Background

Remternetug, previously LY3372993, is an investigational monoclonal antibody. Lilly's development pipeline lists it as an N3pG-Aβ mAb, suggesting it recognizes a pyroglutamated form of Aβ that is aggregated in amyloid plaques. LY3372993 is a follow-on to donanemab, the company's FDA-approved antibody also against pyroglutamated Aβ.

Findings

In November 2018, Lilly started a Phase 1 trial with the intention to compare LY3372993 to placebo in 100 healthy adults and people with MCI due to Alzheimer's disease or mild to moderate AD. The study delivered intravenous infusions of single or multiple escalating doses of LY3372993, and assessed adverse events, LY3372993 exposure in blood, and its ability to affect brain amyloid as measured by florbetapir PET. This study was set to run at eight U.S. centers until October 2020, but in April 2019, Lilly decided to terminate the trial after testing 36 healthy adults, and never enrolled any participants with AD. Study results were not made public.

In July 2020, Lilly began a separate Phase 1 study in people with AD. Thirty participants with clinically diagnosed mild cognitive impairment due to AD, or AD dementia, are receiving multiple escalating doses of antibody, or placebo, over nine months. The primary outcome is the number of serious adverse events; secondary outcomes include pharmacokinetics and change in brain amyloid from baseline to week 25. In 2021, the company added a second part to this trial, enrolling an additional 32 healthy adults of first-generation Japanese origin to receive a single infusion of antibody or placebo. Through 2021 and 2022, enrollment was adjusted upward twice to a final of 224, the treatment period increased to 61 weeks, and the study added subcutaneous dosing. Conducted at 10 U.S. sites and three in Japan, the trial will run through November 2024.

The company presented interim Phase 1 data at the March-April 2023 AD/PD Conference in Gothenburg, Sweden (Apr 2023 conference news). They reported on 41 participants who received 250, 700, 1,400, or 2,800 mg of remternetug, monthly, or placebo, for six months. One cohort was titrated from 700 to 1,400 mg. After six months, plaque was dose-dependently reduced in all cohorts. On 2,800 mg, every participant dropped below the amyloid positivity threshold within three months. Safety data remains blinded, but overall there were 10 ARIA-E and seven ARIA-H cases, without obvious dose correlation. All the ARIA-E cases occurred in APOE4 carriers; one was symptomatic. Neither antidrug antibodies nor systemic infusion reactions were identified.

In August 2022, Lilly started a Phase 3 called TRAILRUNNER-ALZ1. It was initially going to randomize 400 people with early symptomatic AD to receive antibody or placebo for one year, with dosing by either intravenous infusion or subcutaneous injection. The primary outcome is percentage of patients whose amyloid plaques are cleared by the end of treatment period. Secondary outcomes further measure amyloid clearance, pharmacokinetics, and anti-drug antibodies. The trial includes a year-long blinded extension, where remternetug recipients will cross over to placebo, and placebo recipients to drug. An additional safety cohort of 400 patients will receive open-label intravenous remternetug for one year. In 2023, enrollment in the placebo-controlled study was increased to 600. The safety cohort expanded to 640, and added subcutaneous dosing. Another expansion brought the safety cohort to 974. The study is running at 73 sites in the U.S. and three in Japan. The blinded portion of the study finished in June 2024. Study completion is expected in March 2026.

On May 7, 2024, the Dominantly Inherited Alzheimer Network announced that remternetug would be tested in the Knight Family DIAN-TU Primary Prevention Trial (press release). According to a presentation at the 2024 AAIC, the trial will enroll 240 people as young as 18, and will include mutation carriers and noncarriers (Aug 2024 news). Participants will get remternetug four times annually for two years, via subcutaneous injection. The primary outcome is amyloid accumulation, with fluid biomarkers as secondaries. A four-year open-label extension will be offered to mutation carriers, and include cognition as a secondary outcome. Enrollment began in November 2024, with completion anticipated in 2034. This study was originally planned to begin in December 2022 and test Roche’s gantenerumab, but its launch was delayed when development of that antibody stopped.

In October 2024, a Phase 3 trial began to test remternetug in early Alzheimer’s patients. The TRAILRUNNER-ALZ 3 study plans to enroll 1,200 participants for 18 months of home treatment with subcutaneous injections, followed by a blinded observation period, against a primary endpoint of time to progression on the Clinical Dementia Rating (Nov 2024 conference news). Secondary outcomes include the CDR-SB, and a battery of cognitive, behavioral, and functional tests, serum antibody concentrations, and adverse events. Participants must have plasma pTau217 consistent with amyloid pathology, and no or minimal cognitive or functional impairment. The trial includes an amyloid and tau PET substudy, and an open-label extension. It is planned to run until 2029.

For all trials of LY3372993, see clinicaltrials.gov.