Two months after announcing clinical and biomarker results from its Phase II SHINE trial (COG0201; NCT03507790) that rattled investors, Cognition Therapeutics has presented additional data from a pre-specified subgroup of mild-to-moderate Alzheimer’s disease patients showing significant slowing of cognitive decline following treatment with the company’s lead candidate CT1812.
A pool of 45 patients who had baseline plasma p-tau217 below median level showed 95% slowing of cognitive decline following treatment with either 100 mg or 300 mg dosages of CT1812, as measured by the 11-task Alzheimer’s Disease Assessment Scale (ADAS-Cog 11).
That slowing accelerated to 108% in those patients when measured by Mini-Mental State Examination (MMSE), meaning that the patients were performing better at the end of the study than their baseline at the start. The 24 patients randomized to placebo in both analyses showed cognitive decline.
“They were essentially at the same score at the end of the study as at the beginning of the study, meaning that they hadn’t really progressed meaningfully at all or worsened at all,” Anthony Caggiano, MD, PhD, Cognition’s chief medical officer and head of R&D, told GEN Edge. “Furthermore, the active and placebo individuals were continuing to separate over the course of the six months of the study, which make us even more excited about seeing the total possible effect that CT1812 might have as we do larger and longer studies.”
The lower the levels of p-tau217 in patients—who are in earlier stages of Alzheimer’s—the better they fared following treatment with CT1812 in the SHINE trial, researchers from Cognition and its clinical partners reported. Associate prof. Michael Woodward, MD, head of dementia research and former head of the Memory Clinic at Austin Health in Melbourne, Australia, presented findings from SHINE at the 17th Annual Clinical Trials on Alzheimer’s Disease (CTAD) conference, held last week in Madrid, Spain.
Based on its latest results, Cognition plans to hold an end-of-Phase II meeting with FDA officials in 2025.
“To me as a drug developer, it’s nice because now we really have a clear idea of how we would run the next phase of studies, how we’d recruit individuals,” Caggiano elaborated. “And we have a much better idea of how many we would need to recruit and randomize and how long studies would have to be.”
Cognition has yet to decide if the low p-tau217 subgroup should become the principal treatment population for CT1812 going forward. Caggiano said the company is weighing whether to only recruit individuals below or near that threshold, or instead recruit a wider range of patients but base its primary analyses on the low p-tau217 subgroup.
Kisunla and Leqembi
In considering the latter, Cognition cites the clinical data generated by two recently approved Alzheimer’s disease drugs—Eli Lilly’s Kisunla® (donanemab-azbt), and Leqembi® (lecanumab-irmb), developed by Eisai in partnership with Biogen. Both drugs showed effectiveness in patients with lower levels of tau.
Kisunla won FDA approval in July as the first amyloid plaque-targeting therapy with evidence to support stopping therapy when amyloid plaques are removed. The FDA based its approval of Kisunla in part on data from the Phase III TRAILBLAZER-ALZ 2 trial (NCT04437511) showing that treatment with Kisunla slowed disease progression by 35% in the primary analysis population of patients with low to medium levels of p-tau217, compared with a 22.3% slowing of disease progression in a combination of patients with low-to-intermediate and high tau levels.
Kisunla is a once-monthly injection treatment indicated for adults with early symptomatic Alzheimer’s, including mild cognitive impairment, or mild dementia stage of disease with confirmed amyloid pathology.
Also in July, Eisai released data from its 1,795-patient Phase III Clarity AD trial (NCT03887455) showing that in patients with low to no accumulation of tau in the brain, 24 of 41 patients (59%) showed improvement or no decline, while 21 of the 41 patients (51%) showed improvement from baseline on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) endpoint.
Those percentages improved to 63% of patients showing improvement or no decline, and 61% showing improvement, as measured on the 14-task Alzheimer’s Disease Assessment Scale (ADAS-Cog14) measurement scale. On the Activities of Daily Living Scale for use in Mild Cognitive Impairment (ADCS-ADL-MCI) scale, 63% of patients showed improvement or no decline and 59% showed improvement.
Cognition acknowledges it will need many more patients than it recruited for SHINE in order to carry out Phase III studies—though how large a population has yet to be determined. Also to be determined is dosing for Phase III, though the company will look into doses smaller than 300 mg since the 100 mg performed nearly as well or as well, depending on the outcome being studied.
CT1812 is a sigma-2 receptor modulator that is designed to displace and prevent the binding of toxic oligomers of alpha-synuclein and amyloid beta.
Financing challenge
As it plans to advance CT1812 into Phase III studies, Cognition faces another key challenge—namely, funding them.
Cognition reported $28.533 million in cash and cash equivalents as of June 30, down about 5% from $29.922 million as of December 31, 2023. That cash, plus income from non-dilutive grants, gives Cognition a financial runway stretching only into the second quarter of 2025.
Because cash and cash equivalents were not sufficient to fund operations for one year as of August 8, “therefore substantial doubt exists about the Company’s ability to continue as a going concern,” Cognition acknowledged in its Form 10-Q quarterly report for the second quarter. (At deadline, no date had been announced for release of third quarter results).
To raise capital for future trials, “the company is looking at everything,” including potential partnerships with larger biopharmas, Cognition’s president and CEO Lisa Ricciardi told GEN Edge.
“We always apprise the pharmaceutical companies of the results of our current tests. They all have an appetite to address large markets. This is a huge market. It’s unaddressed. It’s wide open. So, we’re looking at a number of ways of raising money,” Ricciardi said. “Wouldn’t it be ideal to have non-dilutive funding and a partner to help with this work? It’s one of the things being evaluated.”
An estimated 6.9 million Americans aged 65 and older live with Alzheimer’s, according to the Alzheimer’s Association. Among people with Alzheimer’s disease, 50.4% had mild disease, 30.3% had moderate disease, and 19.3% had severe disease, according to a study published in 2021 based on data from the Framingham Heart Study.
In its pre-specified analysis, Cognition said, CT1812 showed a slowing of cognitive decline that was more robust than that reported from the trial’s full population of 153 patients in July as measured via ADAS-Cog11, according to Cognition.
In those full-population results, Cognition acknowledged, CT1812 did not achieve statistical significance on its first secondary efficacy endpoint—namely a slowdown in cognitive decline in a pooled population of patients dosed with either dose of the drug compared to placebo patients, as measured by ADAS-Cog 11. CT1812 patients showed ADAS-Cog11 scores that declined by an average of 1.66 points, compared with the 2.7 point-decline shown by the placebo patients.
Cognition presented the 39% slower decline in condition shown by CT1812 patients as a key positive finding, and defended the results as showing consistent positive changes for the drug in patients with mild to moderate Alzheimer’s.
But the resulting difference of 1.04 points between CT1812 and placebo was a marked drop from the three-point decline seen after six months in the first 24 patients enrolled in SHINE, according to data that Cognition announced in November 2023. That difference sparked an investor selloff that sent Cognition shares plunging 69% between July 29 and August 2, from $2.37 to 73 cents.
Surging, falling, plateauing
Investors initially anticipated Cognition to present positive results at CTAD, sending Cognition shares rising 25% from 48 cents to 60 cents on October 23 after the company said that day it would present the SHINE results at CTAD. Since the data came out on October 29, however, shares tumbled 17.5% from 57 cents to 47 cents Thursday, where they plateaued through Monday.
SHINE has been one of four Phase II trials in progress for CT1812. Cognition hopes investors will be more positive later this year when it reports results from the 130-patient SHIMMER trial (COG1201; NCT05225415), which is assessing two dosages of CT1812 (100 mg and 300 mg) in patients ages 50-80 diagnosed with mild to moderate dementia with Lewy bodies (DLB).
SHIMMER—which has been funded with an approximately $29.5 million grant from NIA—is set to read out data by year’s end. Cognition researchers are conducting SHIMMER with James E. Galvin, MD, director of the comprehensive center for brain health at the University of Miami Miller School of Medicine and the Lewy Body Dementia Association (LBDA).
At CTAD, researchers from Cognition and partners presented a poster detailing baseline characteristics of the 130 participants enrolled in the study.
“We’re very optimistic that with these (SHINE) results and strong results in DLB, that investors will see much more value in the story than what had been the message over the summer,” Cognition’s president and CEO Lisa Ricciardi said.
CT1812 is also under study for:
- Early-to-mild Alzheimer’s—CT1812 is under study in the Phase II START trial (COG0203; NCT05531656), which is projected to enroll up to 540 participants to be randomized 1:1:1 to receive either 100mg or 200mg of CT1812 or placebo. START is being conducted in collaboration with the Alzheimer’s Clinical Trials Consortium (ACTC).
- Geographic atrophy caused by dry AMD—A 200 mg dose of CT1812 is under study in the Phase II MAGNIFY trial (COG2201; NCT05893537), which is set to enroll up to 246 adults who will be randomized to receive either the drug or placebo or 24 months. Enrollment has continued since the first patient was dosed last year.
