Phase 3 Trial of Remternetug for Early Alzheimer's Disease Assesses Subcutaneous Administration
Key Insights
A Phase 3 trial, TRAILRUNNER-ALZ 3, is set to evaluate remternetug, an IgG1 monoclonal antibody, in early-stage Alzheimer's disease (search), with enrollment beginning in October 2024.
The study will assess subcutaneous remternetug versus placebo over 52 weeks, followed by an extension period, and includes a safety cohort receiving open-label remternetug.
The primary endpoint is the change in Clinical Dementia Rating score, with secondary outcomes evaluating cognition, behavior, function, safety, pharmacokinetics, and immunogenicity.
Eli Lilly's remternetug, an investigational IgG1 monoclonal antibody, is under evaluation in the Phase 3 TRAILRUNNER-ALZ 3 trial for patients with early-stage Alzheimer's disease (search) (AD). The trial, designed to assess the efficacy and safety of subcutaneous remternetug, commenced enrollment in October 2024. This study aims to determine if remternetug can slow the progression of Alzheimer's disease by targeting deposited amyloid plaques (search) in the brain.
The TRAILRUNNER-ALZ 3 trial is a combined onsite and remote study involving 600 participants with early AD. During the initial double-blind phase, participants will receive either subcutaneous remternetug or a placebo over a 52-week period. Following this, participants can continue in an extension period for up to 76 weeks. An additional safety cohort of 974 participants with early AD will receive open-label remternetug via subcutaneous injection or intravenous infusion; however, these participants will not be eligible for the extension period.
The primary endpoint of the study is the change in Clinical Dementia Rating (CDR) score. Secondary outcomes include assessments of cognition, behavior, and function, as well as descriptive safety, pharmacokinetics, and immunogenicity. The trial will also incorporate decentralized elements, such as cognitive outcome measures assessed by a remote central rater, according to lead author Kevin M. Biglan, MD, MPH, from the University of Rochester School of Medicine.
Remternetug, an N3pH-Aβ monoclonal antibody, is a follow-on to Eli Lilly’s donanemab, targeting pyroglutamated amyloid-β. Inclusion criteria for the trial require patients to have experienced a gradual and progressive change in cognitive function for at least six months prior to screening and a Mini-Mental State Exam (MMSE) score between 20 and 30 at screening. Exclusion criteria include prior treatment with passive anti-amyloid immunotherapy, active immunization against amyloid-β in another study, or evidence of significant abnormalities suggesting an alternative etiology for progressive dementia.
In a Phase 1 multiple ascending dose (MAD) study, remternetug demonstrated significant amyloid plaque removal in patients with mild cognitive impairment or mild to moderate dementia due to AD. Interim analysis from the 2023 AD/PD Conference included 41 participants randomized 1:5 to intravenous infusions of placebo or remternetug at doses ranging from 250 to 2800 mg every four weeks. By day 169, 75% (18 of 24) of participants receiving remternetug doses between 700 and 2800 mg every four weeks showed amyloid clearance totaling less than 24.1 centiloids. The therapy was generally well-tolerated, with no treatment-emergent antidrug antibodies detected. Amyloid-related imaging abnormalities (ARIA) were the most common treatment-emergent adverse event, observed in 10 participants, with one symptomatic event.
Earlier in 2024, the Dominantly Inherited Alzheimer Network announced that remternetug would be tested in the Knight Family DIAN-TU Primary Prevention Trial, replacing gantenerumab. This trial will enroll 240 participants as young as 18, including both mutation carriers and non-carriers, who will receive remternetug four times annually for two years via subcutaneous injection. The primary assessment will focus on changes in amyloid accumulation, with fluid biomarkers serving as secondary endpoints.