Randomized, placebo-controlled Phase 2 trial will enroll patients with C9orf72-associated ALS

SOUTH SAN FRANCISCO, CA, USA I September 09, 2021 I Alector, Inc. (Nasdaq: ALEC), a clinical-stage biotechnology company pioneering immuno-neurology, today announced that the first participant has been dosed in a Phase 2 clinical study evaluating the safety, tolerability, pharmacokinetics and pharmacodynamics of AL001 in people with amyotrophic lateral sclerosis (ALS) who carry a C9orf72 mutation. AL001 is being developed in collaboration with GlaxoSmithKline (GSK).

AL001 is a potential first-in-class monoclonal antibody designed to elevate progranulin, a key regulator of immune activity in the brain. Alector is also actively enrolling the Phase 3 INFRONT-3 pivotal clinical study of AL001 in individuals at-risk for and symptomatic patients with frontotemporal dementia (FTD) who carry a progranulin mutation (FTD-GRN), as well as currently enrolling the Phase 2 INFRONT-2 study in symptomatic patients with FTD who carry a C9orf72 mutation (FTD-C9orf72).

“AL001 has shown encouraging results in patients with FTD-GRN, rapidly increasing progranulin levels and normalizing inflammatory biomarkers along the disease cascade that contribute to neurodegeneration,” said Sam Jackson, M.D., Alector’s interim Chief Medical Officer. “Frontotemporal dementia and amyotrophic lateral sclerosis share common clinical, pathological and genetic features and it is now recognized that FTD and ALS are two diseases that form a broad neurodegenerative continuum. ALS is the first of several potential indications beyond frontotemporal dementia where we believe AL001 may have a positive impact on brain health by elevating progranulin levels.”

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, including ALS, where 95% of patients with ALS have TDP-43 pathology. In preclinical studies using multiple models of acute and chronic neurodegeneration, increasing progranulin levels has been shown in the literature to reverse and be protective against TDP-43 pathology.

Dr. Jackson continued, “We have seen consistent clinical and preclinical evidence of AL001’s ability to increase progranulin levels in the brain, and we are optimistic that in doing so, we may be able to mitigate or halt the downstream damage caused to motor neurons by excess TDP-43, and thereby slow the progression of ALS. We look forward to exploring the potential of AL001 to improve outcomes for ALS patients.”

“ALS, also known as Lou Gehrig’s disease, is a progressive and ultimately fatal neurodegenerative condition, with few FDA-approved treatment options. As we learn more about the genetic and biologic underpinnings of ALS, there is an opportunity to develop targeted treatments that address the mechanism of disease,” said Katharine Nicholson, M.D., neurologist and ALS clinical trialist at the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital, and the principal investigator for the Phase 2 study of AL001. “TDP-43 accumulation is found in the majority of patients with ALS, and by elevating progranulin levels, it is hoped that AL001 may have a neuroprotective effect. I look forward to working with Alector to study AL001’s disease-modifying potential in ALS.”

The Phase 2 trial of AL001 is a randomized, double-blind, placebo-controlled, multicenter study that is expected to enroll approximately 45 adult participants with C9orf72-associated ALS. Participants will receive AL001 or placebo intravenously every four weeks for 24 weeks added to their current treatment regimen. The primary endpoint of the study is safety, tolerability, pharmacokinetics and pharmacodynamics of AL001, including plasma and cerebrospinal fluid (CSF) progranulin levels. The Phase 2 will also gather data on changes to multiple liquid biomarkers. Taken together, these data are intended to inform trial design and dosing for future efficacy studies of AL001 in ALS.

About Amyotrophic Lateral Sclerosis
Amyotrophic lateral sclerosis (ALS) is a devastating, fatal, progressive neurodegenerative disorder. In ALS, the motor neurons in the brain and spinal cord die, resulting in weakness, muscle atrophy, paralysis and frequently, cognitive impairment, before resulting in death from respiratory failure. Each year, more than 5,000 people in the U.S. are diagnosed with ALS and an estimated 20,000 are living with the disease. Mutations within multiple genes, including the C9orf72 gene, are believed to cause the disease. Such mutations can lead to an accumulation of TDP-43 in the cells resulting in neuronal death and an estimated 95% of ALS cases are linked to TDP-43 pathology. Approximately 40-50% of all familial ALS and up to 10% of sporadic ALS cases are attributed to the C9orf72 mutation. Currently approved medications for ALS confer only a modest survival benefit and new treatment options are urgently needed.

About AL001
Decreased levels of PGRN, a key regulator of immune response, lysosomal function, and neuronal survival in the brain, are genetically linked to many neurodegenerative disorders. AL001 is a novel human monoclonal antibody that elevates levels of progranulin by blocking the sortilin receptor responsible for progranulin degradation. AL001 is currently in a pivotal Phase 3 clinical study in people at risk for or with frontotemporal dementia due to a progranulin gene mutation (FTD-GRN). AL001 is also being evaluated in a Phase 2 study in symptomatic patients with FTD who carry a C9orf72 mutation, and a Phase 2 study in patients with amyotrophic lateral sclerosis (ALS) who carry a C9orf72 mutation. In July 2021, Alector and GSK announced a global collaboration to co-develop AL001 for a range of neurodegenerative diseases, including FTD, ALS, Parkinson’s disease and Alzheimer’s disease.

About Alector
Alector is a clinical-stage biotechnology company pioneering immuno-neurology, a novel therapeutic approach for the treatment of neurodegenerative diseases. Immuno-neurology targets immune dysfunction as a root cause of multiple pathologies that are drivers of degenerative brain disorders. Alector has discovered and is developing a broad portfolio of innate immune system programs, designed to functionally repair genetic mutations that cause dysfunction of the brain’s immune system and enable the rejuvenated immune cells to counteract emerging brain pathologies. Alector’s immuno-neurology product candidates are supported by biomarkers and target genetically defined patient populations in frontotemporal dementia and Alzheimer’s disease. This scientific approach is also the basis for the company’s immuno-oncology programs. Alector is headquartered in South San Francisco, California. For additional information, please visit www.alector.com.

SOURCE: Alector