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 October 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. The study plans to run at 75 sites in the U.S. and two in Japan. Recruiting began in October 2022, with completion expected in October 2025.

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. 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.

For all trials of LY3372993, see clinicaltrials.gov.