The Lancet: Low-dose IL-2 Therapy Improves Survival in ALS Patients

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a rare motor neuron disease involving the loss of motor neurons in the brain and spinal cord, leading to irreversible disability and death. The median survival time from symptom onset to death is only 2–3 years.

Riluzole, an FDA-approved drug for ALS, typically extends survival by only a few months. Therefore, there remains an urgent need for more effective treatments. However, the lack of understanding of ALS-related targets and the clinical and pathological heterogeneity of the disease have hindered the development of more effective therapies.

Neuroinflammation has been shown to contribute to the wide spectrum of ALS phenotypes, offering a promising therapeutic target. Modifying the inflammatory components of ALS pathogenesis may improve survival and slow functional decline. CD4+ FOXP3+ regulatory T cells (Tregs) are a T cell subset with broad immunoregulatory functions. Damage to their number and function is associated with ALS severity, progression, and survival. The generation, activation, and survival of Tregs require the cytokine interleukin-2 (IL-2), providing a feasible and measurable treatment pathway to enhance immune tolerance and suppress neuroinflammation.

Recently, the internationally renowned medical journal The Lancet published a clinical research article titled: 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.

The results of this clinical trial provide encouraging evidence that adding low-dose IL-2 to standard riluzole therapy can reduce the risk of death in ALS patients. This finding suggests that modulating the immune system may be an effective strategy to slow disease progression. Low-dose IL-2 may be considered a safe and well-tolerated treatment option to enhance the therapeutic effect of riluzole.

ALS is a life-threatening disease characterized by progressive motor neuron loss with limited treatment options. In this latest study, researchers evaluated the efficacy and safety of low-dose IL-2 as an add-on to riluzole in treating ALS.

In this phase 2b randomized, double-blind, placebo-controlled trial, ALS patients aged 18–76, with symptoms for ≤24 months, forced vital capacity ≥70%, and no prior riluzole treatment underwent a 12–18 week riluzole-only lead-in period. Afterward, they were randomized 1:1 to receive either low-dose IL-2 (2 million IU subcutaneously for 5 days every 28 days) or placebo for 18 months. The primary endpoint was survival at 640 days (21 months). Secondary endpoints included safety, ALS Functional Rating Scale-Revised (ALSFRS-R) scores, and biomarker analysis (Treg cells, cerebrospinal fluid phosphorylated neurofilament heavy chain (CSF-pNFH), plasma/CSF chemokine CCL2).

Between June 19, 2017, and October 16, 2019, 304 ALS patients were screened. Of these, 220 (72%) met all randomization criteria after the riluzole lead-in. Among the randomized participants, 136 (62%) were male, and 84 (38%) were female. All 220 patients were either deceased (90 cases, 41%) or alive (130 cases, 59%) at study completion, with no loss to follow-up.

The unadjusted analysis of the primary endpoint showed a 19% reduction in death risk in the IL-2LD group, which was not statistically significant and did not meet the predefined goal of halving the death risk. However, after adjusting for prespecified prognostic covariates at the time of randomization, the IL-2LD group showed a significant 68% reduction in death risk. Furthermore, there was a significant interaction between CSF-pNFH levels and treatment effects. IL-2LD was well-tolerated, significantly increased Treg cells, and reduced plasma CCL2 levels at all time points.

Stratified analysis by baseline CSF-pNFH showed that in the 70% lower-level group (750–3700 pg/mL), IL-2LD significantly reduced death risk by 48%, whereas in the 21% higher-level group (>3700 pg/mL), no significant difference was observed.

Despite the unadjusted analysis of the primary endpoint showing a non-significant 19% reduction in death risk, the preplanned adjusted analysis revealed a significant benefit of IL-2LD, with a strong interaction with pNFH levels. Thus, this phase 2b randomized, double-blind, parallel-group, placebo-controlled trial confirms that long-term low-dose IL-2, as an add-on to riluzole, can safely improve survival and slow functional decline in ALS patients.