Design of a patient‐ and investigator‐blind, randomized, placebo‐controlled study to evaluate efficacy, safety, and tolerability of bepranemab, UCB0107, in prodromal to mild Alzheimer’s disease: The TOGETHER Study, AH0003

Abstract

AbstractBackgroundBepranemab is a recombinant, humanized, full‐length immunoglobulin G4 monoclonal antibody that binds to a central tau epitope (amino acids 235–250). Bepranemab is being developed to block or reduce the spread of tau pathology in people living with tau‐mediated diseases, like Alzheimer’s disease (AD).MethodTOGETHER (AH0003; NCT04867616) is a global, multicenter, patient‐blind, investigator‐blind, placebo‐controlled, parallel‐group study, investigating the efficacy, safety, and tolerability of bepranemab (intravenously, every 4 weeks) versus placebo in patients with prodromal (40%) or mild (60%) AD over an 80‐week treatment period, followed by an optional 48‐week open‐label extension (OLE). The primary objective is the change from baseline to Week 80 in the Clinical Dementia Rating (CDR) Scale Sum of Boxes total score. Secondary objectives include: pharmacokinetics (PK); safety and tolerability; the effect of bepranemab on tau positron emission tomography (PET) imaging at Weeks 56 and 80; and the changes from baseline in the 14‐item Alzheimer’s Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog14), Amsterdam‐Instrumental Activities of Daily Living, and Mini‐Mental State Examination (MMSE) at Weeks 56 and 80. The OLE will assess the long‐term safety and tolerability of bepranemab. Approximately 150 patients per arm will be enrolled across 3 study arms (low‐dose and high‐dose bepranemab, and placebo; randomized 1:1:1). Eligible patients will meet the National Institute of Aging‐Alzheimer’s Association (NIA‐AA) 2018 Stage 3 or 4 definitions of prodromal or mild AD, respectively. Patients will have a global CDR score indicative of prodromal AD (0.5) or mild AD (0.5 or 1.0) and a CDR‐Memory Box score ≥0.5 at screening and baseline. Patients will have a score of ≤85 for the delayed recall domain of the Repeatable Battery for the Assessment of Neuropsychological Status, MMSE ≥20 at screening and must meet the NIA‐AA 2018 definition of cerebral beta‐amyloid (Aβ) accumulation, by either a positive centrally read PET scan or a positive cerebrospinal fluid pTau181/Aβ1‐42 ratio.ResultPatient enrollment and assessment will begin in Quarter 2 2021.ConclusionTOGETHER is a proof‐of‐concept study that will employ clinical outcome measures, imaging, PK, biomarkers, and safety to assess the ability of bepranemab to slow the progression of AD when administered in the prodromal/mild stages of disease.