medwireNews: Adding low-dose interleukin-2 (IL-2LD) to riluzole does not significantly reduce mortality in the majority of patients with amyotrophic lateral sclerosis (ALS) but may have significant benefit for those with less aggressive disease, suggest findings from the phase 2b MIROCALS study.
In the study’s primary unadjusted analysis, 110 patients who, in addition to riluzole treatment, received daily injections of IL-2LD at a dose of 2 million IU for 5 days every 28 days over an 18-month period had a nonsignificant 19% reduction in the risk for death compared with 110 patients who received placebo alongside riluzole.
This was less than the “expected two-fold decrease,” say the researchers. However, they also report a significant effect of cerebrospinal fluid-phosphorylated-neurofilament heavy-chain (CSF-pNFH) levels on the treatment outcome. And when they stratified patients according to this prognostic biomarker, the 70% of patients with low levels (750–3700 pg/mL), indicating a less aggressive disease course, had a significant 48% reduced risk for death if they received IL-2LD rather than placebo.
By comparison, there was a nonsignificant 37% increased risk for death with IL-2LD treatment for the 21% of patients with high CSF-pNFH levels (>3700 pg/mL).
The trial involved 220 patients (median age 60 years, 62% men) who had either a possible, laboratory-supported probable, probable, or definite ALS diagnosis, a symptom duration of no more than 24 months, and a slow vital capacity of 70% or more. Patients had a median time to diagnosis of 1.4 months and 11% had possible ALS.
The participants were naïve to riluzole treatment prior to a required 12–18-week run-in period before treatment randomization. At which point, the biomarkers CSF-pNFH, regulatory T-cells (Tregs), and plasma and CSF-chemokine ligand 2 (CCL2) levels were measured to control for disease heterogeneity.
Gilbert Bensimon (Pitié-Salpêtrière Hospital, Paris, France) and colleagues report in The Lancet that at 21 months, no patients were lost to follow-up and 59% were still alive.
Among the 90 participants who died, 54% received IL-2LD treatment and 46% received placebo, with a nonsignificant hazard ratio (HR) for death of 0.81.
Multivariate analysis identified age, ALS Functional Rating Scale-Revised score, plasma CCL2 levels, absolute numbers of Tregs, and CSF-pNFH levels as significant, independent predictors of survival. However, only the latter showed a significant interaction with treatment, with patients in the IL-2LD group 68% less likely to die than those in the placebo group when this factor was taken into consideration.
This finding supports “our strategy for controlling crucial prognostic factors in this highly heterogenous disease,” say Bensimon and team.
They also point out that IL-2LD was a “safe and well-tolerated agent” that significantly increased Tregs and decreased plasma CCL2 at all timepoints.
Serious adverse events (AEs) unrelated to the study drug were mostly associated with disease progression, with just four drug-related serious AEs reported among patients in the IL-2LD arm and five among those in the placebo arm. Those related to IL-2LD included two episodes of pneumonia in one patient, one instance of altered state of consciousness, and one case each of hypersensitivity vasculitis, maculopapular rash, and autoimmune thyroiditis.
In a related comment, Michael Benatar (University of Miami, Florida, USA) and Michael McDermott (University of Rochester, New York, USA) say that the 68% reduction in the adjusted analysis, driven by the interaction with CSF-pNFH levels, could be “misinterpreted,” since “it reflects the relative hazard of death only when CSF-pNFH is zero, which is well below the limit of quantification.” They point out that “[t]he HR rises as CSF-pNFH increases.”
The commentators add that “the results of the MIROCALS trial do not adequately inform the values of CSF-pNFH that might be used clinically to differentiate patients who stand to potentially benefit or be harmed by IL-2LD.” Nevertheless, they add the results raise the prospect of the biomarker as a useful clinical measure for identifying a subset of patients suitable for IL-2LD treatment.
Benatar and McDermott conclude that given the “paucity of available treatments for ALS patients” and the potential shown by IL-2LD treatment in the study, there is an “urgency” for a large phase 3 trial “that incorporates all the lessons learned from this important phase 2 study to provide, as swiftly as possible, definitive answers to questions about the efficacy of IL-2LD and which, if any, subset of ALS patients stands to benefit from this treatment.”
medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2025 Springer Healthcare Ltd, part of Springer Nature
Lancet 2025; doi:10.1016/S0140-6736(25)00262-4
Lancet 2025; doi:10.1016/S0140-6736(25)00901-8
