Cognition's SHINE data for Alzheimer's drug dulls prospects

Cognition Therapeutics has reported phase 2 data with its Alzheimer's disease candidate, claiming the results show proof-of-concept for the drug, although the study missed its main endpoint.

Cognition's stock lost more than 40% of its value in trading after the data was presented yesterday, and slipped another 20% after hours, despite assertions by the New York biotech that its CT182 drug showed "consistent" improvements in cognitive outcomes compared to placebo in the SHINE study.

The primary concern for shareholders was that while there was a statistical improvement on cognition measures at day 98, the midpoint of the study, the difference between the drug and placebo had narrowed by the primary endpoint at 182 days and was no longer significant.

The study enrolled 153 subjects with mild-to-moderate Alzheimer's who were randomised to one of two doses (100 mg or 300 mg) of CT182, a small-molecule antagonist of the sigma2 receptor, or a placebo. The premise behind the drug is that blocking the receptor can interrupt a process in which amyloid beta oligomers bind to receptors on neurons and cause them to degenerate.

There were statistically significant reductions in the ADAS-Cog 11 cognition scale – the primary efficacy measure – as well as the mini-mental state examination (MMSE) at day 98, based on pooled data from both doses of the drug.

By 182 days, there was a difference between the two arms on ADAS-Cog 11, with a 1.66-point fall for CT182 compared to a 2.7-point decline for placebo, which Cognition said represented a 39% slowing of decline.

The trial had been powered to detect a 3-point difference on ADAS-Cog 11 – and in fact achieved that with the first 24 patients in SHINE based on data reported last November – so the diminished one-point efficacy signal now comes as a disappointment for investors.

The safety profile of the drug was good and consistent with earlier clinical trials, said Cognition, and there were also "favourable changes" in neurofilament light chain (NfL), which is a biomarker for neurodegenerative disease.

Cognition's chief medical officer and head of R&D, Anthony Caggiano, insisted however that the programme remains on track and the trials fulfilled its objective, which was "to provide evidence of cognitive benefit potential with CT1812 treatment."

"We are pleased about the consistent cognitive effect and signals of functional benefit across the entire study," he added. "We intend to utilise these findings to enable us to design and power future clinical trials to advance the development of CT1812 in Alzheimer's disease."

There were some mild and transient increases in liver function test scores with the 300 mg dose of CT182, but none with the 100 mg dose which will be taken forward in future studies.

Chief executive Lisa Ricciardi pointed out that the 39% difference in cognition scores is "comparable in magnitude to what was achieved with currently approved antibodies" at six months, with easier once-daily oral administration and less patient burden.

At the moment, there are two FDA-approved, antibody-based amyloid therapies for Alzheimer's – Eisai/Biogen's Leqembi (lecanemab) and Eli Lilly's Kisunla (donanemab) – which are given as infusions.

Ricciardi said on a conference call that the trial represents an "enormous milestone" for Cognition and provides "a path forward, with a novel drug, that could be used as monotherapy or in combination with other…drugs to mitigate the devastating impact of Alzheimer's disease."