Axoltis' Phase II ALS Trial Misses Primary Endpoints — Exploratory Analyses Show Promising Functional Signals

Axoltis Pharma is conducting further analyses after its Phase II SEALS study (NCT06365216) of NX210c in amyotrophic lateral sclerosis (ALS) failed to meet its co-primary biomarker endpoints at six weeks.

Primary Outcomes

The trial did not show a statistically significant benefit versus placebo on the prespecified co-primary biomarkers: blood neurofilament light chain (NfL) concentrations and the cerebrospinal fluid-to-blood albumin quotient (Qalb) after six weeks. Although 25.4% of patients in the NX210c arms had reductions in blood NfL versus 11.8% in placebo, this numerical difference was not statistically significant. NfL is a widely used biomarker of neuronal and axonal injury.

Exploratory and Post-hoc Findings

Axoltis reported what it described as "consistent positive trends" across several secondary and exploratory measures. In post-hoc analyses, the decline in clinical function measured by the Harmonised Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) slope was slower in treated patients: after six weeks the monthly ALSFRS-R decline was 0.67 points for the 5 mg/kg arm, 0.90 points for the 10 mg/kg arm, and 1.14 points for placebo — equating to an average reduction in decline of ~41% for 5 mg/kg and ~21% for 10 mg/kg. Axoltis says this effect continued to improve through week 10 and out to four months.

Benefits were particularly notable on the ALSFRS-R motor subscale, with average reductions in decline of about 64% for the 5 mg/kg group and ~33% for the 10 mg/kg group at weeks 6 and 10. These analyses are post-hoc and exploratory, and so require confirmation in prospectively designed studies.

Biomarker Signal: Claudin-5

The company also reported a statistically significant decrease in blood claudin-5 in the 10 mg/kg cohort. Claudin-5 is a tight-junction protein whose presence in blood can indicate blood–brain barrier (BBB) disruption; Axoltis interprets this change as a potential sign of partial BBB recovery. This finding is hypothesis-generating and will need validation in larger samples and over longer follow-up.

Next Steps and Context

Axoltis is performing additional analyses, including a 10-month clinical follow-up of Phase II participants and pharmacokinetic/pharmacodynamic (PK/PD) evaluations to help define an optimal dosing regimen. Full data are slated for presentation at Neuroscience 2026 in Washington, D.C., on 14–18 November.

The results underscore the ongoing challenges in developing disease-modifying ALS therapies. Recent setbacks in the field include Novartis' discontinuation of VHB937B1 after a negative Phase II readout (ASTRALS), the market withdrawal of Amylyx's Relyvrio following a failed confirmatory trial, and other mid-stage failures from Sanofi/Denali and Ferrer. By contrast, Biogen's tofersen (Qalsody) received FDA approval in 2023 for SOD1-related ALS, highlighting both progress and the high bar for broadly effective ALS treatments.

Takeaway

While NX210c did not achieve its primary biomarker goals at six weeks, Axoltis' exploratory and post-hoc analyses suggest potential functional benefits and a biomarker signal that warrant further investigation. These findings are preliminary; confirmation in larger, prospectively powered trials will be necessary before clinical conclusions can be drawn.