The trials showing real signals

AP-101: Clearing misfolded SOD1

This monoclonal antibody targets misfolded SOD1 protein—a specific mechanism for the 2% of ALS patients with SOD1 mutations, but potentially relevant to sporadic ALS where protein misfolding also occurs. Phase II data showed prolonged survival and delayed need for ventilatory support. Phase III is now planned following these results.

Pridopidine: Sigma-1 receptor agonism

The PREVAiLS Phase III trial starts in 2026 based on strong Phase II data: 32% slowing of functional decline (p=0.03) and 62% reduction in respiratory worsening in early rapid-progressive patients. The sigma-1 receptor modulates cellular stress responses and mitochondrial function—mechanisms relevant across neurodegenerative diseases.

CNM-Au8: Gold nanocrystals for neuroprotection

Clene's approach uses gold nanocrystals to reduce neuroinflammation and enhance energy metabolism. The biomarker data is compelling: significant reductions in neurofilament light chain (a marker of neuronal damage) and GFAP (astrocyte activation). With over 1,000 patient-years of exposure showing safety, an NDA submission is planned for 2026.

Lenzumestrocel: Stem cell immunomodulation

Autologous mesenchymal stem cells delivered intrathecally shift microglia from pro-inflammatory to anti-inflammatory states via TGF-β1 and MCP-1 modulation. Phase III is testing single versus repeated cycles in 115 patients. The mechanism—immune modulation rather than cell replacement—represents a refined stem cell approach.

NX210c: Blood-brain barrier repair

This peptide aims to restore BBB integrity, addressing a growing recognition that vascular dysfunction contributes to ALS progression. Phase II continues through September 2026 with 80 patients.

Why this wave might succeed where others failed

First, biomarker-driven enrollment: trials now stratify patients based on NfL levels, C9orf72 status, or progression rate—ensuring homogeneous populations where mechanisms are more likely to show effects.

Second, mechanism diversity: instead of betting everything on single targets like BDNF or anti-excitotoxicity, the field is testing parallel pathways—protein homeostasis, mitochondrial support, immune modulation, and vascular health.

Third, regulatory evolution: the FDA's 2018 ALS guidance and the accelerated approval pathway mean drugs with biomarker improvement and functional preservation signals can reach patients faster, even before survival data matures.

The gap: MS and spinal cord injury

Notably, the current Phase II/III landscape lacks comparable regenerative or novel mechanistic trials for MS or SCI. ALS dominates 2026's neurodegeneration pipeline, possibly because its fatal prognosis enables riskier mechanisms in trial design. The absence is puzzling—SCI in particular has seen decades of preclinical regenerative success with limited clinical translation.

Testable predictions

1. At least one of these mechanisms will show statistically significant functional preservation in Phase III by 2027
2. Biomarker responders (NfL reduction >30%) will correlate with clinical benefit, validating surrogate endpoints
3. The first approved regenerative therapy for ALS will come from the stem cell or BBB repair category, not protein clearance alone

What would falsify the optimism

If Phase III trials show the same pattern as previous ALS failures—biomarker improvement without functional benefit, or subpopulation effects that do not replicate—the field is back to square one. The burden of proof remains high: functional preservation must be meaningful to patients, not just statistically significant.

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Research synthesis via Aubrai