Rare Daily Staff

Immuno-neurology drug developer Alector presented positive results from the company’s INFRONT-2 phase 2 clinical trial of AL001, its experimental therapy for at risk for or with symptomatic frontotemporal dementia due to a progranulin gene mutation.

FTD is a rare neurodegenerative disease, but it is the most common form of dementia for people under the age of 60.  It affects an estimated 50,000 to 60,000 people in the United States and roughly 110,000 in the European Union, with potentially higher prevalence in Asia and Latin America. There are multiple heritable forms of frontotemporal dementia, and FTD-GRN patients represent 5 percent to 10 percent of all people with FTD. Patients with FTD frequently develop symptoms such as behavioral changes, lapses in judgment, and diminished language skills when they are in their 40’s and 50’s with the disease running its course in seven to 10 years. There are currently no FDA-approved treatment options available for any form of frontotemporal dementia.

AL001 is a potential first-in-class monoclonal antibody designed to elevate progranulin, a key regulator of immune activity in the brain. Decreased progranulin levels due to genetic mutations are a known cause FTD.

The open-label INFRONT-2 phase 2 study was designed primarily to assess the safety and tolerability of chronic dosing of AL001 over 96 weeks. INFRONT-2 included three cohorts of FTD patients: asymptomatic FTD-GRN patients, symptomatic FTD-GRN patients and FTD-C9orf72 patients. Biomarker and clinical results focused on the symptomatic FTD-GRN cohort and included 12-month data for up to twelve patients who received 60mg/kg of AL001 every four weeks. As of the data cut, nine FTD-GRN patients had completed twelve months of treatment, and between seven and nine patients were able to complete all assessments.

The company presented data that focused on up to twelve symptomatic FTD-GRN patients treated over twelve months in an open-label study designed to assess safety, pharmacokinetics and pharmacodynamics, exploratory biomarkers and efficacy. AL001 showed a favorable safety profile and rapidly restored progranulin levels to normal ranges in both plasma and cerebrospinal fluid (CSF) for the duration of treatment.

Among the symptomatic FTD-GRN cohort, AL001 treatment resulted in rapid and sustained 2 to 2.5-fold elevations of progranulin comparable to normal levels from an age-matched procured control group of healthy volunteers.

While the INFRONT-2 phase 2 study was not designed to demonstrate clinical benefit, clinical outcome assessments using the CDR plus NACC FTLD-SB scale, a standard clinical rating instrument that assesses cognitive, functional, behavioral, and language impairments in FTD over time, found that AL001 treatment slowed clinical progression by 47 percent compared to a matched control cohort of participants from the Genetic FTD Initiative. Additionally, multiple disease-relevant biomarkers of lysosomal function, complement activation, and neuronal health trended toward normalization or remained stable.

Safety data was reported across all three cohorts who received a median of 15 doses of AL001. AL001 showed a favorable safety profile in the phase 2 study. Six of the 27 patients reported mild treatment-related adverse events. The most common adverse events observed on study in more than two patients were falls (18.5 percent) and rash (11.1 percent). Three patients in the FTD-GRN cohort experienced serious adverse events, but none of these were attributed to treatment with AL001.

“Though this is a small open-label study, the totality of the data presented from the INFRONT-2 Phase 2 study paint an encouraging picture of AL001’s potential to slow disease progression in patients with FTD, a devastating disease for which there are currently no approved treatment options,” said Robert Paul, Alector’s chief medical officer. “Chronic treatment with AL001 demonstrated durable, on-target activity with a complete reversal of the progranulin deficiency that is causing disease. The effect of AL001 treatment on clinical disease progression, and consistent improvements observed across diverse biomarkers, strengthen our confidence that AL001 is working as designed.”

Alector is actively enrolling the INFRONT-3 phase 3 pivotal clinical study of AL001 in at-risk and symptomatic carriers of the progranulin mutation causative of FTD. The global randomized, double-blind, placebo-controlled study is designed to assess the efficacy and safety of AL001 in inhibiting disease progression with the primary endpoint, CDR plus NACC FTLD-SB scale. AL001 is also being studied in FTD patients with a C9orf72 mutation, with plans to begin testing AL001 in C9orf72 amyotrophic lateral sclerosis (ALS) in the second half of 2021.

Photo: Robert Paul, Alector’s chief medical officer

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