Phase 3 INFRONT-3 Study Details Baseline Characteristics of Participants With FTD-GRN

At the 2025 American Academy of Neurology (AAN) Annual Meeting, held April 5-9, in San Diego, California, researchers presented baseline characteristics for participants in the INFRONT-3 study (NCT04374136), a phase 3 trial evaluating investigational latozinemab (Alector) for frontotemporal dementia (FTD) caused by GRN mutations.¹ The INFRONT-3 trial, a pivotal, multicenter, randomized, double-blind, placebo-controlled study spanning 96 weeks, may provide insights on the disease progression of this specific patient population.

The trial enrolled participants in 2 cohorts: an At-risk Cohort with a Clinical Dementia Rating (CDR) plus National Alzheimer’s Disease Coordinating Center Frontotemporal Lobar Degeneration Sum of Boxes (NACC FTLD-SB) score of at most 0.5 and elevated serum neurofilament light chain (NfL) levels, and a Symptomatic Cohort with a CDR plus NACC FTLD-SB score more than 0.5 and clinical symptoms of behavioral variant FTD (bvFTD) or primary progressive aphasia (PPA).

Presented by lead author Lawrence Carter, PhD, vice president of clinical development at Alector, a total of 119 participants were enrolled, including 103 in the Symptomatic Cohort. Overall, global CDR scores at baseline were 0 (n = 15), 0.5 (n = 25), 1 (n = 47), and 2 (n = 32) for the enrolled patients. Researchers noted that the mean participant age was 62 years (range, 37-85), with 51% women and 89% Caucasian.

Additional baseline findings showed that the At-risk Cohort had a mean CDR-SB score of 0.0 (± 0.13) and a median serum NfL of 14.4 pg/mL (range, 7.8-42.9). In contrast, the Symptomatic Cohort had a mean CDR-SB score of 6.9 (± 4.05) and a median serum NfL of 66.9 pg/mL (range, 6.5-190.0). Among symptomatic participants, authors reported that 64 were diagnosed with bvFTD, 28 with PPA, and 7 with both bvFTD and PPA.

Latozinemab, which modulates progranulin (PGRN) levels by blocking the sortilin receptor, has previously shown potential in increasing PGRN to physiologic levels and slowing disease progression. The INFRONT-3 study aims to assess the efficacy and safety of latozinemab as a potential first-in-class treatment for FTD-GRN, encompassing a broad range of disease severity in its participant population.

In November 2024, Alector announced that its investigational agent AL002, a triggering receptor expressed on myeloid cells 2 (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 noted it would stop the long-term extension study.²

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 CDR 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.

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 because of AD for 67% of participants and mild dementia due to AD for 33% of the participants.³

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, whereas increasing TREM2 activity could potentially activate the brain's immune system to target multiple AD pathologies.

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).³

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REFERENCES
1. Carter L, Borroni B, Mummery C, et al. Baseline Characteristics for INFRONT-3: A Phase 3 Double-Blind, Placebo-Controlled 96-Week Study Evaluating Latozinemab in FTD-GRN. Presented at: 2025 AAN Annual Meeting; April 5-9; San Diego, CA.
2. 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 April 4, 2025. 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 April 4, 2025. https://alector.gcs-web.com/news-releases/news-release-details/alector-presents-baseline-characteristics-invoke-2-phase-2