LeonaBio Presents on ATH-1105 at 5th Annual ALS Drug Development Summit

LeonaBio Details Brelgometon's ALS Clinical Development Strategy

LeonaBio, Inc. announced that its Chief Medical Officer presented on brelgometon (ATH-1105) at the 5th Annual ALS Drug Development Summit. The presentation, titled “Advancing ATH-1105 in ALS: Strategic Trial Design, Biomarker Integration & Adaptive Methodologies,” provided an overview of the drug's clinical development program for amyotrophic lateral sclerosis (ALS). Brelgometon is an oral, brain-penetrant positive modulator of the neurotrophic HGF system. The company highlighted preclinical and Phase 1 clinical evidence supporting its advancement into a Phase 2 proof-of-concept study, targeted for initiation in the second half of 2026. The completed Phase 1 trial in 80 healthy volunteers demonstrated a favorable safety and tolerability profile, dose-proportional pharmacokinetics, and central nervous system penetration.

• LeonaBio's Chief Medical Officer, Dr. Javier San Martin, detailed the strategic trial design for brelgometon (ATH-1105) in ALS. The design for the planned Phase 2 study integrates validated biomarkers, such as neurofilament light chain, alongside clinically meaningful endpoints. This approach aims to reflect both translational science and the realities of ALS, providing a robust framework for evaluating the drug's potential.
• Brelgometon (ATH-1105) is characterized as a novel, orally available, brain-penetrant small molecule designed to positively modulate the neurotrophic HGF system. Preclinical studies have shown statistically significant improvements in nerve and motor function, biomarkers of inflammation and neurodegeneration, and survival in various ALS models. The completed Phase 1 trial (NCT06432647) in 80 healthy volunteers confirmed a favorable safety and tolerability profile, along with dose-proportional pharmacokinetics and central nervous system penetration.
• LeonaBio plans to initiate a randomized, double-blind, placebo-controlled Phase 2 proof-of-concept and dose-ranging study of brelgometon in people with ALS during the second half of 2026. This study will evaluate the efficacy, safety, and pharmacodynamic activity of the drug. The company believes brelgometon's neuroprotective profile and translational rationale offer a meaningful opportunity to address the significant unmet medical need in ALS, a progressive and fatal neurodegenerative disease with limited treatment options.

Addressing the Significant Unmet Need in ALS Treatment

ALS presents substantial therapeutic challenges that have persisted despite decades of intensive research and clinical investigation. The disease remains fatal with no available causal or disease-modifying therapies, and current treatment options provide limited meaningful extension of survival for most patients.

• Absence of disease-modifying therapies: No causal or disease-modifying treatments are currently available for ALS, with decades of clinical trials yielding largely negative results until recent developments in precision medicine approaches

• Limited survival benefit: Current therapeutic interventions fail to meaningfully extend survival, despite continuously emerging targets and putative treatments being studied in clinical trials

• Diagnostic complexity: ALS is often difficult to diagnose, creating delays in treatment initiation and complicating early intervention strategies

• Inadequate management of behavioral symptoms: Management of behavioral disorders remains severely limited despite their 30-60% prevalence and significant negative impact on prognosis, management, and quality of life

• Poor understanding of neurobiological mechanisms: The underlying neurobiology of behavioral disorders in ALS is poorly understood, and the natural history of behavioral dysfunctions and their relationship to frontotemporal lobe degeneration remains incompletely characterized

• Complex outcome assessment: Evaluating treatment efficacy is challenging due to the need to assess multiple outcomes across several dimensions of neurological function as well as survival, complicating both test selection and result interpretation

• Limited applicability of precision medicine: Only a minority of ALS patients carry SOD1 mutations, restricting the use of targeted therapies like tofersen to a small patient subset and limiting broader therapeutic impact

• Unclear exercise therapy benefits: While exercise therapy is recommended, its effects on muscle mass and intramuscular conditions remain unclear, with potential benefits potentially counteracted by concurrent muscle mass loss

HGF Modulation: LeonaBio's Strategic Advance in ALS

The announcement from LeonaBio regarding brelgometon (ATH-1105) represents a significant step forward in the relentless pursuit of effective treatments for amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease with limited therapeutic options. Brelgometon is an oral, brain-penetrant small molecule designed to positively modulate the hepatocyte growth factor (HGF) system, a pathway increasingly recognized for its neuroprotective and anti-inflammatory roles in the central nervous system.

Preclinical studies have painted a compelling picture, demonstrating that ATH-1105 augments key signaling pathways, attenuates glutamate excitotoxicity, protects motor neurons and neuromuscular junctions, and mitigates inflammation. Crucially, in relevant ALS mouse models, it has shown the ability to improve motor function, preserve nerve integrity, reduce pathological protein accumulation (phospho-TDP-43), and extend survival. Furthermore, research indicates a synergistic effect when combined with riluzole, the current standard of care, suggesting a potential for enhanced therapeutic benefit through combination strategies.

This novel mechanism of action, coupled with its oral and brain-penetrant properties, positions brelgometon as a potentially differentiated therapy in a crowded and challenging therapeutic landscape. The successful completion of a Phase 1 trial, confirming safety and CNS penetration, provides a solid foundation for its progression. However, the journey ahead is not without its complexities. The HGF/Met pathway's broad involvement in various biological processes, including cancer, means that careful monitoring for potential off-target effects, such as nephrotoxicity or cardiovascular issues observed with other HGF/Met modulators, will be paramount. Moreover, the historical difficulty in translating promising preclinical ALS data to human efficacy underscores the inherent risks in this field. As LeonaBio targets a Phase 2 proof-of-concept study in late 2026, the integration of robust biomarkers will be critical to guide patient selection and demonstrate clear clinical benefit, ultimately determining its potential to reshape ALS treatment paradigms.