Amylyx Begins Dosing in Phase 1 LUMINA Trial of AMX0114 for ALS
Amylyx Pharmaceuticals, Inc. (NASDAQ: AMLX), a biopharmaceutical company dedicated to the development of innovative treatments for neurodegenerative diseases, has announced a significant milestone in its mission to combat amyotrophic lateral sclerosis (ALS). The company has dosed the first participant in its Phase 1 LUMINA clinical trial evaluating AMX0114, an investigational antisense oligonucleotide (ASO) designed to inhibit calpain-2, a protease implicated in axonal degeneration.
The LUMINA trial (NCT06665165) is a multinational, randomized, double-blind, placebo-controlled, multiple ascending dose study that marks the first-in-human clinical evaluation of AMX0114. Designed with both scientific rigor and patient safety in mind, the trial will assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of AMX0114 in individuals diagnosed with ALS, a progressive neurodegenerative disorder that severely affects voluntary muscle movement and currently lacks a curative treatment.
A Strategic Step in ALS Drug Development
With a planned enrollment of approximately 48 participants across North America, the LUMINA trial is structured to provide robust early-stage data on AMX0114’s safety and biological activity. Participants will be randomized in a 3:1 ratio to receive either AMX0114 or placebo, administered intrathecally — directly into the cerebrospinal fluid (CSF) — once every four weeks, for a total of up to four doses.
Importantly, the trial will incorporate the analysis of key ALS biomarkers, including neurofilament light chain (NfL) levels, which are increasingly recognized as a sensitive indicator of neuroaxonal damage and disease progression in ALS. Changes in NfL levels will offer insights into the biological effects of calpain-2 inhibition and help evaluate AMX0114’s mechanism of action in humans.
Amylyx expects to report preliminary data from the early cohorts of the study in 2025. These data will be instrumental in guiding future development of AMX0114 and shaping the design of subsequent clinical trials.
Targeting Calpain-2: A Novel Mechanism in ALS
AMX0114 represents a novel approach in ALS therapeutics by targeting calpain-2, a calcium-activated protease involved in axonal degeneration. Axons are the long projections of neurons that transmit electrical signals to muscles and other neurons. In Amylyx ALS and other neurodegenerative diseases, pathological activation of calpain-2 contributes to the breakdown of these critical neuronal structures, ultimately leading to muscle weakness, paralysis, and respiratory failure.
“In preclinical models, overactive calpain-2 has been shown to play a central role in axonal degeneration, making it a compelling therapeutic target,” said Dr. Camille L. Bedrosian, Chief Medical Officer at Amylyx Pharmaceuticals. “Through the inhibition of calpain-2, AMX0114 demonstrated improved neuronal survival and a reduction in extracellular NfL levels — a promising signal in multiple ALS disease models.”
Bedrosian emphasized that moving AMX0114 into clinical development is a critical step for the company’s pipeline and could represent a new frontier in the treatment of ALS. “We are committed to bringing forward innovative therapies that address the underlying biology of neurodegenerative diseases. AMX0114 is the first antisense therapeutic we have advanced into clinical trials, and it underscores our continued pursuit of science-driven solutions to one of medicine’s most urgent challenges.”
Building on a Legacy of Innovation in ALS
Amylyx gained prominence in the ALS community with the development and regulatory approval of RELYVRIO® (AMX0035), a combination therapy that emerged as a new standard of care for people living with ALS. With the initiation of LUMINA, Amylyx is deepening its engagement with the ALS research community and expanding its focus to include genetically and molecularly targeted therapeutics.
The company’s R&D strategy emphasizes a modular approach, combining deep mechanistic insights with patient-centered drug development. AMX0114, developed as an antisense oligonucleotide, fits squarely into this strategy. ASOs work by binding to specific RNA molecules to modulate the production of disease-related proteins — in this case, suppressing calpain-2 to prevent axonal degeneration.
The LUMINA trial also reflects a broader trend in neurodegenerative disease research, in which biomarker-driven and genetically informed strategies are increasingly being prioritized. The inclusion of NfL measurements and other exploratory biomarkers will help evaluate the biological activity of AMX0114 and may also serve as surrogate endpoints in later-phase trials.
Collaboration with Leading ALS Researchers and Institutions
The LUMINA trial is being conducted in collaboration with several leading academic centers and ALS research organizations across North America. Among the principal investigators is Dr. Sabrina Paganoni, MD, PhD, a well-known ALS researcher at the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital. Dr. Paganoni Amylyx is also a key member of the Scientific Advisory Board of the Northeast Amyotrophic Lateral Sclerosis Consortium (NEALS), one of the largest ALS clinical research networks in the world.
“ALS is a devastating and rapidly progressive condition that continues to challenge patients, families, and healthcare providers,” said Dr. Paganoni. “With limited treatment options currently available, there is an urgent need for new approaches that can intervene earlier in the disease process and modify its trajectory. AMX0114’s mechanism of targeting calpain-2 offers an exciting possibility to slow or even prevent axonal degeneration.”
She added, “Dosing the first participant in the LUMINA trial is a meaningful step toward potentially transforming the treatment landscape for ALS. We look forward to working with Amylyx and the ALS community to advance this important research.”
A Vision for the Future
Amylyx’s pipeline expansion comes at a time when ALS drug development is gaining momentum worldwide. Advances in genetics, biomarkers, and neuroimaging have opened new possibilities for personalized medicine in ALS, and pharmaceutical companies are increasingly investing in targeted therapies that address the disease at its roots.
The initiation of the LUMINA trial positions Amylyx as a key player in this evolving field. By exploring new mechanisms like calpain-2 inhibition, the company hopes to bring novel, disease-modifying treatments to a patient population that continues to face limited therapeutic options and significant unmet needs.
“Our vision is to transform what it means to live with a neurodegenerative disease,” said Bedrosian. “Through scientific innovation, patient engagement, and collaboration with the broader research ecosystem, we are striving to create a future where people with ALS have more time, more function, and more hope.”
As the LUMINA trial progresses, the ALS community — including patients, caregivers, and researchers — will be watching closely. If AMX0114’s early promise translates into meaningful clinical benefits, it could signal a new era in the fight against ALS and pave the way for similar approaches in other neurodegenerative conditions.
