Alector Presents AL001 (latozinemab) Data from the FTD-C9orf72 Cohort of the INFRONT-2 Phase 2 Clinical Trial
Treatment with AL001 (latozinemab) demonstrated target engagement and resulted in increases in progranulin levels in all patients
FTD-C9orf72 patients treated with latozinemab demonstrated a trend
toward a delay in disease progression relative to the ALLFTD matched control cohort
First clinical dataset in an indication where latozinemab elevated progranulin above physiological levels
Company to host webcast to review results today at
In 2021, Alector presented results showing that latozinemab elevated progranulin levels in a cohort of symptomatic carriers of the progranulin mutation causative of FTD (FTD-GRN) patients for the duration of treatment, and as compared to matched controls, showed associated changes in exploratory biomarkers and a trend toward a delay in annual disease progression. Today’s data from the FTD-C9orf72 cohort build upon the results observed in the Company’s studies to date in FTD-GRN patients.
The results presented include 12-month data from up to 10 symptomatic FTD-C9orf72 patients treated with 60 mg/kg of latozinemab every four weeks in an open-label study designed to primarily assess the safety and tolerability of chronic dosing. The study also includes exploratory clinical outcomes assessments and biomarkers. Highlights from the presentation included the following observations:
- Latozinemab was generally well tolerated when administered monthly for a year or more, consistent with other study cohorts.
- Latozinemab elevated progranulin in both plasma and cerebrospinal fluid (CSF) in FTD-C9orf72 patients for the duration of treatment.
- Clinical outcome assessments using the CDR® plus NACC FTLD-SB scale, a standard FTD clinical rating instrument that assesses cognitive, functional, behavioral and language impairments over time, found that when compared to a matched control cohort from the ALLFTD consortium, treatment with latozinemab in FTD-C9orf72 patients resulted in a trend toward a delay of approximately 54 percent in annualized disease progression.
- Mean levels of neurofilament light chain (NfL), a marker of axonal damage, remained stable over the course of treatment in both plasma and CSF in latozinemab-treated FTD-C9orf72 patients.
- Mean levels of glial fibrillary acidic protein (GFAP), a biomarker of astrogliosis that is an indicator of disease and/or injury to the central nervous system, decreased over 12 months in both plasma and CSF in latozinemab-treated FTD-C9orf72 patients.
In published preclinical studies from the literature, using multiple models of acute and chronic neurodegeneration, increased progranulin levels have been shown to be protective against TDP-43 pathology. TDP-43 pathology has been shown to be associated with the C9orf72 repeat expansion.
“Mutations in the C9orf72 gene are the most common genetic cause of frontotemporal dementia, a devastating disease with no approved treatments. These mutations are also an important cause of ALS,” said
Alector is actively enrolling the Phase 3 INFRONT-3 pivotal clinical study of latozinemab in at-risk and symptomatic FTD-GRN patients. The global randomized, double-blind, placebo-controlled study is designed to assess the efficacy and safety of latozinemab in inhibiting disease progression as measured through the primary endpoint, CDR® plus NACC FTLD-SB scale. Latozinemab is being developed in collaboration with GSK.
INFRONT-2 Phase 2 Clinical Trial Results
The open-label study was designed to assess safety and tolerability of chronic dosing of latozinemab, as well as to gather data related to pharmacokinetics and pharmacodynamics, exploratory biomarkers of pharmacologic activity and efficacy. INFRONT-2 included three cohorts of patients with FTD: asymptomatic FTD-GRN mutation carriers, symptomatic FTD-GRN patients, and symptomatic FTD-C9orf72 patients. Data presented today focused on the FTD-C9orf72 cohort and included 12-month data for up to 10 patients with at least one post-baseline clinical outcomes assessment, who received 60 mg/kg of latozinemab every four weeks. As of the data cut, six FTD-C9orf72 patients had completed 12 months of treatment and all biomarker and clinical outcomes assessments.
Latozinemab was well tolerated in the INFRONT-2 study. Twenty-eight study participants from all three cohorts were assessed for safety, with twenty-one patients treated for 12 months or more. Within the FTD-C9orf72 cohort there were a total of seven treatment related AEs, all of which were mild or moderate.
Treatment with latozinemab in the FTD-C9orf72 cohort resulted in elevated levels of progranulin when measured in both the plasma and CSF.
|Table 1: Progranulin Levels from Baseline to 12 months with Latozinemab Treatment (ng/mL)|
|123.6 (13.49)||324.4 (37.41)||315.7 (21.12)||4.4 (0.42)||9.3 (1.31)||8.7 (0.90)|
- CSF: cerebrospinal fluid, mean (standard error of the mean)
The CDR® plus NACC FTLD-SB scores in the ALLFTD matched control cohort had a projected annual increase of 3.4 points from baseline over one year. By comparison, the projected annual increase in the latozinemab treated FTD-C9orf72 cohort (N=10) from baseline was estimated at 1.6 points over one year. This suggested a trend toward an approximately 54 percent decrease in the annualized rate of clinical progression for patients treated with latozinemab. The CDR® plus NACC FTLD-SB scale is the primary endpoint being used to measure latozinemab’s efficacy in Alector’s ongoing INFRONT-3 Phase 3 clinical study.
|Table 2: Clinical Outcomes Assessment as Measured by the CDR® plus NACC FTLD-SB|
|Annual Change in ALLFTD matched control (n=10)1||3.4||[1.30,5.60]|
|Annual Change in latozinemab-treated group (n=10)2||1.6||[-0.63,3.78]|
|Difference in Annual Change (ALLFTD – latozinemab)3||1.9||[-1.21,4.95]|
|Percentage Decrease in Rate of Disease Progression||~54%||n/a|
1. ALLFTD matched control – one post-baseline timepoint at ~12 months.
2. Latozinemab-treated group – all available post-baseline assessments (range from 3 to 12 months).
3. Model – Random coefficient model with repeated measurements.
In order to provide context for the clinical outcomes assessed in the FTD-C9orf72 patients enrolled in the open-label INFRONT-2 study, a matched control cohort of FTD-C9orf72 patients from the ALLFTD database was created using propensity score matching and blinded clinical adjudication. ALLFTD is a comprehensive natural history study of FTD collecting cognitive and behavior assessment data, as well as imaging, blood and CSF biomarkers co-directed by Dr.
Changes in exploratory biomarkers from baseline to 12-months were also assessed. NfL, a marker of axonal damage, was measured in plasma and CSF. During the 12-month period of treatment, NfL levels in plasma and CSF remained stable in the latozinemab-treated FTD-C9orf72 cohort.
GFAP, a biomarker of astrogliosis that is an indicator of disease and/or injury to the central nervous system and is associated with faster rates of brain atrophy in FTD, was also measured. Treatment with latozinemab resulted in a decline of GFAP in both plasma and CSF in the latozinemab-treated FTD-C9orf72 cohort.
Conference Call Information
Alector management will host a conference call to review and discuss data presented at AD/PD™ today at
C9orf72 repeat expansions are the most common genetic cause of the neurodegenerative diseases frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Both decreased progranulin levels and mutations in the chromosome 9 open reading frame 72 (C9orf72) gene are associated with abnormal accumulation of the TAR DNA-binding protein 43 (TDP-43). Excess aggregation of TDP-43 in brain cells is thought to lead to neuronal cell death and is associated with multiple neurodegenerative diseases.
About Frontotemporal Dementia
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
Alector is a clinical-stage biotechnology company pioneering immuno-neurology, a novel therapeutic approach for the treatment of neurodegenerative diseases.
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Source: Alector, Inc.