders in the field.”