Amyloid clearance was achieved by 75% of participants who received remternetug at doses ranging from 700 to 2800 mg IV Q4Q by day 169.
New interim data from a phase 1 multiple ascending dose (MAD) study (NCT04451408) of patients with mild cognitive impairment or mild to moderate dementia due to Alzheimer disease (AD) showed that treatment with remternetug, an investigational agent developed by Eli Lilly, resulted in rapid and robust amyloid plaque reduction.1
The interim analysis, presented at the 2023 International Conference on Alzheimer’s and Parkinson’s Diseases and related neurological disorders (AD/PD), included 41 participants who were randomly assigned 1:5 to intravenous infusions of placebo or remternetug at a dose range of 250 to 2800 mg every 4 weeks. Patients were between 59 and 84 years old and had amyloid plaque levels measured by florbetapir PET at screening, day 85 and day 169.
Remternetug, an N3pH-Aß monoclonal antibody, is a follow-on to donanemab, Eli Lilly’s phase 3 antibody also designed against pyroglutamated amyloid-ß. Initiated in July 2020, the newly presented findings showed dose-dependent amyloid plaque lowering across all dosing regimens tested. Through mixed model repeated measures, investigators observed P values of less than 0.001 relative to placebo for each group except those on 250 mg Q4W at day 85.
Presented by Yan Jin, MD, MS, vice president of Exploratory Medicine and Pharmacology, Eli Lilly, the data revealed that 75% (18 of 24) of participants on remternetug doses between 700 to 2800 mg Q4W had amyloid clearance totaling less than 24.1 centiloids by day 169. In addition to its positive efficacy, the agent was shown to be well-tolerated, with no treatment-emergent antidrug antibodies detected. Amyloid-related imaging abnormalities (ARIA), an issue that has plagued the AD community, was the most common treatment-emergent adverse event, observed in 10 participants, with 1 reporting a symptomatic event.
At the conclusion of the study, Jin and colleagues concluded that the safety, tolerability, and pharmacokinectic/pharmacodynamic data support the ongoing phase 3 trial (NCT05463731), which was initiated in August 2022. Named TRAILRUNNER-ALZ1, this study will enroll 600 participants with early symptomatic AD into a double-blind period where they will receive remternetug or placebo for 52 weeks. Following the main study period, participants will continue participation for an additional 52 weeks in an extension period, with both groups crossing over to the opposite treatment.
The phase 3 trial, expected to complete in March 2025, will use percentage of patients who reach amyloid plaque clearance on amyloid PET as the primary outcome measure, with other secondary outcomes that include mean absolute change in brain amyloid plaque, time to reach complete amyloid plaque clearance, and pharmacokinetics, among others. Eligible patients must have a Mini-Mental State Examination score of 20 to 28, have phosphorylated tau scan consistent with the presence of brain amyloid pathology, and have gradual and progressive change in cognitive function at least 6 months prior to screening. An additional safety cohort of 640 participants will receive open-label intravenous remternetug for 1 year and will not be eligible for the extension period.