TY - JOUR
T1 - Safety and Efficacy of Semorinemab in Individuals with Prodromal to Mild Alzheimer Disease
T2 - A Randomized Clinical Trial
AU - Teng, Edmond
AU - Manser, Paul T.
AU - Pickthorn, Karen
AU - Brunstein, Flavia
AU - Blendstrup, Mira
AU - Sanabria Bohorquez, Sandra
AU - Wildsmith, Kristin R.
AU - Toth, Bali
AU - Dolton, Michael
AU - Ramakrishnan, Vidya
AU - Bobbala, Ashwini
AU - Sikkes, Sietske A. M.
AU - Ward, Michael
AU - Fuji, Reina N.
AU - Kerchner, Geoffrey A.
N1 - Funding Information:
a patent for semorinemab pending (no royalties received) and is a shareholder of F. Hoffmann La Roche Ltd as a full-time employee of Genentech Inc. Dr Manser reported personal fees from Genentech Inc during the conduct of the study and is a shareholder of F. Hoffmann La Roche Ltd. Dr Blendstrup is a shareholder of F. Hoffmann La Roche Ltd as an employee of Genentech Inc. Dr Sanabria Bohorquez reported personal fees from Genentech during the conduct of the study and outside the submitted work. Dr Wildsmith reported personal fees from Genentech Inc outside the submitted work and is a shareholder of F. Hoffmann La Roche Ltd as a previous employee of Genentech Inc. Dr Dolton is a shareholder of F. Hoffmann La Roche Ltd as an employee of Genentech Inc. Dr Ramakrishnan is a shareholder of F. Hoffmann La Roche Ltd as an employee of Genentech Inc. Dr Sikkes is the developer of the Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL-Q) and reported license fees for this during the conduct of the study; grants from Health~Holland and Topsector Life Sciences & Health outside the submitted work; consultancy fees from Toyama, Boehringer, Biogen, and Lundbeck outside the submitted work; and a patent for A-IADL-Q licensed to Genentech, Roche, Vivoryon, Alzheon, VtV Therapeutics, Green Valley; all consultancy and license fees, and grants are paid to the organization. Dr Ward reported a patent for semorinemab pending (no royalties received). Dr Kerchner is a shareholder of F. Hoffmann La Roche Ltd as an employee of Genentech Inc and has a patent for semorinemab pending (no royalties received). No other disclosures were reported. Funding/Support: This work was supported by Genentech Inc. Role of the Funder/Sponsor: The funding organization participated in design and conduct of the study; collection, management, analysis, and interpretation of the data, preparation, review, or approval of the manuscript, and decision to submit the manuscript for publication.
Publisher Copyright:
© 2022 American Medical Association. All rights reserved.
PY - 2022/8/1
Y1 - 2022/8/1
N2 - Importance: Neurofibrillary tangles composed of aggregated tau protein are one of the neuropathological hallmarks of Alzheimer disease (AD) and correlate with clinical disease severity. Monoclonal antibodies targeting tau may have the potential to ameliorate AD progression by slowing or stopping the spread and/or accumulation of pathological tau. Objective: To evaluate the safety and efficacy of the monoclonal anti-tau antibody semorinemab in prodromal to mild AD. Design, Setting, and Participants: This phase 2 randomized, double-blind, placebo-controlled, parallel-group clinical trial was conducted between October 18, 2017, and July 16, 2020, at 97 sites in North America, Europe, and Australia. Individuals aged 50 to 80 years (inclusive) with prodromal to mild AD, Mini-Mental State Examination scores between 20 and 30 (inclusive), and confirmed β-amyloid pathology (by positron emission tomography or cerebrospinal fluid) were included. Interventions: 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. Main Outcomes and Measures: The primary outcomes were change from baseline on the Clinical Dementia Rating-Sum of Boxes score from baseline to week 73 and assessments of the safety and tolerability for semorinemab compared with placebo. Results: In the modified intent-to-treat cohort (n = 422; mean [SD] age, 69.6 [7.0] years; 235 women [55.7%]), similar increases were seen on the Clinical Dementia Rating-Sum of Boxes score in the placebo (n = 126; Δ = 2.19 [95% CI, 1.74-2.63]) and 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]) arms. In the safety-evaluable cohort (n = 441), similar proportions of participants experienced adverse events in the placebo (130 [93.1%]) and semorinemab (1500 mg: 89 [88.8%]; 4500 mg: 132 [94.7%]; 8100 mg: 90 [92.2%]) arms. Conclusions and Relevance: In participants with prodromal to mild AD in this randomized clinical trial, semorinemab did not slow clinical AD progression compared with placebo throughout the 73-week study period but did demonstrate an acceptable and well-tolerated safety profile. Additional studies of anti-tau antibodies may be needed to determine the clinical utility of this therapeutic approach. Trial Registration: ClinicalTrials.gov Identifier: NCT03289143.
AB - Importance: Neurofibrillary tangles composed of aggregated tau protein are one of the neuropathological hallmarks of Alzheimer disease (AD) and correlate with clinical disease severity. Monoclonal antibodies targeting tau may have the potential to ameliorate AD progression by slowing or stopping the spread and/or accumulation of pathological tau. Objective: To evaluate the safety and efficacy of the monoclonal anti-tau antibody semorinemab in prodromal to mild AD. Design, Setting, and Participants: This phase 2 randomized, double-blind, placebo-controlled, parallel-group clinical trial was conducted between October 18, 2017, and July 16, 2020, at 97 sites in North America, Europe, and Australia. Individuals aged 50 to 80 years (inclusive) with prodromal to mild AD, Mini-Mental State Examination scores between 20 and 30 (inclusive), and confirmed β-amyloid pathology (by positron emission tomography or cerebrospinal fluid) were included. Interventions: 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. Main Outcomes and Measures: The primary outcomes were change from baseline on the Clinical Dementia Rating-Sum of Boxes score from baseline to week 73 and assessments of the safety and tolerability for semorinemab compared with placebo. Results: In the modified intent-to-treat cohort (n = 422; mean [SD] age, 69.6 [7.0] years; 235 women [55.7%]), similar increases were seen on the Clinical Dementia Rating-Sum of Boxes score in the placebo (n = 126; Δ = 2.19 [95% CI, 1.74-2.63]) and 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]) arms. In the safety-evaluable cohort (n = 441), similar proportions of participants experienced adverse events in the placebo (130 [93.1%]) and semorinemab (1500 mg: 89 [88.8%]; 4500 mg: 132 [94.7%]; 8100 mg: 90 [92.2%]) arms. Conclusions and Relevance: In participants with prodromal to mild AD in this randomized clinical trial, semorinemab did not slow clinical AD progression compared with placebo throughout the 73-week study period but did demonstrate an acceptable and well-tolerated safety profile. Additional studies of anti-tau antibodies may be needed to determine the clinical utility of this therapeutic approach. Trial Registration: ClinicalTrials.gov Identifier: NCT03289143.
UR - https://www.scopus.com/pages/publications/85132835366
UR - https://www.ncbi.nlm.nih.gov/pubmed/35696185
UR - https://www.scopus.com/pages/publications/85132835366
U2 - 10.1001/jamaneurol.2022.1375
DO - 10.1001/jamaneurol.2022.1375
M3 - Article
C2 - 35696185
SN - 2168-6149
VL - 79
SP - 758
EP - 767
JO - JAMA Neurology
JF - JAMA Neurology
IS - 8
ER -