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Phase 3 TRAILRUNNER-ALZ 3 to Test Effects of IgG1 Monoclonal Antibody Remternetug in Early Alzheimer Disease
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Key Takeaways
- The phase 3 study will assess remternetug's efficacy in early-stage Alzheimer's, focusing on amyloid plaque reduction and cognitive outcomes.
- The trial design includes a double-blind period, an extension phase, and a safety cohort, with decentralized elements for remote assessments.
The multicenter, randomized, double-blind, placebo-controlled, parallel-group, event-driven trial will use time to clinical progression, defined as an increase in Clinical Dementia Rating score, as the primary end point.
Kevin Biglan, MD, MPH
At the 2024 Clinical Trials on Alzheimer’s Disease (CTAD) conference, held October 29-November 1 in Madrid, Spain, a poster covered the trial design of a phase 3 study assessing remternetug (Eli Lilly), an investigational agent, in patients with early-stage Alzheimer disease (AD). Enrollment for the study is anticipated to open in October 2024 to test the effects of the agent, an IgG1 monoclonal antibody directed at deposited brain amyloid plaques.1
This unique study, which is conducted both onsite and remotely, will evaluate subcutaneous remternetug vs placebo in an initial double-blind period of 600 participants with early AD. Following the 52-week main study period, participants will continue participation for up to an additional 76 weeks in an extension period. The trial also includes an addendum safety cohort, featuring 974 participants with early AD, who will be administered open label remternetug via subcutaneous injection or intravenous infusion. Of note, participants enrolled into the addendum safety cohort are not eligible for the extension period.
Lead author Kevin M. Biglan, MD, MPH, a professor of neurology and associate chair for Clinical Research in the Department of Neurology at the University of Rochester School of Medicine, and colleagues, will use change in Clinical Dementia Rating score as the primary end point of the study. The study also includes other secondary outcomes that assess cognition, behavior and function, descriptive safety, pharmacokinetics, and immunogenicity. In addition, the study will supposedly implement multiple decentralized elements including cognitive outcome measures assessed by a remote central rater.
Remternetug, an N3pH-Aß monoclonal antibody, is a follow-on to donanemab, Eli Lilly’s approved anti-amyloid antibody also designed against pyroglutamated amyloid-ß. To be included in the trial, patients must have a gradual and progressive change in cognitive function at least 6 months prior to screening, as well as have a Mini-Mental State Exam score of 20 to 30 at screening. The study excludes those who’ve had prior treatment with a passive anti-amyloid immunotherapy, have received active immunization against amyloid-ß in any other study, or has evidence of significant abnormality that would suggest another potential etiology for progressive dementia.
READ MORE: Risk of ARIA-E in Donanemab Attenuated Through New Enhanced Titration Method of Delivery
In a phase 1 multiple ascending dose (MAD) study, remternetug demonstrated significant amyloid plaque removal among patients with mild cognitive impairment or mild to moderate dementia due to AD. 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 169.2
By day 169 of treatment, 75% (18 of 24) of participants on remternetug doses between 700 and 2800 mg Q4W had amyloid clearance totaling less than 24.1 centiloids. The therapy was considered well-tolerated, with no treatment-emergent antidrug antibodies detected. Amyloid-related imaging abnormalities (ARIA), an issue for anti-amyloid therapies, was the most common treatment-emergent adverse event, observed in 10 participants, with 1 reporting a symptomatic event.
Earlier this year, the Dominantly Inherited Alzheimer Network announced that remternetug would be tested in the Knight Family DIAN-TU Primary Prevention Trial, replacing gantenerumab after its discontinuation. The trial will enroll 240 patients as young as 18 and will include mutation and noncarriers. Participants will receive remternetug 4 times annual for 2 years, via subcutaneous injection. Investigators will primarily assess changes in amyloid accumulation, with fluid biomarkers as secondary end points.3
Click here for more coverage of CTAD 2024.
