Semorinemab was well tolerated among patients with prodromal to mild Alzheimer disease (AD), but it did not significantly decrease cerebral tau accumulation compared with placebo. These are the findings of a randomized clinical trial published in JAMA Neurology.
Semorinemab, a humanized IgG4 monoclonal antibody, targets the N-terminal domain of tau. A murine version of it was shown to lower tau-related toxicity in cell culture and its accumulation in a transgenic mouse model of tauopathy. In a phase 1 study, semorinemab produced dose-dependent target engagement and a favorable safety profile.
The objective of this study was to evaluate its use as a therapeutic intervention in early AD. This is the first study of phase 2 clinical data of an anti-tau monoclonal antibody in prodromal to mild AD, according to the researchers.
In the phase 2 Tauriel study (ClinicalTrials.gov Identifier: NCT03289143), researchers randomized patients with prodromal to mild AD to receive intravenous infusions of 1500 mg, 4500 mg, or 8100 mg of semorinemab or placebo for a blinded study period of 73 weeks. The modified intent-to-treat cohort (mITT) included 422 individuals (91.9% White; aged mean 69.6 years; 55.7% women). Seventy-two patients missed 112 planned doses between March 2020 and the end of the blinded period.
The researchers found that the placebo and experimental groups had similar increases on the Clinical Dementia Rating-Sum of Boxes score (placebo n=126; Δ=2.19 [95% CI, 1.74-2.63] semorinemab 1500 mg: n=86; Δ=2.36 [95% CI, 1.83-2.89]; 4500 mg: n=126; Δ=2.36 [95%CI, 1.92-2.79]; 8100 mg: n=84; Δ=2.41 [95% CI, 1.88-2.94]).
The 441 participants who received at least 1 dose of either semorinemab or placebo reported similar adverse events (AE).
Higher-grade AEs were reported in the semorinemab groups, but they did not appear to be dose-dependent or associated with an individual system organ class, the researchers said. Twenty-two participants, who tended to be in the placebo arm, discontinued due to AEs. There were more serious AEs in the semorinemab arms in infections/infestations (placebo 2 [1.5%] 1500 mg: 3 [3.4%]; 4500 mg: 4 [3.0%]; 8100 mg: 6 [6.7%]) and psychiatric disorders (placebo: 1 [0.8%]; 1500 mg: 2 [2.2%]; 4500 mg: 4 [3.0%]; 8100 mg: 3 [3.3%]). Four deaths occurred in phase 2. Two semorinemab group participants died; 1 was taking 4500 mg while the other was taking 8100 mg. The researchers said the deaths were unrelated to the study drug.
The researchers also found no significant difference between placebo and semorinemab dose arms in Alzheimer’s Disease Assessment Scale-Cognitive Subscale, Repeatable Battery for the Assessment of Neuropsychological Status, Alzheimer’s Disease Cooperative Study-Activities of Daily Living Scale, Amsterdam Instrumental Activities of Daily Living Questionnaire, or [18F]GTP1 tau positron emission tomography (PET).
Study limitations included missed doses and clinical assessments due to the COVID-19 pandemic, relatively few longitudinal CSF samples, and generalization outside of race and ethnic diversity of trial participants.
“Semorinemab failed to demonstrate meaningful efficacy on clinical endpoints or reduction of tau accumulation across 18 months in participants with prodromal to mild AD at the doses administered,” the researchers concluded.
Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies, which included Genentech Inc, which supported the research. Please see the original reference for a full list of authors’ disclosures.
Teng E, Manser PT, Pickthorn K, et al. Safety and efficacy of semorinemab in individuals with prodromal to mild Alzheimer disease. JAMA Neurol. Published online June 13, 2022. doi: 10.1001/jamaneurol.2022.1375