Dementia Pipeline Update: Phase 2 and 3 Developments in Alzheimer Disease and Lewy Body Dementia

New Multi-Arm, Multi-Stage UK Trial to Test Alzheimer Treatments

The Cambridgeshire and Peterborough NHS Foundation Trust has launched AD-SMART (Alzheimer Disease Systematic Multi-arm Adaptive Randomised Trial), a UK platform trial designed to accelerate therapeutic discovery in Alzheimer disease. The first trial of its kind to test multiple drugs simultaneously, it initially evaluates 2 repurposed agents, one approved for type 2 diabetes and one for attention-deficit/hyperactivity disorder. Participants will be randomized to either agent or placebo, with investigators assessing effects on cognitive symptoms and quality of life. An international expert panel and individuals with lived experience selected the agents and helped define success measures. Interim reviews will allow agents without benefit to be dropped and replaced, limiting exposure to ineffective treatment and shortening evaluation time. Because the drugs are already approved, successful agents could reach secondary approval faster than novel compounds. Up to 20 NHS sites are expected to open over 12 to 18 months, with a target enrollment of 1200 participants.

Sleep Disruption and Alzheimer Disease: A Bidirectional, Treatable Relationship

Winnie Pao, MD, described sleep disruption as a treatable contributor to cognitive decline, though sleep is not among the 14 modifiable dementia risk factors identified by the Lancet Commission. She outlined a bidirectional relationship in which sleep apnea and other causes of fragmented sleep promote amyloid accumulation, hypoxia, inflammation, and vascular risk, further degrading sleep architecture. Longitudinal studies identify sleep fragmentation, reduced sleep efficiency, reduced rapid eye movement sleep, increased light sleep, and sleep-disordered breathing as predictors of decline in mild cognitive impairment and Alzheimer disease. Research gaps include sleep apnea endotypes, short CPAP trial durations, and possible preexisting neurodegeneration among long sleepers. She encouraged psychiatric clinicians to collaborate with sleep specialists on pharmacologic management.

FDA Aligns on Key Elements of Phase 3 Study of Zervimesine for Dementia With Lewy Bodies

The US Food and Drug Administration and Cognition Therapeutics have aligned on key elements of a phase 3 study of zervimesine for dementia with Lewy bodies (DLB), including patient selection, dose, duration, and endpoints. The registrational trial will randomize participants with mild-to-moderate DLB to once-daily oral zervimesine 100 mg or placebo for 9 months. The primary endpoint is the Neuropsychiatric Inventory items for hallucinations and delusions (NPI-2); a key secondary endpoint is the Alzheimer's Disease Cooperative Study Activities of Daily Living scale. Because no blood-based biomarkers track DLB progression, the company proposes that changes in hallucinations, which are common, appear early, and worsen over time, may serve as a proxy for disease change. Zervimesine is an investigational oral small molecule that blocks toxic oligomer binding to neurons via the sigma-2 receptor. No treatments are currently approved for DLB.

Phase 2 Clinical Study Initiated: Evaluating NBI-'567 for the Treatment of Adults With Alzheimer Disease

Neurocrine Biosciences has initiated a phase 2 study of NBI-1117567 (NBI-'567), an investigational oral M1/M4 muscarinic agonist with M1 preference, as adjunctive treatment for cognitive impairment in mild to moderate Alzheimer disease. The compound is designed to selectively activate its target receptors while limiting activity at other muscarinic subtypes to reduce off-target adverse effects. The randomized, double-blind, placebo-controlled trial will enroll approximately 135 adults aged 50 to 85 years receiving stable acetylcholinesterase inhibitor therapy. Participants will be assigned to a high or low once-daily dose or placebo for 12 weeks, with efficacy, safety, tolerability, and pharmacokinetics assessed. The primary endpoint is change from baseline in a neuropsychological test battery composite score at week 12. Secondary endpoints include change in the 13-item Alzheimer's Disease Assessment Scale–Cognitive Subscale and the Clinical Dementia Rating Sum of Boxes.

Positive Phase 2 Topline Results: Remlifanserin for the Treatment of Alzheimer Disease Psychosis

Acadia Pharmaceuticals announced topline phase 2 results from the RADIANT program evaluating remlifanserin, a selective 5-HT2A receptor inverse agonist, for hallucinations and delusions in Alzheimer disease psychosis. At week 6, once-daily 60 mg produced a change of −12.6 on the Scale for the Assessment of Positive Symptoms–Hallucinations and Delusions vs −10.4 with placebo (effect size, 0.26; P = .06), narrowly missing conventional significance. On the Clinical Global Impression–Severity scale, the change was −1.3 vs −0.9 (effect size, 0.37; nominal P = .008). Separation from placebo widened over time, while the 30-mg dose showed minimal benefit. Adverse event rates were similar to placebo, with no QT prolongation signal, no apparent motor or cognitive effects, and no deaths in treatment arms. Acadia will continue its 2 phase 3 studies without the 30-mg arm. The FDA granted Fast Track designation in July 2026, and detailed results will be presented at the Clinical Trials on Alzheimer's Disease conference in November.

Modified Titration Dosing Reduces ARIA-E Risk With Donanemab, A Discussion With John Sims, MD

John Sims, MD, reviewed Alzheimer's Association International Conference data on donanemab (Kisunla) for early symptomatic Alzheimer disease. In TRAILBLAZER-ALZ 6, modified titration lowered amyloid-related imaging abnormalities with edema/effusion (ARIA-E) over 76 weeks vs standard dosing (15.6% vs 24.2%), including symptomatic ARIA-E (2.8% vs 4.8%). Radiographic severity was reduced across APOE ε4 carrier groups, and amyloid and plasma P-tau217 reductions were preserved. Long-term extension data showed clinical benefit growing over 3 years vs an external ADNI cohort, with the Clinical Dementia Rating Sum of Boxes difference rising from 0.6 at 18 months to 1.2 at 36 months, supporting limited-duration, treat-to-target dosing. Corticosteroid pretreatment did not compromise amyloid lowering and may be considered for infusion-related reactions, though not routinely. An ongoing study is evaluating a single dose 1 year after treatment completion.