Semorinemab Demonstrates Safety, But No Slowing of Alzheimer Disease Progression
Over an 18-month treatment period, patients with prodromal to mild Alzheimer disease demonstrated similar increases in Clinical Dementia Rating-Sum of Boxes scores regardless of treatment with placebo or semorinemab.
Edmond Teng, MD, PhD
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 among patients with prodromal to mild Alzheimer disease (AD), but did not slow the rate of cerebral tau accumulation or clinical decline in 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 on 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]; 4500 mg: Δ = 2.36 [95% CI, 1.92-2.79]; 8100 mg: Δ = 2.41 [95% CI, 1.88-2.94]) vs placebo (Δ = 2.19; 95% CI, 1.74-2.63).
To the study authors’ knowledge, this was the first published phase 2 data of an antitau monoclonal antibody in prodromal to mild AD. Lead investigator Edmond Teng, MD, PhD, senior medical research, 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 monoclonal antitau antibodies that target 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 every 4 weeks thereafter. To be considered 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 recovery sequences.In addition to CDR-SB, efficacy analyses between the 2 treatment arms showed 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 analyses of longitudinal change on the CDR-SB stratified by baseline [18F]GTP1 tau PET standardized uptake 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 sex (male vs female) also failed to demonstrate consistent treatment effects attributable to semorinemab. Across treatment arms, patients demonstrated significant longitudinal declines in whole brain, cerebral cortex, and hippocampal volumes, with concomitant increases in ventricular volume.
Adverse events (AEs) were similar across both the placebo and semorinemab treatment groups and were mostly grade 1 or 2 in severity. Fall, nasopharyngitis, and infusion-related reactions were among the most common AEs. Those in the semorinemab groups had a higher incidence of grade 3 or higher AEs, but these did not appear to be dose-dependent and were broadly distributed across different system organ classes. In total, 4.8% (n = 22) of the cohort discontinued due to AEs, with a higher proportion in the placebo arm.
The semorinemab-treatment group demonstrated a higher rate of serious AEs, primarily 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 related to treatment. MRI abnormalities, including vasogenic edema/sulcal effusion, superficial siderosis, microhemorrhage, and microhemorrhage, were balanced across treatment arms. Notably, 1 patient in the placebo and in the semorinemab 4500-mg arms had asymptomatic sulcal effusions, which resolved spontaneously after study medication was held.
These results slightly differed from the previously conducted phase 2 LAURIET study (NCT03828747), which showed that treatment with semorinemab resulted in a statistically significance 43.6% reduction in ADAS-Cog11, the primary end point, compared with placebo after 49 weeks (P <.0025). Although, the secondary coprimary end point, the change from baseline in ADCS-ADL scale, was not achieved, nor were there significant changes on secondary end points of the MMSE and CDR-SB scores. In total, LAURIET included 272 adult participants with mild-to-moderate AD across 43 study centers globally.2
