A Study of Crenezumab Versus Placebo in Preclinical Presenilin1 (PSEN1) E280A Mutation Carriers to Evaluate Efficacy and Safety in the Treatment of Autosomal-Dominant Alzheimer's Disease (AD), Including a Placebo-Treated Non-Carrier Cohort

Summary

This study consists of 2 periods: \[1\] Study Period A - evaluating the efficacy and safety of Crenezumab versus Placebo in participants who carry the PSEN1 E280A autosomal-dominant mutation and do not meet the criteria for mild cognitive impairment due to AD or dementia due to AD and are thus, in a preclinical phase of AD. Participants will be randomised in a 1:1 ratio to receive either Crenezumab or Placebo subcutaneously (every 2 weeks) or intravenously (every 4 weeks) for at least 260 weeks. A cohort of participants (non-mutation carriers) will also be enrolled and will be dosed solely on Placebo and \[2\] Study Period B - Participants will be offered the opportunity to continue to receive study drug until the results of the study are known and post trial access to Crenezumab is started or development of Crenezumab is discontinued.

Timeline

Start

2013-12-20

Primary completion

2022-03-22

Completion

2023-08-08

Outcome

Missed primary endpoint

registry p = 0.43; Difference in Annualized Rate of Change 0.33 (95% CI -0.48 to 1.13); RCRM NCT01998841 ↗

registry p = 0.16; Difference in Annualized Rate of Change 0.008 (95% CI -0.003 to 0.02); RCRM NCT01998841 ↗

paper Crenezumab therapy administered for 5-8 years did not result in significant benefits on our primary clinical outcomes PMID 41579901 ↗

release “Crenezumab Alzheimer’s disease Phase II API ADAD (Colombia) trial: co-primary endpoints not met” roche.com ↗

release “As previously reported on June 16, 2022 , the trial did not meet its co-primary endpoints” acimmune.com ↗

Publications

• Bittner T, Lopera F, Rios-Romenets S, Schiffman C, Clayton D, Hibar D, Kollmorgen G, Dolton M, Poon V, Nguyen J, Giraldo-Chica M, Acosta-Baena N, Espinosa A, Villegas G, Munoz C, Serna L, Alvarez S, Protas H, Luo J, Sohankar J, Chen Y, Ghisays V, Malek-Ahmadi M, Ashton NJ, Denkinger MN, Cai Y, Xu YR, Ostaszewski B, Selkoe DJ, Alexander RC, Quiroz YT, Su Y, Chen K, Doody RS, Langbaum JB, Tariot PN, Sink KM, Reiman EM. Baseline and placebo-related imaging, cerebrospinal fluid, plasma biomarker, and cognitive findings in unimpaired PSEN1 E280A mutation carriers and non-carriers in the Alzheimer's Prevention Initiative Autosomal Dominant Alzheimer's Disease Colombia Trial. EBioMedicine. 2026 Jul 17;130:106390. doi: 10.1016/j.ebiom.2026.106390. Online ahead of print.
• Tariot PN, Lopera FS, Rios-Romenets S, Sink KM, Giraldo-Chica M, Acosta-Baena N, Villegas G, Espinosa A, Castano ML, Munoz C, Ospina P, Bocanegra Y, Tirado V, Henao E, Cardona E, Luna E, Lopez H, Sanchez G, Collazos MM, Alvarez S, Aguillon D, Hu N, Clayton D, Bittner T, Schneider A, Dolton M, Poon V, Nguyen J, Thomas RG, Schneider LS, Chen K, Su Y, Alexander RC, Quiroz YT, Cai Y, Xu YR, Ostaszewski B, Selkoe DJ, Ashton NJ, Denkinger MN, Jakimovich LJ, Doody RS, Langbaum JB, Reiman EM. Safety and efficacy of crenezumab in cognitively unimpaired carriers of the PSEN1Glu280Ala mutation at risk for autosomal-dominant Alzheimer's disease in Colombia (API ADAD Colombia Trial): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2026 Feb;25(2):147-159. doi: 10.1016/S1474-4422(25)00426-0.
• Ghisays V, Lopera F, Goradia DD, Protas HD, Malek-Ahmadi MH, Chen Y, Devadas V, Luo J, Lee W, Baena A, Bocanegra Y, Guzman-Velez E, Pardilla-Delgado E, Vila-Castelar C, Fox-Fuller JT, Hu N, Clayton D, Thomas RG, Alvarez S, Espinosa A, Acosta-Baena N, Giraldo MM, Rios-Romenets S, Langbaum JB, Chen K, Su Y, Tariot PN, Quiroz YT, Reiman EM; API ADAD Colombia Trial Group. PET evidence of preclinical cerebellar amyloid plaque deposition in autosomal dominant Alzheimer's disease-causing Presenilin-1 E280A mutation carriers. Neuroimage Clin. 2021;31:102749. doi: 10.1016/j.nicl.2021.102749. Epub 2021 Jul 4.
• Ramirez Aguilar L, Acosta-Uribe J, Giraldo MM, Moreno S, Baena A, Alzate D, Cuastumal R, Aguillon D, Madrigal L, Saldarriaga A, Navarro A, Garcia GP, Aguirre-Acevedo DC, Geier EG, Cochran JN, Quiroz YT, Myers RM, Yokoyama JS, Kosik KS, Lopera F. Genetic origin of a large family with a novel PSEN1 mutation (Ile416Thr). Alzheimers Dement. 2019 May;15(5):709-719. doi: 10.1016/j.jalz.2018.12.010. Epub 2019 Feb 10.

Drugs

Evaluation	Drug	Modality	Dose	Route
Subject	Crenezumab	Monoclonal antibody	60 mg/kg	Subcutaneous
Subject	Crenezumab	Monoclonal antibody	720 mg	Subcutaneous

Indications