Early Phase 3 Data Highlight Convenience and Feasibility of Self-Administered Alzheimer Agent Remternetug

A newly presented analysis of the phase 3 TRAILRUNNER-ALZ-1 trial (NCT05463731) showed that remternetug (Eli Lilly), a self-administered investigational monoclonal antibody targeting amyloid-ß (Aß), was feasible to use in patients with Alzheimer disease (AD) in stages 3 and 4. These results suggest that subcutaneous (SC) self-injection is a practical option for remternetug, particularly for earlier-stage patients with AD enrolled in the ongoing TRAILRUNNER-ALZ 3 secondary prevention trial (NCT06653153).¹

Presented at the 2025 Clinical Trials on Alzheimer’s Disease (CTAD) Conference, held December 1-5 in San Diego, California, the analysis investigated the feasibility of SC self-administration of remternetug in a cohort of 197 patients with early AD who received at least 1 injection of the agent or placebo. Presented by Matthew Hufford, director of Neurodegeneration at Eli Lilly, patients were assigned to 2 cohorts and received either subcutaneous remternetug or placebo: cohort 1 received remternetug weekly or monthly, while cohort 2 received monthly remternetug or placebo.

Coming into the study, the majority of the cohort were White (91.4%), with most patients having Mini-Mental State Exam (MMSE) scores between 20-26 (69.0%), considered mild cognitively impaired. Of the 197 participants, 58 (29.4%) self-administered at least once and 112 (56.9%) never self-administered. Of the 58 participants with at least 1 self-injection, the mean number of self-injections was 8.6 (SD, 5.0) and the median was 8 out of a maximum of 19 possible injections.

Compared with participants who never self-administered an injection, those who self-administered at least one were more likely to be ApoEε4 carriers (70.7% vs 59.8%), less likely to be using symptomatic AD treatments (31.0% vs 45.5%), and more likely to have an MMSE score greater than 26 (48.3% vs 21.4%). Notably, there were no clear differences in other baseline characteristics including amyloid burden between the groups.

TRAILRUNNER-ALZ-1 includes a 52-week double-blinded period, followed by a planned open-label extension lasting up to 76 weeks. The trial, which is expected to be completed by 2026, uses percentage of patients who reach amyloid plaque clearance, measured through amyloid PET scans, as the primary outcome measure. Other secondary outcomes include time to reach complete amyloid plaque clearance, pharmacokinetics, and safety, including treatment-emergent anti-drug antibodies.

READ MORE: Incorporation of Mini-Mental State Exam Z-Scores May Increase Eligibility for Anti-Amyloid Treatments, Study Suggests

As mentioned, 56.9% (n = 112) of participants had at least 1 non-healthcare professional (HCP) SC injection. Among these patients, most injections (88.5%; 1019 of 1151) were self-administered (43.1%) or administered by a study partner (45.4%), and only 10.5% were administered by a healthcare professional.

Remternetug, an investigational monoclonal antibody, targets a pyroglutamated Aß, a form of Aß involved in the aggregated amyloid plaque characteristic of AD. The drug is a follow-on to donanemab (Kisulna; Eli Lilly), one of the 2 FDA-approved therapies currently on market that target Aß for patients with AD.

In addition to TRAILRUNNER-ALZ 1, the drug is currently being investigated in TRAILRUNNER-ALZ 3, a large-scale preventive study of patients with early AD lasting up to 255 weeks. TRAILBLAZER-ALZ 3, which had its protocol revealed at CTAD 2024, is a unique study, incorporating both onsite and virtual assessments. The study includes a 52-week double-blind phase, followed by an extension. An additional open-label safety cohort of 974 participants will receive SC or intravenous remternetug; however, those in the safety cohort are not eligible for the extension period.²

In a previously completed phase 1 multiple ascending dose study, remternetug demonstrated strong amyloid-clearing activity in patients with mild cognitive impairment or mild to moderate AD. Interim data from the 2023 AD/PD Conference included 41 participants aged 59 to 84 years randomized 1:5 to placebo or intravenous remternetug at doses of 250 to 2800 mg every four weeks, with amyloid burden measured by florbetapir PET at screening, day 85, and day 169. By day 169, 75 percent of those receiving 700 to 2800 mg (18 of 24 participants) reached amyloid levels below 24.1 centiloids. The therapy was generally well tolerated with no treatment-emergent antidrug antibodies, although amyloid-related imaging abnormalities were common, occurring in 10 participants, including one symptomatic case.³

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REFERENCES
1. Hufford M, Biglan K, Stroud C, et al. Feasibility of Participants With Symptomatic Alzheimer’s Disease to Self-Administer Remternetug Subcutaneously: Results From the TRAILRUNNER-ALZ 1 Phase 3 Trial. Presented at: 2025 Clinical Trials on Alzheimer Disease conference. December 1-5; San Diego, CA. Abstract P040.
2. Biglan K, Rizvi E, Wang T, et al. Study design for TRAILRUNNER-ALZ 3: a double-blind, placebo-controlled, phase 3 clinical trial investigating subcutaneous remternetug in early Alzheimer’s disease. Presented at: Clinical Trials on Alzheimer’s Disease conference; October 29-November 1, 2024; Madrid, Spain. ABSTRACT LB15.
3. Jin Y. Safety and amyloid plaque reduction effects of remternetug in patients with Alzheimer’s disease: interim analysis from a phase 1 study. Presented at: 2023 AD/PD Conference; March 28 to April 1; Gothernburg, Sweden.