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TWELVE-MONTH RESULTS FROM THE INFRONT-2 PHASE 2 OPEN-LABEL STUDY OF AL001 IN FRONTOTEMPORAL DEMENTIA PATIENTS WITH A C9ORF72 MUTATION
Abstract
Aims
Frontotemporal dementia (FTD) is a rare, early-onset form of dementia, and hexanucleotide repeat expansions in the C9orf72 gene is the most common cause of familial FTD. Scientific evidence suggests a common pathway between C9orf72 and progranulin-mediated disease. Variants of GRN that reduce progranulin levels have been linked to shortened survival after disease onset in C9orf72 repeat expansion carriers. FTD-C9orf72 patients exhibit TDP-43 pathology, and in nonclinical studies progranulin was shown to reverse and protect against TDP-43 pathology, suggesting that increasing progranulin levels may reduce TDP-43 pathology in humans. AL001 is a human monoclonal IgG1 antibody that blocks and downregulates sortilin, a receptor in the key degradation pathway of progranulin, and is being developed by Alector for the treatment of FTD.
Methods
INFRONT-2 is an open-label, Phase 2 study investigating the safety, tolerability, pharmacokinetics, and pharmacodynamics of AL001 administered intravenously every four weeks in FTD-C9orf72 and FTD-GRN mutation carriers. Lumbar punctures and MRI scans were performed at baseline and every 6 months. Clinical assessments were done every 3 months. Fluid biomarkers were analyzed in plasma and CSF.
Results
Preliminary results demonstrated that AL001 is generally well tolerated in FTD-C9orf72 participants in INFRONT-2. Chronic dosing led to a sustained increase in progranulin levels throughout treatment. Preliminary data on clinical assessments and biomarkers will be presented for FTD-C9orf72 participants who have received AL001 for up to 12 months.
Conclusions
There is a high unmet need for effective therapies in FTD. AL001 is being developed for the treatment of FTD patients including FTD-C9orf72.