AL-S Pharma Details Planned Phase 3 Trial Design for AP-101 in ALS

AL-S Pharma presented the design of AP101-03, a planned global phase 3 trial evaluating AP-101, an antibody targeting misfolded superoxide dismutase 1 (SOD1), in adults with sporadic and SOD1-associated amyotrophic lateral sclerosis (ALS). The company also reported new post hoc body-weight data from the completed phase 2 trial favoring AP-101 over placebo in both ALS populations.^1,2

Angela Genge, MD, FRCP(C), chief medical officer of AL-S Pharma and a professor at The Neuro (Montreal Neurological Institute-Hospital), McGill University, presented both the phase 3 trial design and the new phase 2 analyses at the 2026 Network of Excellence for ALS (NEALS) Annual Meeting, held October 27-30, 2026, in Clearwater, Florida. AP-101 is a human monoclonal antibody designed to selectively bind misfolded SOD1 while sparing the native, correctly folded protein.^1,2

“Preservation of body weight is particularly relevant in ALS, where weight loss is closely associated with disease progression and poorer outcomes,” Genge said of the new weight analyses.² “These new analyses add an important clinical perspective to our phase 2 findings, demonstrating a consistent trend toward greater weight preservation with AP-101 across different ALS patient populations.”

AP101-03 is planned as a multicenter, double-blind, randomized, placebo-controlled trial with parallel cohorts for sporadic ALS and SOD1-associated ALS. Participants will be randomized 2:1 to receive AP-101 2500 mg intravenously every 3 weeks, or placebo, for 12 months, in addition to standard of care. Eligibility requires ALS diagnosed by Gold Coast or revised El Escorial criteria, symptom onset within 24 months, and slow vital capacity of at least 60% at screening.^1,2

The planned primary analysis will use a joint model combining longitudinal ALS Functional Rating Scale-Revised scores with survival-related events, defined as death or permanent ventilation. The conference abstract describes planned enrollment of approximately 350 participants with sporadic ALS and 100 with SOD1-associated ALS, a total of about 450; the company's October 26, 2026, press release describes the trial as planned to enroll approximately 300 participants and does not break that figure out by population, a discrepancy not otherwise explained in the materials reviewed for this article. AL-S Pharma said the phase 3 trial is planned to begin in 2027.

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In new post hoc analyses of the phase 2 trial's double-blind period, AL-S Pharma reported an adjusted body-weight difference favoring AP-101 of 2.25 kg at week 24 among participants with sporadic ALS. Among participants with SOD1-associated ALS, the difference was 4.82 kg at a 21-day follow-up visit after the double-blind period (P =.0092), and among sporadic ALS participants in the highest tertile of baseline cerebrospinal fluid misfolded SOD1, the difference was 4.59 kg at the same follow-up point (P =.0010).²

Background: the AP101-02 phase 2 trial

AP101-03 follows AP101-02 (NCT05039099), a global phase 2 trial that randomized 73 participants, 52 with sporadic ALS and 21 with SOD1-associated ALS, 2:1 to AP-101 or placebo for 24 weeks, followed by a 24-week open-label extension. AL-S Pharma reported in September 2025 that the trial met its primary safety and tolerability endpoint, with adverse events similar between AP-101 and placebo and no antibody responses induced by AP-101.³

The company also reported reductions in serum neurofilament light chain and cerebrospinal fluid phosphorylated neurofilament heavy chain after 6 months of treatment in the per-protocol population, though specific values for these biomarker changes were not disclosed. AP-101 holds orphan drug designations from the FDA, EMA, and Swissmedic.^2,3

REFERENCES
1. Genge A, Bowden E, Ganti R, Kaneb H, Donley D, Salzmann M. Design of a planned phase 3 confirmatory trial of AP-101, a human antibody targeting misfolded SOD1, in sporadic and SOD1-associated ALS. Presented at: 2026 NEALS Annual Meeting; October 27-30, 2026; Clearwater, FL.
2. AL-S Pharma reports new AP-101 phase 2 weight data and outlines phase 3 clinical trial in ALS at 2026 NEALS Annual Meeting. News release. AL-S Pharma. Published October 26, 2026. Accessed November 2, 2026. https://www.webdisclosure.com/press-release/al-s-pharma-reports-new-ap-101-phase-2-weight-data-and-outlines-phase-3-clinical-trial-in-als-at-2026-neals-annual-meeting-WuUPvFir1G3
3. AL-S Pharma announces positive topline results from phase 2 study of AP-101 for the treatment of amyotrophic lateral sclerosis (ALS). News release. AL-S Pharma. Published September 4, 2025. Accessed November 2, 2026. https://www.prnewswire.com/news-releases/al-s-pharma-announces-positive-topline-results-from-phase-2-study-of-ap-101-for-the-treatment-of-amyotrophic-lateral-sclerosis-als-302545686.html