Latozinemab Shows No Impact on Disease Progression in C9orf72 Frontotemporal Dementia Despite increasing Progranulin Expression

Albert Ludolph, MD, PhD

Full 12-month data from the open-label, phase 2 INFRONT-2 study (NCT03987295) suggested that treatment with latozinemab (Alector), an investigational monoclonal antibody, had no significant impact on disease progression among patients with C9orf72-associated frontotemporal dementia (FTD).¹

Comprised of 16 individuals with FTD-C9orf72 or FTD-GRN mutations, the study assessed the safety, tolerability, and pharmacokinetics of latozinemab, also known as AL001, administered intravenously every 4 weeks. Presented in a late-breaking poster at the 2023 Clinical Trials on Alzheimer’s Disease (CTAD) conference, held October 24-27, in Boston, Massachusetts, investigators used the Clinical Dementia Rating (CDR) plus National Alzheimer’s Coordinating Center (NACC) frontotemporal lobar degeneration-sum of boxes (FLTD-SB) as the primary end point, performed every 3 months.

To compare clinical progression, senior investigator Albert Ludolph, MD, PhD, professor of neurology and chairman of the department of neurology at the University Hospital and Medical Faculty of Ulm, and colleagues, matched participants from the study to ALLFTD, an observational cohort. After 12 months of treatment, findings showed that the rate of clinical progression did not differ between participants receiving latozinemab in INFRONT-2 and untreated matched controls in the Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Research study.

Over this time, investigators observed an estimated treatment effect of –0.5 CDR units (95% CI, –2.98 to 2.05) with latozinemab, although variability was high. In both plasma and cerebrospinal fluid (CSF) assessments, glial fibrillary acidic protein and neurofilament light, 2 biomarkers of neuroaxonal damage, remained unchanged over the course of treatment. Despite not demonstrating clinical efficacy, the therapy was found to be generally safe and well-tolerated among treated individuals. Due to the small sample size and high degree of variability in disease progression in both groups, investigators deemed these findings as uninformative to assess the therapy’s treatment effect.

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C9orf72 repeat expansions are the most common genetic cause of the neurodegenerative diseases FTD and amyotrophic lateral sclerosis. Both decreased progranulin (PGRN) levels and mutations in the C9orf72 gene are associated with abnormal accumulation of the TAR DNA-binding protein 43 (TDP-43). Latozinemab, designed to block and downregulate the sortilin receptor, a degradation pathway for PGRN, resulted in a sustained 2-fold increase in PGRN levels in plasma and CSF throughout the 12-month analysis; however, this did not lead to improved outcomes.

As CTAD was ongoing, Alector also announced that it achieved target enrollment for its pivotal phase 3 INFRONT-3 study assessing latozinemab in patients with FTD due to a progranulin gene mutation (FTD-GRN). After having a type C meeting with the FDA earlier in the year, Alector and GSK aligned to conduct a preliminary analysis on patients with symptomatic FTD-GRN, supporting an enrollment target of approximately 90-100 symptomatic participants in the study.²

INFRONT-3, a randomized, double-blind, placebo-controlled trial, randomizes participants to receive latozinemab or placebo intravenously every 4 weeks for a 96-week trial duration. Following the treatment period, patients have the option to continue receiving therapy an open-label extension. The primary end point of the study is change in disease progression, as measured by the NACC FTLD-SB, a validated instrument of FTD severity. In addition to other clinical and functional outcome assessments, the study will look at CSF and plasma biomarkers assessing PGRN levels, along with multiple disease-relevant biomarkers of lysosomal function, complement activation, astrocyte function, neurodegeneration, and brain atrophy.

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REFERENCES
1. Carter L, Ljubenkov P, Seelaar H, et al. Twelve-month results in FTD-C9orf72 participants from INFRONT-2: a phase 2 study of latozinemab (AL001) in FTD. Presented at: Clinical Trials on Alzheimer’s Disease conferece; Oct 24-27, 2023; Boston, MA. POSTER LB27.
2. Alector announces achievement of target enrollment in the pivotal INFRONT-3 phase 3 clinical trial of latozinemab in individuals with frontotemporal dementia due to a progranulin gene mutation (FTD-GRN). News release. October 27, 2023. Accessed October 30, 2023. https://investors.alector.com/news-releases/news-release-details/alector-announces-achievement-target-enrollment-pivotal-infront