Slide 1: Study Update
Study Update Lauren Kett, MD, PhD Sabrina Paganoni, MD, PhD Senior Medical Director Co-Director, Neurological Clinical Research Institute, Amylyx Pharmaceuticals Sean M. Healey & AMG Center for ALS at MGH For Scientific meeting use only. Do not duplicate, distribute, or disseminate. Copyright © 2025
Slide 2: Please Note
Please Note • AMX0114 is an investigational drug and has not been approved by any health authority. • This presentation is intended to provide scientific information about AMX0114. The statements and content shared in this presentation have not been evaluated by any health authority. Disclosures LK
Slide 3: Presentation Overview
Presentation Overview Modulating Neurodegeneration in ALS: Calpain-2 and AMX0114 • Role of Calpain-2 in Axonal Degeneration and ALS • About AMX0114 • AMX0114 Preclinical Data • Elucidating the Biomarker Signature of Calpain-2 Activation LUMINA Study Design For Scientific meeting use only. Do not dup
Slide 4: Modulating Neurodegeneration in ALS: Calpain-2 and AMX0114
Modulating Neurodegeneration in ALS: Calpain-2 and AMX0114 For Scientific meeting use only. Do not duplicate, distribute, or disseminate. Copyright © 2025 Amylyx Pharmaceuticals, Inc.
Slide 5: Calpain-2 Drives Axonal Degeneration and Is Implicated in ALS
Calpain-2 is a Ca2+-Activated Cysteine Protease that Drives Axonal Degeneration and Has Been Implicated in the Pathogenesis of ALS1-6 Rationale for Targeting Calpain-2 in ALS • Calpain-2 levels are upregulated in ALS4,6 • CAPN2 mRNA upregulated in biopsied muscle samples of people with ALS4 • Ratio
Slide 6: AMX0114: An Antisense Oligonucleotide (ASO) Targeting Calpain-2
AMX0114: An Antisense Oligonucleotide (ASO) Targeting Calpain-2 Selectivity of the ASO modality of AMX0114 may offer distinct advantages over earlier, small molecule-based approaches to targeting calpain-2 including: • Inhibition of calpain-2 without disrupting the function of other calpains or calp
Slide 7: AMX0114 Reduces Extracellular NfL and Improves Neuron Survival in TDP-43 ALS Models
AMX0114 Has Been Shown to Reduce Extracellular NfL Levels and Improve Neuron Survival in TDP-43 ALS Models AMX0114 Reduced Extracellular NfL1 AMX0114 Improved Neuron Survival1 Treatment with 0.1 µM AMX0114 resulted in ~60% decrease in 67.8% lower hazard ratio for TDP-43 mutant (M337V) cells treated
Slide 8: Calpain-2 Substrates Allow for a Unique Biomarker Strategy
Calpain-2 Substrates Allow for a Unique Biomarker Strategy to Evaluate AMX0114 Target Engagement + Efficacy Markers of Target Engagement Calpain-2 Activation ▪ SBDP-145 (calpain-specific breakdown product of αII-spectrin) ▪ NfL ▪ Calpain-specific NfL fragments Markers of Axonal Injury Axonal ▪ SBDP-
Slide 9: Study Design & Updates
Study Design & Updates For Scientific meeting use only. Do not duplicate, distribute, or disseminate. Copyright © 2025 Amylyx Pharmaceuticals, Inc.
Slide 10: Phase 1, Multicenter, Randomized, Placebo-Controlled Multiple Ascending Dose Study
Is a Phase 1, Multicenter, Randomized, Placebo- Controlled Multiple Ascending Dose Study Study Objectives: • Evaluate the safety and tolerability of AMX0114 administered intrathecally for a total of up to 4 doses per dose level • Evaluate the pharmacokinetics of AMX0114 in CSF and plasma • Assess th
Slide 11: Multiple Ascending Dose Study Design
Multiple Ascending Dose Study Design Cohort 4 (X mg - planned) Open-Label Extension AMX0114 (n=9); Placebo (n=3) Dose Escalation The open-label extension may be Cohort 3 (X mg – planned) implemented if safety and efficacy data AMX0114 (n=9); Placebo (n=3) support a positive benefit-risk profile Dose
Slide 12: Study Endpoints
Study Endpoints Primary Endpoints Tertiary Endpoints • Incidence of adverse events (AEs), serious Pharmacodynamics/Biomarkers adverse events (SAEs) and dose limiting toxicities (DLTs) • Change from baseline of plasma and CSF pharmacodynamic measures of ALS and • Incidence of abnormalities in clinica
Slide 13: Key Takeaways
Key Takeaways AMX0114 is an ASO that achieves robust Calpain-2 is a critical effector of knockdown of calpain-2 mRNA and axonal degeneration, a key early protein across multiple disease-relevant contributor to the pathogenesis of cell types and models of axonal amyotrophic lateral sclerosis degenera
Slide 14: Questions?
We extend our deepest gratitude to trial participants as well as the ALS clinicians, NEALS SAB, people living with ALS, and caregivers who provided feedback and advice on the study design. QUESTIONS? Join Tonight’s Lightning Talks and Visit Poster #11 to Explore: Scan to Learn More • Biomarkers of c