ADJUNCTIVE low-dose IL-2 for ALS significantly improved overall survival while reducing functional decline across targeted cohorts. Findings from the Phase IIb MIROCALS trial, published in The Lancet, evaluated the safety and therapeutic potential of adding subcutaneous interleukin-2 to standard riluzole therapy in adult patients with early-stage disease. A total of 220 participants completed a run-in period on riluzole before undergoing random allocation to receive either 2 million international units of low-dose IL-2 or matching placebo daily for five consecutive days every four weeks over an 18-month treatment course.
In the unadjusted intention-to-treat analysis, low-dose IL-2 showed a non-significant 19% reduction in the risk of death compared with placebo over the 21-month follow-up window. However, prespecified multivariate Cox proportional hazards modeling accounting for baseline clinical covariates and disease heterogeneity revealed a significant 68% decrease in mortality risk. Crucially, baseline cerebrospinal fluid phosphorylated neurofilament heavy chain levels served as an independent predictor of therapeutic response, demonstrating a statistically significant treatment-by-biomarker interaction.
Stratification based on baseline neurofilament burden revealed that participants within the low phosphorylated neurofilament heavy chain stratum, representing 70% of the study cohort, derived substantial clinical benefit. Among these responders, low-dose IL-2 for ALS conferred a statistically significant 48% reduction in mortality risk alongside a 23% slower rate of functional decline on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale. Conversely, individuals presenting with high baseline neurofilament levels exceeding 3,700 pg/mL did not experience therapeutic benefit, reflecting an aggressive disease biology that appeared refractory to the tested regimen.
Biological target engagement was confirmed by persistent expansions in regulatory T cell populations and systemic reductions in plasma chemokine ligand 2 across multiple treatment cycles. The investigational regimen demonstrated an acceptable safety profile, with adverse events largely restricted to transient injection site reactions and mild flu-like symptoms. These pivotal observations indicate that combining low-dose IL-2 with riluzole represents a viable neuroprotective strategy when targeted to biomarker-defined patient subsets.
Reference
Bensimon G et al. Efficacy and safety of low-dose IL-2 as an add-on therapy to riluzole (MIROCALS): a phase 2b, double-blind, randomised, placebo-controlled trial. Lancet. 2025;405:1837-50.
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