CT1812 Meets Primary End Point in Phase 2 SHIMMER Study for Dementia with Lewy Bodies

James E. Galvin, MD, MPH

(Credit: University of Miami Miller School of Medicine)

Topline results from the phase 2 SHIMMER study (NCT05225415) assessing CT1812 (Cognition Therapeutics), an investigational therapy for dementia with Lewy bodies (DLB), revealed that the treatment met its primary end point of safety and tolerability, with data also showing improvement in behavioral, functional, cognitive and movement measures among those treated with the agent relative to placebo at 6 months. The company noted that detailed data from the trial will be presented at the 2025 International Lewy Body Dementia Conference, held in January 29-31, in Amsterdam, the Netherlands.¹

“The results from this exploratory Phase 2 trial demonstrated CT1812 could have a meaningful, positive impact on DLB patients across multiple measures of cognitive, behavioral, movement, and functional performance. DLB is a multifactorial disease where patients experience a constellation of symptoms, and the results of this study suggest CT1812 holds promise for DLB patients and their care providers,” principal investigator James E. Galvin, MD, MPH, director of the Comprehensive Center for Brain Health at the University of Miami Miller School of Medicine, said in a statement.¹ “I believe the SHIMMER topline results are both exciting and very promising, and I am looking forward to working with the team at Cognition as they determine the appropriate next steps for CT1812.”

Among 130 adults with mild-to-moderate DLB enrolled in the trial, the company reported an 82% slowing in the total neuropsychiatric inventory (NPI) with specifically a strong reduction in anxiety, hallucinations, and delusions in the CT181 treated arms. Furthermore, findings revealed a marked reduction in caregiver distress, suggesting a positive impact on the day-to-day lives of patients who received the drug. Participants treated with CT1812 also had a slowing of decline across 3 cognitive measures compared with placebo such as fluctuations in attention, which reduced by 91%.

“These topline results exceeded our expectations and support the broad potential of CT1812 across neurodegenerative disorders,” Anthony Caggiano, MD, PhD, chief medical officer and head of R&D at Cognition, said in a statement.¹ “Analysis of CT1812’s activity in DLB will continue as additional data become available. We look forward to reporting these findings at future medical meetings and reviewing them with the FDA in an end-of-Phase 2 meeting.”

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Designed as a signal-finding study, SHIMMER is an exploratory, double-blind, placebo-controlled phase 2 trial that randomized patients with mild-to-moderate DLB to receive 1 of 2 oral doses of CT1812 or placebo daily for six months. Participants were assessed using the NPI to measure changes in hallucinations, anxiety, and delusions; the Montreal Cognitive Assessment (MoCA) and the Cognitive Drug Research Battery (CDR) to track cognitive performance; the Clinician Assessment of Fluctuation (CAF) to evaluate the frequency and duration of cognitive fluctuations; and the MDS-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III, an objective measure of parkinsonism.

“With the SHIMMER and SHINE results, we are confident in CT1812’s clinical activity given that it has demonstrated broad neurologic and neuroprotective activity in DLB and Alzheimer’s disease,” Lisa Ricciardi, president and CEO at Cognition, said in a statement.¹ “People with these diseases, particularly DLB, have few therapeutic options leading to a cascade of symptoms that are painful to the individual and their caregivers. We are eager to continue the development of CT1812 in late-stage clinical trials with the hope of providing a once-daily pill that can treat these devasting neurodegenerative conditions.”

CT1812 is an experimental orally delivered small molecule designed to penetrate the blood-brain barrier and selectively to the sigma-2 receptor complex. The drug candidate is currently being assessed in larger proof-of-concept studies, including the START study (NCT05531656) of early Alzheimer disease (AD), and SHINE trial (NCT03507790) of mild-to-moderate AD.

A previously conducted prespecified analysis of data from SHINE showed that those treated with CT1812 who had baseline plasma p-tau217 below the median experienced a 95% slowing of cognitive decline, as measured by the 11-item Alzheimer’s Disease Assessment Scale–Cognitive subscale. The company noted that these same participants showed a 108% slowing, when measured by Mini-Mental State Examination. Notably, patients in the placebo groups for both analyses reported cognitive decline. Researchers also noted that complete results from this trial are anticipated to offer evidence as to whether the therapy can modify the disease course in this patient population.

These results were presented at the 2024 Clinical Trials on Alzheimer’s Disease (CTAD) conference, held October 29 to November 1, in Madrid, Spain, by lead author Michael Woodward, MD, FRACP, head of dementia research at Austin Health. Following the presentation, Woodward and Caggiano sat down with NeurologyLive^®to further discuss the findings of the presentation at the meeting. The duo talked about how baseline plasma phospho-tau level influenced treatment response in patients with AD and the implications of targeting low phospho-tau subgroups for future AD clinical trials. In addition, the experts spoke about the ways that CT1812 affected exploratory end points across different tau level subgroups.

REFERENCES
1. Cognition Therapeutics Announces Positive Results in Phase 2 Study of CT1812 in Dementia with Lewy Bodies. News Release. Cognition Therapeutics. Published December 18, 2024. Accessed December 18, 2024. https://ir.cogrx.com/press_releases/cognition-therapeutics-announces-positive-results-in-phase-2-study-of-ct1812-in-dementia-with-lewy-bodies/
2. Cognition Therapeutics Announces Results of Pre-specified Analysis of SHINE Study Data Presented at CTAD. News Release. Cognition Therapeutics. Published October 29, 2024. Accessed December 18, 2024. https://ir.cogrx.com/press_releases/cognition-therapeutics-announces-results-of-pre-specified-analysis-of-shine-study-data-presented-at-ctad/