AL002 Falls Short in Phase 2 INVOKE-2 Trial of Early Alzheimer Disease

Gary Romano, MD, PhD

In a company update, Alector announced that its investigational agent AL002, a TREM2-targeting therapy, did not meet any of its primary, secondary, or exploratory end points in the phase 2 INVOKE-2 trial (NCT04592874) of patients with early-stage Alzheimer disease (AD). As a result, the company is stopping the long-term extension study.¹

Alector also wrote that topline data from the pivotal phase 3 INFRONT-3 (NCT04374136) trial assessing its investigational agent latozinemab in frontotemporal dementia is expected in late 2025 or early 2026. Additionally, the company noted that the global phase 2 PROGRESS-AD trial, a study of AL101/GSK4527226 in early AD, has enrolled over one-third of its target of 282 participants.

INVOKE-2 was a double-blind, placebo-controlled, dose-ranging, multicenter study, that randomly assigned patients to 3 dose regimens of AL002 (15 mg/kg IV/Q4W; 40 mg/kg IV/Q4W, 60 mg/kg IV/Q4W) or placebo. Conducted at multiple sites across 11 countries, the trial utilized a common close design with up to 96 weeks of randomized treatment, where all participants remained on their assigned regimen until the last participant completed 48 weeks of treatment.

All told, results showed that treatment with AL002 failed to demonstrate statistical significance against placebo on the primary end point of Clinical Dementia Rating-Sum of Boxes score. Overall, investigators observed no significant effects on AD fluid biomarkers, as well as no treatment-related reduction of brain amyloid levels on amyloid PET imaging. Furthermore, the agent demonstrated no significant effect on secondary clinical and functional end points, indicating no therapeutic benefit.

"We, at Alector, recognize the importance of advancing therapeutics to treat Alzheimer’s disease and remain committed in our mission to develop safe and effective treatments for the millions of people worldwide impacted by neurodegenerative diseases," Gary Romano, MD, PhD, chief medical officer at Alector, said in a statement.¹ "With a robust dataset from the INVOKE-2 trial, we plan to further explore TREM2 biology. We extend our deepest gratitude to the dedicated investigators, patients and caregivers who made this important trial possible. We plan to share the results of the trial with the scientific community in the near future in the hopes of contributing to the understanding of AD pathophysiology and advancing effective therapeutics for this terrible disease."

INVOKE-2 featured 381 participants, with a median age of 71 years, and 78% of the cohort being 65 years of age or older. Overall, 50% of the participants were female and 94% were Caucasian. The clinical diagnosis at enrollment was mild cognitive impairment due to AD for 67% of participants and mild dementia due to AD for 33% of the participants.²

READ MORE: Alzheimer Agent Simufilam Fails to Meet Primary End Point in Phase 3 Study

Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane receptor protein expressed on some immune cells and microglia. AL002, an investigational, humanized monoclonal antibody that targets TREM2, was developed in collaboration with AbbVie. Previous large-scale genome-wide studies have shown genetic links to sporadic AD, with research suggesting that impaired TREM2 function may contribute to AD and dementia, while increasing TREM2 activity could potentially activate the brain's immune system to target multiple AD pathologies.

Recently, at the 2024 Alzheimer’s Association International Conference, Alector presented baseline characteristics for INVOKE-2. Treatment-emergent brain MRI changes resembling amyloid-related imaging abnormalities (ARIA) were observed in the trial, with higher incidence and severity in homozygous APOE e4 carriers. As a result, the company decided to discontinue these participants early. Of the 381 enrolled, 59% were heterozygous APOE e4 carriers. All participants were confirmed amyloid-positive prior to enrollment via cerebrospinal fluid analysis or amyloid PET. For the 244 participants with baseline amyloid PET data, the mean centiloid value was 100.1 (SD, 38.9).²

Alector’s will continue to test the effects of its other agent, AL001, in patients with or at risk for frontotemporal dementia due to progranulin gene mutation (FTD-GRN). The study is comprised of 180 patients with FTD-GRN mutations across approximately 50 sites in the US, Europe, and Australia. In the trial, symptomatic and presymptomatic patients receive AL001 or placebo intravenously every 4 weeks, with patients’ clinical decline assessed through CDR-SB.³

REFERENCES
1. Alector Announces Results from AL002 INVOKE-2 Phase 2 Trial in Individuals with Early Alzheimer’s Disease and Provides Business Update. News release. November 25, 2024. Accessed November 26, 2024. https://investors.alector.com/news-releases/news-release-details/alector-announces-results-al002-invoke-2-phase-2-trial
2. Alector Presents Baseline Characteristics for INVOKE-2 Phase 2 Clinical Trial of AL002 at the Alzheimer's Association International Conference® 2024 (AAIC®). News release. Alector. July 28, 2024. Accessed November 26, 2024. https://alector.gcs-web.com/news-releases/news-release-details/alector-presents-baseline-characteristics-invoke-2-phase-2
3. Alector doses first patient in pivotal phase 3 INFRONT-3 trial evaluating AL001 in patients with frontotemporal dementia. News release. Alector. Published online July 24, 2020. Accessed November 26, 2024. https://investors.alector.com/news-releases/news-release-details/alector-doses-first-patient-pivotal-phase-3-infront-3-trial