The FDA has lifted the clinical hold on Amylyx Pharmaceuticals' Phase 1 clinical trial of AMX0114, an investigational antisense oligonucleotide (ASO) for the treatment of amyotrophic lateral sclerosis (ALS). This decision allows Amylyx to proceed with opening U.S. sites for screening, enrollment, and dosing in the Phase 1 LUMINA study.
The LUMINA trial (NCT06665165) is a multicenter, randomized, placebo-controlled, multiple ascending dose trial designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of AMX0114 in 48 adults living with ALS. Participants will be randomized in a 3:1 ratio to receive either AMX0114 or a placebo, administered intrathecally (into the spinal cord) once every four weeks for a total of four doses.
AMX0114: Targeting Calpain-2 in ALS
AMX0114 is an ASO that targets calpain-2 (CAPN2), a protease implicated in axonal degeneration, a key pathological feature of ALS. Preclinical studies have demonstrated that AMX0114 can effectively reduce CAPN2 mRNA and protein levels in cell models relevant to axonal degeneration. This reduction has been associated with improved neuronal survival, including in models of TDP-43 ALS, and decreased levels of extracellular neurofilament light (NfL), a biomarker of neuronal damage.
According to Camille L. Bedrosian, MD, Chief Medical Officer of Amylyx, "Based on several preclinical efficacy studies and what is known about the central role of calpain-2 in the process of axonal degeneration, we believe AMX0114 has the potential to be a treatment for ALS and other diseases."
LUMINA Trial Design and Endpoints
The LUMINA trial will not only assess the safety and tolerability of AMX0114 but also evaluate changes from baseline in calpain-2 levels, neurofilament light (NfL) levels, and other pharmacodynamic biomarkers of ALS. The trial is expected to begin in Canada in early 2025, and Amylyx anticipates early cohort data from LUMINA in 2025.
The FDA's initial hold on the trial followed Amylyx's request to initiate first-in-human studies for AMX0114. The agency had initially restricted dosing to an amount lower than the proposed starting dose of 12.5 mg and requested additional information, leading to the regulatory pause. With the hold now lifted, Amylyx can proceed with its clinical development plans.
Background: ALS and the Need for New Therapies
Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease, is a progressive and fatal neurodegenerative disorder characterized by the death of motor neurons in the brain and spinal cord. This leads to muscle weakness, loss of motor control, respiratory paralysis, and ultimately, death. Over 90% of ALS cases are sporadic, with no clear family history.
The need for effective ALS therapies remains urgent. Amylyx previously faced challenges with its drug Relyvrio (sodium phenylbutyrate and taurursodiol), which was voluntarily withdrawn from the market after failing to meet its primary endpoint in a Phase 3 clinical trial. The company has since refocused its efforts on AMX0114, hoping to provide a new therapeutic option for patients with this devastating disease.
