Axoltis ALS drug misses Phase 2 endpoint
French biotech Axoltis Pharma’s NX210c missed the primary endpoint of a Phase 2 trial in amyotrophic lateral sclerosis (ALS), but post-hoc analyses showing slower functional decline are giving the company enough encouragement to plan further development.
Why it matters: ALS remains notoriously difficult to treat, and the SEALS study did not establish an effect on its prespecified biomarkers. The more encouraging clinical findings come from post-hoc analyses, making them signals that will need confirmation in a larger trial.
Zoom in: The 82-patient study randomized participants to intravenous NX210c at 5 mg/kg or 10 mg/kg, or placebo, three times weekly for four weeks. The trial’s primary endpoint looked for changes at week six in neurofilament light chain, or NfL, and Qalb, a measure of blood-brain barrier integrity. Neither showed a significant treatment effect.
- Post-hoc analyses painted a more positive picture on the ALSFRS-R scale, which measures patients’ ability to perform everyday functions. At week 10, monthly functional decline was 0.77 points with the 5 mg/kg dose and 1.06 points with 10 mg/kg, versus 1.57 points for placebo. The difference for the lower dose corresponded to a 51% reduction and reached statistical significance, according to Axoltis. At four months, the reductions versus placebo were 36% and 32%, respectively.
Reality check: The stronger functional result came from the lower dose, rather than showing a clear dose-response relationship, and the analyses were not the study’s primary endpoint. The trial was also relatively small and exposed patients to treatment for only four weeks.
- The week-six functional signal itself is not entirely new. Axoltis presented preliminary SEALS data at the ENCALS meeting in June, including ALSFRS-R decline rates of 0.67 points per month with 5 mg/kg, 0.9 with 10 mg/kg and 1.14 with placebo.
How it works: NX210c is a synthetic 12-amino-acid peptide derived from SCO-spondin, a large protein produced in the brain that is involved in nervous system development and maintaining the integrity of the blood-brain barrier. Axoltis is developing it around three proposed effects: restoring the blood-brain barrier, protecting neurons and improving neurotransmission.
- The company pointed to a significant reduction in plasma claudin-5 at the 10 mg/kg dose as evidence of target engagement. Claudin-5 enters circulation when the blood-brain barrier is disrupted, so Axoltis argues that lower levels could indicate barrier restoration.
Big picture: ALS drug development has produced more failures than approvals. Biogen’s tofersen became the first treatment aimed at a genetic cause of ALS when it won accelerated FDA approval for SOD1-ALS in 2023. Tofersen itself initially missed its primary functional endpoint before longer follow-up strengthened the case for benefit — a reminder of how difficult short ALS trials can be to interpret.
- Meanwhile, developers are testing increasingly different ways to slow neurodegeneration. UK biotech Alchemab Therapeutics has moved ATLX-1282, an antibody discovered by studying people unusually resilient to neurodegenerative disease, into Phase 1. Eli Lilly licensed the program in a deal worth up to $415 million and will take over development after the first-in-human study.
- That also gives NX210c a clearer position in the field: unlike mutation-specific programs such as tofersen, Axoltis is trying to address mechanisms that could apply across a broader ALS population, particularly blood-brain barrier dysfunction and neuronal protection.
What’s next: Axoltis is analyzing a 10-month follow-up and the relationship between drug exposure and response to help choose a dose and treatment schedule. It plans to present fuller results at the Society for Neuroscience meeting in Washington on Nov. 15 and discuss the next development steps with regulators.
