Cognition Therapeutics’ phase 2 SHINE trial has taken some of the luster off the Alzheimer’s disease drug candidate CT1812. The oral sigma-2 antagonist failed to statistically beat placebo—or clear Cognition’s own bar for success—on the main efficacy endpoint that focused on symptom severity, but the biotech wants to forge ahead.
Investigators randomized 153 adults with mild to moderate Alzheimer’s to take one of two oral doses of CT1812 or placebo daily for 182 days. The primary endpoint looked at adverse events. ADAS-Cog 11, a measure of the severity of cognitive symptoms of dementia, was the key efficacy endpoint. Cognition powered the trial to detect a three-point change in ADAS-Cog 11. The results were posted at the Alzheimer’s Association’s International Conference in Philadelphia.
The biotech saw a three-point change when it reported data on the first 24 patients in November 2023. At a Needham investor event in April, Lisa Ricciardi, CEO of Cognition, said success for the full trial “looks like having a three-point difference, or results, rather, that replicate what we're seeing here in the early study.”
Cognition didn’t report a three-point difference in the full data. It barely reported a one-point difference. After 182 days, ADAS-Cog 11 scores had worsened by 2.7 points in the placebo cohort, compared to a 1.66-point decline in the CT1812. The difference between the cohorts was 1.04 points.
The biotech framed the result differently, calling it a 39% slowing of decline favoring CT1812 and putting it in the context of other data. In a statement, Ricciardi said “our results are comparable in magnitude to what was achieved with currently approved antibodies, with great ease of administration as a once daily dose, and less patient burden.”
However, Ricciardi was aiming higher than comparable results to Eisai and Biogen’s Leqembi and Eli Lilly’s Kisunla when she discussed the trial in April. The CEO’s belief that CT1812 would have a bigger effect on cognition than the approved drugs was based on differences in the study populations.
“I would anticipate that with a more advanced population, we have the ability to show a greater impact. The reason being, it's not about our companies or anything else, it's about more advanced patients are declining more quickly,” Ricciardi said. “So, in a study you're able to capture those differences, whereas they had to wait ... for those earlier patients to show decline.”
Lacking a hit on the main efficacy endpoint, Cognition focused the press release on statistically significant improvements on ADAS-Cog 11 and another measure of cognitive impairment after 98 days and trends favoring CT1812 across the trial. Cognition claimed that CT1812 "showed a consistent trend in cognitive improvement compared to placebo across all cognitive measures" and suggested there were "signals of improvement in functional measures," in the release.
The efficacy data come from a pooled analysis of the low 100-mg dose and the high 300-mg dose. The biotech reported a “favorable safety and tolerability profile, particularly in the 100 mg dose cohort,” and plans to advance the low dose into additional clinical trials. Cognition ended March with $34.7 million in cash and equivalents, plus $62.3 million in remaining National Institute on Aging grants.
Cognition's shares dropped 15% to around $2.04 in pre-market trading Monday compared to a prior close of $2.37.