Alzheimer’s: failure of an anti-tau antibody early in the disease

Why is that important?

Alzheimer’s disease is a tauopathy in which dementia is particularly associated with a Neurofibrillary Degeneration Associated with Phosphorylated Tau Protein. Preclinical studies have shown that passive immunotherapy directed against the tau protein can slow down the progression of this degeneration, specific monoclonal antibodies have been developed. Semorinemab (or RG6100) is a humanized monoclonal antibody that targets the N-terminal domain of the tau protein and has the advantage of being able to bind to all tau protein isoforms with high affinity and specificity. The experiments in mice were convincing and the phase 1 study showed a dose-dependent effect. The development of the molecule was therefore continued.

methodology

The Tauriel study is a phase 2, multi-center, randomized, double-blind, placebo-controlled study. It included subjects aged 50 to 80 years with prodromal to mild AD associated with a Mini-Mental State Examination (MMSE) score of 20 to 30 points and β-amyloid pathology confirmed by imaging or cerebrological fluid analysis .

Patients were randomized (2:3:2:3) to receive 1500 mg, 4500 mg, and 8100 mg semorinemab and placebo for 73 weeks. The primary endpoint was change in CDR-SB score (scored between 0 and 18, with higher scores indicating greater impairment), which assesses six cognitive/functional domains (memory, orientation, judgment and problem solving, business, home and leisure, and body care).

Secondary measures of effectiveness included change from baseline to week 73 on the 13-item version of the Alzheimer’s Disease Rating Scale – Cognitive Subscale (ADAS-Cog-13), RBANS, and the ADCS-ADL and A-IADL-Q activities of the day living scales.

Principle results

A total of 457 patients were recruited and divided into the 4 groups (mean age 69-70 years, 51-59% female, 76-82% higher education, 72-75% APOE4 carrier) and 58-66% with mild AD).

In the modified intention-to-treat cohort (n = 422), the change in CDR-SB score between admission and 73e week was comparable to placebo (difference 2.19 [1,74-2,63]) and semorinemab (difference between 2.36 [1,83-2,89] and 2.41 [1,88-2,94] depending on dosage).

After 73 weeks, total plasma concentrations of tau increased in a dose-dependent manner in the different semorinemab groups (plateau above 4500 mg), which is explained by the fact that anti-tau antibodies increase the circulating half-life of the semorinemab protein. This rate was unchanged with placebo. In contrast to the observations under placebo with semorinemab, a moderate, non-dose-dependent decrease in tau concentration was observed in CSF.

In terms of safety, the frequency of adverse events was comparable in the placebo (93.1%) and semorinemab arms (between 88.8% and 94.7% depending on the dose).

financing

This study was sponsored by Genentech Inc.

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