Newly published data from the phase 2 Tauriel study (NCT03289143) showed that semorinemab (AC Immune SA/Genentech), a humanized IgG4 monoclonal antibody, was safe and well tolerated in patients with prodromal to mild Alzheimer’s disease (AD) , but do not slow the rate of cerebral tau accumulation or clinical decline over a 73 week treatment period.1
The modified intent-to-treat (mITT) cohort, which included 422 individuals aged 50 to 80 years with prodromal to mild AD, showed similar increases in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) for those on semorinemab at multiple doses (1500 mg: Δ = 2.36 [95% CI, 1.83-2.89]† 4500mg: = 2.36 [95% CI, 1.92-2.79]† 8100mg: = 2.41 [95% CI, 1.88-2.94]) versus placebo (Δ = 2.19; 95% CI, 1.74–2.63).
To the best of the study authors’ knowledge, these were the first published Phase 2 data of an antitau monoclonal antibody in prodromal to mild AD. Lead researcher Edmond Teng, MD, PhD, senior medical researcher, Genentech and colleagues concluded that “Nevertheless, while the specific role of tau in AD pathogenesis remains uncertain, it remains a compelling target. Additional studies of anti-tau monoclonal antibodies targeting on other tau epitopes and/or different stages of AD will help determine whether this mechanistic approach remains viable or whether other antitau strategies should be prioritized for future clinical drug development.”1
In this double-blind, parallel-group study, patients were blinded to intravenous infusions of placebo (n = 126) or semorinemab 1500 mg (n = 86), 4500 mg (n = 126) or 8100 mg (n = 84) every 2 weeks for the first 3 infusions and then every 4 weeks. To be eligible for the study, patients must have had Mini-Mental State Examination (MMSE) scores between 20 and 30, and confirmed ß-amyloid pathology shown on PET or cerebrospinal fluid assessment.
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MRI scans were performed at screening, Week 9, Week 49, and Week 73, and included T1, T2, and T2 fluid attenuated inversion repair sequences. In addition to CDR-SB, efficacy analyzes between the 2 treatment arms revealed no differences in rates of clinical decline on the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog-13), RBANS Total Index, Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS) -ADL) or Amsterdam Instrumental Activities of Daily Living Questionnaire (A -IADL-Q).
Planned Subgroup Analyzes of Longitudinal Change on the CDR-SB Stratified by Baseline [18F]GTP1 tau PET standardized exposure value ratio (SUVR) in the temporal lobe (high [≥1.3] vs low [<1.3]), diagnosis (prodromal vs mild AD), age (≤65 vs >65 years), APOE status (ε4+ vs. ε4−), and gender (male vs. female) also failed to demonstrate consistent treatment effects attributable to samorinemab. Across the treatment arms, patients showed significant longitudinal decreases in whole brain, cerebral cortex, and hippocampal volume, with concomitant increases in ventricular volume.
Adverse reactions (AEs) were similar in both the placebo and samorinemab treatment groups and were mostly Grade 1 or 2 in severity. Falls, nasopharyngitis and infusion-related reactions were among the most common adverse reactions. Those in the samorinemab groups had a higher incidence of grade 3 or higher adverse reactions, but these did not appear to be dose dependent and were broadly distributed across different system organ classes. Overall, 4.8% (n = 22) of the cohort discontinued due to adverse events, with a greater proportion in the placebo arm.
The semorinemab-treated group had a higher rate of serious adverse events, mainly in the infections/infestations (placebo: 2.5%; 1500 mg: 3.4%; 4500 mg: 3.0%; 8100 mg; 6.7%) and psychiatric disorders (placebo: 0.8%; 1500 mg: 2.2%; 4500 mg: 3.0%; 8100 mg: 3.3%) system organ classes. Four deaths occurred during the blinded portion of the study, although none were considered treatment-related. MRI abnormalities, including vasogenic edema/sulfur effusion, superficial siderosis, microbleeding, and microbleeding, were distributed across the treatment arms. Notably, 1 patient in the placebo and semorinemab 4500 mg arms had asymptomatic sulcal effusions, which resolved spontaneously after study drug ingestion.
These results differed slightly from the previously conducted Phase 2 LAURIET study (NCT03828747), which showed that treatment with semorinemab resulted in a statistically significant 43.6% reduction in ADAS-Cog11, the primary endpoint, compared to placebo at 49 weeks (p <.0025). Although the secondary co-primary endpoint, change from baseline in ADCS-ADL scale, was not achieved, nor were there significant changes on secondary endpoints of the MMSE and CDR-SB scores. In total, LAURIET included 272 adult participants with mild to moderate AD in 43 study centers worldwide.2