Phase 2 Trial of AIT-101 in Patients With C9orf72 Mutations Enrolling

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by Vanda Pinto, PhD |

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AI Therapeutics has launched a Phase 2 clinical trial into AIT-101 (apilimod dimesylate) as a potential oral treatment for amyotrophic lateral sclerosis (ALS) associated with C9orf72 mutations.

The trial (NCT05163886) is currently recruiting at the Massachusetts General Hospital and is expected to soon open at sites in Iowa and Maryland. Additional information can be found here.

Researchers intend to enroll a total of 12 adult patients, who will be randomly assigned to AIT-101 or a placebo given twice daily for three months. All will continue with their standard of care treatment. Patients who complete this 12-week study will be eligible to enter its open-label extension, where all will be treated with AIT-101 for three months.

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The trial’s main goals are to evaluate the safety, tolerability, and biological effects of AIT-101, including changes in disease biomarkers. Disability progression, measured via the ALS Functional Rating Scale Revised (ALSFRS-R), and changes in lung health and cognitive function will also be examined.

“We are excited to have begun our first clinical trial for AIT-101 in ALS patients and are optimistic that it has the potential to change the course of this terrible disease,” Murat Gunel, MD, chairman of the scientific advisory board of AI Therapeutics and chair of the neurosurgery department at Yale University, said in a press release.

Defects in the C9orf72 gene are among the most common genetic causes of ALS, accounting for up to 50% of hereditary cases and up to 10% of sporadic cases. C9orf72 carries instructions for a protein of the same name that is necessary for the production lysosomes — cell organelles that break down faulty or unwanted molecules — in motor neurons. Lack of a working C9orf72 protein can result in the accumulation of toxic proteins.

AIT-101 is a selective PIKfyve kinase inhibitor designed to increase the number of lysosomes and, by doing so, clear existing toxic protein clumps and prevent more from forming.

Specifically, AIT-101 works to activate the transcription factor TFEB — which AI Therapeutics calls “the master regulator of lysosomal biogenesis [production].” TFEB is known to be at lower levels in the brains of  ALS patients, and its activation is expected to lead to the removal of the harmful proteins.

“AIT-101 employs a novel approach in aiming to clear the abnormal protein aggregates that lead to motor neuron degeneration,” said Katharine Nicholson, MD, neurologist and ALS clinical trial investigator at the Sean M. Healey Center for ALS at Massachusetts General Hospital in Boston.

“The study is designed to evaluate AIT-101 in this subpopulation [of ALS patients with a C9orf72 mutation] prior to consideration of a larger trial in the broader ALS population,” she added. This patient group allows investigators to “effectively measure the breakdown of proteins specific to the C9 repeat expansion as well as proteins found in all people with ALS.”

AIT-101 was originally identified as a possible ALS treatment by AI Therapeutics’ artificial intelligence-based platform, called Guardian Angel. The platform works to synthesize public and proprietary data on medications and diseases to find new indications among the company’s chemical products. The candidate was initially being tested as a treatment for lymphoma.

“AIT-101 is a very promising molecule as it is incredibly specific for its target, PIKfyve kinase, and has been safely dosed in hundreds of patients in other clinical trials,” Gunel said.

An interim analysis of safety and other Phase 2 trial measures is planned and will be conducted by an independent trial monitoring board.