Amylyx Pharmaceuticals resumes AMX0114 clinical trials for ALS after FDA clears path

Amylyx Pharmaceuticals, Inc. (NASDAQ: AMLX) has announced that the U.S. Food and Drug Administration (FDA) has lifted the clinical hold on its Phase 1 trial for AMX0114, a groundbreaking investigational treatment for amyotrophic lateral sclerosis (ALS). This marks a pivotal milestone in the company’s efforts to develop novel therapies for this debilitating neurological disorder.

With regulatory approval to proceed, Amylyx Pharmaceuticals is gearing up to launch trial sites across the United States, complementing its previously announced plans to begin dosing in Canada under its Phase 1 LUMINA study in early 2025.

What Is AMX0114, and How Does It Target ALS?

AMX0114 is an antisense oligonucleotide (ASO) that targets calpain-2 (CAPN2), a protease known to play a central role in axonal degeneration. Axonal degeneration is a critical process in ALS progression, leading to the loss of motor neurons that control movement. By reducing CAPN2 mRNA and protein levels, AMX0114 aims to preserve neuronal function and slow disease progression.

Preclinical studies demonstrated that AMX0114 significantly lowered levels of CAPN2 and improved neuronal survival in ALS models, including those mimicking TDP-43 protein pathology. Moreover, treatment resulted in a dose-dependent reduction in neurofilament light (NfL), a key biomarker for axonal injury. These findings position AMX0114 as a potentially transformative therapy for ALS and other neurological diseases.

Dr. Camille L. Bedrosian, Chief Medical Officer at Amylyx Pharmaceuticals, noted, “Calpain-2 has emerged as a promising target in ALS and other neurological conditions due to its role in axonal degeneration. We are committed to exploring AMX0114’s potential as a therapy to improve outcomes for people living with ALS.”

How Does the Phase 1 LUMINA Study Aim to Advance ALS Research?

The LUMINA study is designed to assess the safety, tolerability, and biological activity of AMX0114. This multicenter, randomized, placebo-controlled trial will enroll 48 participants with ALS, who will be randomized 3:1 to receive either AMX0114 or a placebo. The drug will be administered intrathecally once every four weeks for up to four doses.

A key focus of the study is evaluating changes in ALS biomarkers, including CAPN2 and NfL levels, which are critical indicators of disease progression and therapeutic impact. Amylyx Pharmaceuticals plans to collect and analyze early cohort data in 2025, shedding light on the drug’s pharmacokinetics and pharmacodynamics.

Why Was the Trial Initially Held, and What Does the FDA’s Decision Mean?

In November 2024, Amylyx Pharmaceuticals received approval from Health Canada to proceed with its Clinical Trial Application for AMX0114, allowing dosing at a starting level of 12.5 mg. However, the FDA raised concerns about the proposed starting dose and requested additional toxicology data, resulting in a temporary clinical hold.

The company responded by submitting robust preclinical toxicology data demonstrating a safety margin exceeding 10 times the no observed adverse effect level (NOAEL) at the 12.5 mg dose. This evidence satisfied the FDA’s requirements, paving the way for U.S. trials to commence.

The FDA’s decision underscores the potential of AMX0114 to address the unmet medical needs of ALS patients while highlighting the importance of thorough regulatory scrutiny in early-stage drug development.

What Could AMX0114 Mean for the Future of ALS Treatment?

Amylyx’s work on AMX0114 reflects a broader trend in ALS research toward targeting the molecular pathways underlying axonal degeneration. By focusing on calpain-2 inhibition, AMX0114 may offer a novel approach to slowing disease progression and preserving motor function.

Experts in the field emphasize the need for biomarker-driven clinical trials to accelerate the development of effective ALS therapies. The inclusion of biomarkers like NfL and CAPN2 in the LUMINA study not only enhances the scientific rigor of the trial but also aligns with emerging best practices in neurodegenerative research.

What’s Next for Amylyx Pharmaceuticals and AMX0114?

With the FDA hold lifted, Amylyx Pharmaceuticals is working closely with clinical trial sites across North America to initiate screening and enrollment. The company remains on track to start dosing in Canada and anticipates generating early cohort data from the LUMINA trial by late 2025.

The road ahead will involve scaling the study to additional regions, analyzing data to refine dosing protocols, and preparing for subsequent trial phases. The outcomes of the LUMINA study will likely influence the broader trajectory of ALS research, shaping how future therapies are developed and tested.

Amylyx Pharmaceuticals’ successful navigation of regulatory hurdles marks a critical step forward in its mission to combat ALS. As the company prepares to launch its LUMINA trial, AMX0114 holds the potential to redefine therapeutic possibilities for this devastating disease. With early data expected in 2025, the world will be watching closely as Amylyx Pharmaceuticals continues its work to bring hope to ALS patients and their families.