Anti-tau antibody Semorinemab fails to slow Alzheimer's disease progression: JAMA

USA: A 73-week, phase 2, randomized clinical trial data published in JAMA Neurology showed that semorinemab did not slow clinical AD progression compared to placebo but it did demonstrate an acceptable and well-tolerated safety profile, in participants with prodromal to mild Alzheimer's disease (AD).

Neurofibrillary tangles (NFTs) are aggregates of hyperphosphorylated tau protein that are most commonly known as a primary biomarker of Alzheimer's disease and correlate with clinical disease severity. Monoclonal antibodies targeting tau may have the potential to improve AD progression by slowing or stopping the spread and/or accumulation of pathological tau.

Semorinemab is an investigational, monoclonal, anti-tau antibody that targets the N-terminal domain of tau. It was selected for development as it binds all known isoforms of full-length tau and has high affinity, specificity, and manufacturability. A phase 1 study of semorinemab demonstrated dose-dependent target engagement and a favorable safety profile. These encouraged further clinical investigations of semorinemab as a therapeutic intervention in early AD.

A Phase 2 Trial was conducted by Edmond Teng, Genentech Inc, California, and his team to evaluate the safety and efficacy of the monoclonal anti-tau antibody semorinemab in prodromal to mild AD.

Investigators conducted this trial at 97 sites in North America, Europe, and Australia enrolling 457 participants (aged 50 - 80 years) with prodromal to mild AD, Mini-Mental State Examination scores between 20 and 30, and confirmed β-amyloid pathology (by positron emission tomography or cerebrospinal fluid). During the 73-week blinded study period, participants received intravenous infusions of placebo or semorinemab (1500 mg, 4500 mg, or 8100 mg) every 2 weeks for the first 3 infusions and every 4 weeks thereafter.

Key findings of the trial,

• Semorinemab was not shown to significantly reduce cerebral tau accumulation versus placebo over 73 weeks.

• Semorinemab demonstrated a reasonable safety profile comparable to placebo, the most common adverse events being falls, nasopharyngitis, and infusion-related reactions.

Investigators concluded that semorinemab failed to demonstrate meaningful efficacy on clinical endpoints or reduction of tau accumulation across 73 weeks in participants with prodromal to mild AD at the doses administered but semorinemab demonstrated an acceptable and well-tolerated safety profile.

The specific role of tau in AD pathogenesis is uncertain, but it remains a compelling therapeutic target. Further studies of monoclonal anti-tau antibodies that target other tau epitopes and/or different stages of AD will help determine whether this mechanistic approach remains viable or whether other anti-tau strategies should be prioritized for future clinical drug development, the authors commented.

Reference:

Teng E, Manser PT, Pickthorn K, et al. Safety and Efficacy of Semorinemab in Individuals With Prodromal to Mild Alzheimer Disease: A Randomized Clinical Trial. JAMA Neurol. Published online June 13, 2022. doi:10.1001/jamaneurol.2022.1375