ALS治療に新たな知見:MIROCALS臨床試験の成果(New insights into the treatment of ALS: MIROCALS clinical trial results published in The Lancet)

2025-05-13 サセックス大学

<関連情報>

• https://www.sussex.ac.uk/research/full-news-list?id=68125
• https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)00262-4/fulltext

リルゾールの上乗せ療法としての低用量IL-2の有効性と安全性(MIROCALS):第2b相二重盲検無作為化プラセボ対照試験 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

Gilbert Bensimon, PhD ∙ Prof P Nigel Leigh, PhD ∙ Prof Timothy Tree, PhD ∙ Prof Andrea Malaspina, PhD ∙ Christine AM Payan, MD ∙ Hang-Phuong Pham, PhD ∙ et al.
The Lancet  Published: May 9, 2025
DOI:https://doi.org/10.1016/S0140-6736(25)00262-4

Summary

Background

Amyotrophic lateral sclerosis (ALS) is a life-threatening disease characterised by progressive loss of motor neurons with few therapeutic options. The MIROCALS study tested the hypothesis that low-dose interleukin-2 (IL-2_LD) improves survival and function in ALS.

Methods

In this randomised, double-blind, placebo-controlled trial, male and female riluzole-naive participants, with either a possible, laboratory-supported probable, probable, or definite ALS diagnosis (revised El Escorial criteria), aged 18–76 years, with symptom duration of 24 months or fewer, and slow vital capacity of 70% or more, underwent a riluzole-only 12–18 week run-in period before randomisation in a 1:1 ratio to either 2 million international units (MIU) IL-2_LD or placebo by subcutaneous injection daily for 5 days every 28 days over 18 months. The primary endpoint was survival at 640 days (21 months). Secondary outcomes included safety, ALS Functional Rating Scale-Revised (ALSFRS-R) score, and biomarker measurements including regulatory T-cells (Tregs), cerebrospinal fluid (CSF)-phosphorylated-neurofilament heavy-chain (CSF-pNFH), and plasma and CSF-chemokine ligand 2 (CCL2). The primary endpoint analysis used unadjusted log-rank and Cox’s model adjusted analyses using pre-defined prognostic covariates to control for the disease and treatment response heterogeneity. The study was 80% powered to detect a two-fold decrease in the risk of death by the log-rank test in the intention-to-treat (ITT) population, including all randomly allocated participants. MIROCALS is registered with ClinicalTrials.gov (NCT03039673) and is complete.

Findings

From June 19, 2017, to Oct 16, 2019, 304 participants were screened, of whom 220 (72%) met all criteria for random allocation after the 12-to-18-week run-in period on riluzole. 136 (62%) of participants were male and 84 participants (38%) were female. 25 (11%) of the 220 randomly allocated participants were defined as having possible ALS under El Escorial criteria. At the cutoff date there was no loss to follow-up, and all 220 patients who were randomly allocated were documented as either deceased (90 [41%]) or alive (130 [59%]), so all participants were included in the ITT and safety populations. The primary endpoint unadjusted analysis showed a non-significant 19% decrease in risk of death with IL-2_LD (hazard ratio 0·81 [95% CI 0·54–1·22], p=0·33), failing to demonstrate the expected two-fold decrease in risk of death. The analysis of the primary endpoint adjusted on prognostic covariates, all measured at time of random allocation, showed a significant decrease of the risk of death with IL-2_LD (0·32 [0·14–0·73], p=0·007), with a significant treatment by CSF-pNFH interaction (1·0003 [1·0001–1·0005], p=0·001). IL-2_LD was safe, and significantly increased Tregs and decreased plasma-CCL2 at all timepoints. Stratification on CSF-pNFH levels measured at random allocation showed that IL-2_LD was associated with a significant 48% decrease in risk of death (0·52 [0·30–0·89], p=0·016) in the 70% of the population with low (750–3700 pg/mL) CSF-pNFH levels, while in the 21% with high levels (>3700 pg/mL), there was no significant difference (1·37 [0·68–2·75], p=0·38).

Interpretation

With this treatment schedule, IL-2_LD resulted in a non-significant reduction in mortality in the primary unadjusted analysis. However, the difference between the results of unadjusted and adjusted analyses of the primary endpoint emphasises the importance of controlling for disease heterogeneity in ALS randomised controlled trials. The decrease in risk of death achieved by IL-2_LD therapy in the trial population with low CSF-pNFH levels requires further investigation of the potential benefit of this therapy in ALS.

Funding

European Commission H2020 Programme; French Health Ministry PHRC2014; and Motor Neurone Disease Association.