PMID- 33464300 OWN - NLM STAT- MEDLINE DCOM- 20220111 LR - 20230919 IS - 2168-6157 (Electronic) IS - 2168-6149 (Print) IS - 2168-6149 (Linking) VI - 78 IP - 3 DP - 2021 Mar 1 TI - Findings of Efficacy, Safety, and Biomarker Outcomes of Atabecestat in Preclinical Alzheimer Disease: A Truncated Randomized Phase 2b/3 Clinical Trial. PG - 293-301 LID - 10.1001/jamaneurol.2020.4857 [doi] AB - IMPORTANCE: Atabecestat, a nonselective oral beta-secretase inhibitor, was evaluated in the EARLY trial for slowing cognitive decline in participants with preclinical Alzheimer disease. Preliminary analyses suggested dose-related cognitive worsening and neuropsychiatric adverse events (AEs). OBJECTIVE: To report efficacy, safety, and biomarker findings in the EARLY trial, both on and off atabecestat treatment, with focus on potential recovery of effects on cognition and behavior. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled, phase 2b/3 study conducted from November 2015 to December 2018 after being stopped prematurely. The study was conducted at 143 centers across 14 countries. Participants were permitted to be followed off-treatment by the original protocol, collecting safety and efficacy data. From 4464 screened participants, 557 amyloid-positive, cognitively normal (Clinical Dementia Rating of 0; aged 60-85 years) participants (approximately 34% of originally planned 1650) were randomized before the trial sponsor stopped enrollment. INTERVENTIONS: Participants were randomized (1:1:1) to atabecestat, 5 mg (n = 189), 25 mg (n = 183), or placebo (n = 185). MAIN OUTCOMES AND MEASURES: Primary outcome: change from baseline in Preclinical Alzheimer Cognitive Composite score. Secondary outcomes: change from baseline in the Cognitive Function Index and the Repeatable Battery for the Assessment of Neuropsychological Status total scale score. Safety was monitored throughout the study. RESULTS: Of 557 participants, 341 were women (61.2%); mean (SD) age was 70.4 (5.56) years. In May 2018, study medication was stopped early owing to hepatic-related AEs; participants were followed up off-treatment for 6 months. Atabecestat, 25 mg, showed significant cognitive worsening vs placebo for Preclinical Alzheimer Cognitive Composite at month 6 (least-square mean difference, -1.09; 95% CI, -1.66 to -0.53; P < .001) and month 12 (least-square mean, -1.62; 95% CI, -2.49 to -0.76; P < .001), and at month 3 for Repeatable Battery for the Assessment of Neuropsychological Status (least-square mean, -3.70; 95% CI, -5.76 to -1.63; P < .001). Cognitive Function Index participant report showed nonsignificant worsening at month 12. Systemic and neuropsychiatric-related treatment-emergent AEs were greater in atabecestat groups vs placebo. After stopping treatment, follow-up cognitive testing and AE assessment provided evidence of reversibility of drug-induced cognitive worsening and AEs in atabecestat groups. CONCLUSIONS AND RELEVANCE: Atabecestat treatment was associated with dose-related cognitive worsening as early as 3 months and presence of neuropsychiatric treatment-emergent AEs, with evidence of reversibility after 6 months off treatment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02569398. FAU - Sperling, Reisa AU - Sperling R AD - Brigham and Women's Hospital, Boston, Massachusetts. FAU - Henley, David AU - Henley D AD - Janssen Research & Development LLC, Titusville, New Jersey. AD - Indiana University School of Medicine, Indianapolis. FAU - Aisen, Paul S AU - Aisen PS AD - Alzheimer's Therapeutic Research Institute, University of Southern California, Los Angeles. FAU - Raman, Rema AU - Raman R AD - Alzheimer's Therapeutic Research Institute, University of Southern California, Los Angeles. FAU - Donohue, Michael C AU - Donohue MC AD - Alzheimer's Therapeutic Research Institute, University of Southern California, Los Angeles. FAU - Ernstrom, Karin AU - Ernstrom K AD - Alzheimer's Therapeutic Research Institute, University of Southern California, Los Angeles. FAU - Rafii, Michael S AU - Rafii MS AD - Alzheimer's Therapeutic Research Institute, University of Southern California, Los Angeles. FAU - Streffer, Johannes AU - Streffer J AD - Janssen Research & Development LLC, Titusville, New Jersey. AD - Translational Medicine Neuroscience, UCB Biopharma SRL, Braine-l'Alleud, Belgium. AD - Reference Center for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. FAU - Shi, Yingqi AU - Shi Y AD - Janssen Research & Development LLC, Titusville, New Jersey. FAU - Karcher, Keith AU - Karcher K AD - Janssen Research & Development LLC, Titusville, New Jersey. FAU - Raghavan, Nandini AU - Raghavan N AD - Janssen Research & Development LLC, Titusville, New Jersey. FAU - Tymofyeyev, Yevgen AU - Tymofyeyev Y AD - Janssen Research & Development LLC, Titusville, New Jersey. FAU - Bogert, Jennifer AU - Bogert J AD - Janssen Research & Development LLC, Titusville, New Jersey. FAU - Brashear, H Robert AU - Brashear HR AD - Janssen Research & Development LLC, Titusville, New Jersey. AD - Department of Neurology, University of Virginia, Charlottesville. FAU - Novak, Gerald AU - Novak G AD - Janssen Research & Development LLC, Titusville, New Jersey. FAU - Thipphawong, John AU - Thipphawong J AD - Janssen Research & Development LLC, Titusville, New Jersey. FAU - Saad, Ziad S AU - Saad ZS AD - Janssen Research & Development LLC, Titusville, New Jersey. FAU - Kolb, Hartmuth AU - Kolb H AD - Janssen Research & Development LLC, Titusville, New Jersey. FAU - Rofael, Hany AU - Rofael H AD - Janssen Research & Development LLC, Titusville, New Jersey. FAU - Sanga, Panna AU - Sanga P AD - Janssen Research & Development LLC, Titusville, New Jersey. FAU - Romano, Gary AU - Romano G AD - Janssen Research & Development LLC, Titusville, New Jersey. AD - Passage Bio, Philadelphia, Pennsylvania. LA - eng SI - ClinicalTrials.gov/NCT02569398 PT - Clinical Trial, Phase II PT - Clinical Trial, Phase III PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't PL - United States TA - JAMA Neurol JT - JAMA neurology JID - 101589536 RN - 0 (Biomarkers) RN - 0 (Pyridines) RN - 0 (Thiazines) RN - 2834W8D6GK (atabecestat) RN - EC 3.4.- (Amyloid Precursor Protein Secretases) SB - IM MH - Aged MH - Aged, 80 and over MH - Alzheimer Disease/*diagnosis/*drug therapy/enzymology MH - Amyloid Precursor Protein Secretases/*antagonists & inhibitors/metabolism MH - Biomarkers/metabolism MH - Double-Blind Method MH - Female MH - Follow-Up Studies MH - Humans MH - Male MH - Mental Disorders/chemically induced MH - Middle Aged MH - Pyridines/*administration & dosage/*adverse effects MH - Thiazines/*administration & dosage/*adverse effects MH - Treatment Outcome PMC - PMC7816119 COIS- Conflict of Interest Disclosures: Dr Sperling has received research funding from Janssen, and has served as a consultant to AC Immune, Biogen, Eisai, Janssen, Roche, and Takeda. Drs Raman and Ernstrom have received research funding from the National Institutes of Health, Janssen, and Eli Lilly. Drs Henley, Shi, Karcher, Raghavan, Bogert, Tymofyeyev, Novak, Thipphawong, Saad, Kolb, Rofael, and Sanga are employees of Janssen Research & Development and may own stock/stock options in Johnson & Johnson. Drs Brashear, Romano, and Streffer were at Janssen Research & Development during the time the study was conducted and may own stock/stock options in Johnson & Johnson. Dr Donohue reported grants from Eli Lilly and the National Institutes of Health during the conduct of the study; grants and other support from Janssen Pharmaceuticals; and personal fees from Eli Lilly, Roche, Neurotrack, Biogen, and Vivid Genomics outside the submitted work; in addition, Dr Donohue is married to an employee of Janssen Research & Development who may own stock/stock options in Johnson & Johnson. Dr Aisen reported personal fees from Merck, Roche, Biogen, ImmunoBrain Checkpoint, and Samus and grants from Janssen Research & Development, Eli Lilly, and Eisai outside the submitted work. Dr Raman reported grants from Janssen during the conduct of the study and grants from Eli Lilly and Eisai outside the submitted work. Dr Streffer reported personal fees from UCB Biopharma outside the submitted work. Dr Romano reported personal fees from Janssen Research & Development outside the submitted work. No other disclosures were reported. EDAT- 2021/01/20 06:00 MHDA- 2022/01/12 06:00 PMCR- 2022/01/19 CRDT- 2021/01/19 12:14 PHST- 2021/01/20 06:00 [pubmed] PHST- 2022/01/12 06:00 [medline] PHST- 2021/01/19 12:14 [entrez] PHST- 2022/01/19 00:00 [pmc-release] AID - 2774863 [pii] AID - noi200095 [pii] AID - 10.1001/jamaneurol.2020.4857 [doi] PST - ppublish SO - JAMA Neurol. 2021 Mar 1;78(3):293-301. doi: 10.1001/jamaneurol.2020.4857.