Repeated 5-day cycles of low dose aldesleukin in amyotrophic lateral sclerosis (IMODALS): A phase 2a randomised, double-blind, placebo-controlled trial

EBioMedicine. 2020 Sep:59:102844. doi: 10.1016/j.ebiom.2020.102844. Epub 2020 Jul 7.

Abstract

Background: Low-dose interleukin-2 (ld-IL-2) enhances regulatory T-cell (Treg) function in auto-inflammatory conditions. Neuroinflammation being a pathogenic feature of amyotrophic lateral sclerosis (ALS), we evaluated the pharmacodynamics and safety of ld-IL-2 in ALS subjects.

Methods: We performed a single centre, parallel three-arm, randomised, double-blind, placebo-controlled study. Eligibility criteria included age < 75 years, disease duration < 5 years, riluzole treatment > 3 months, and a slow vital capacity ≥ 70% of normal. Patients were randomised (1:1:1) to aldesleukin 2 MIU, 1 MIU, or placebo once daily for 5 days every 4 weeks for 3 cycles. Primary outcome was change from baseline in Treg percentage of CD4+ T cells (%Tregs) following a first cycle. Secondary laboratory outcomes included: %Treg and Treg number following repeated cycles, and plasma CCL2 and neurofilament light chain protein (NFL) concentrations as surrogate markers of efficacy. Safety outcomes included motor-function (ALSFRS-R), slow vital capacity (SVC), and adverse event reports. This trial is registered with ClinicalTrials.gov, NCT02059759.

Findings: All randomised patients (12 per group), recruited from October 2015 to December 2015, were alive at the end of follow-up and included in the intent-to-treat (ITT) analysis. No drug-related serious adverse event was observed. Non-serious adverse events occurred more frequently with the 1 and 2 MIU IL-2 doses compared to placebo, including injection site reactions and flu-like symptoms. Primary outcome analysis showed a significant increase (p < 0·0001) in %Tregs in the 2 MIU and 1 MIU arms (mean [SD]: 2 MIU: +6·2% [2·2]; 1 MIU: +3·9% [1·2]) as compared to placebo (mean [SD]: -0·49% [1·3]). Effect sizes (ES) were large in treated groups: 2 MIU ES=3·7 (IC95%: 2·3-4·9) and 1 MIU ES=3·5 (IC95%: 2·1-4·6). Secondary outcomes showed a significant increase in %Tregs following repeated cycles (p < 0·0001) as compared to placebo, and a dose-dependent decrease in plasma CCL2 (p = 0·0049). There were no significant differences amongst the three groups on plasma NFL levels.

Interpretation: Ld-IL-2 is well tolerated and immunologically effective in subjects with ALS. These results warrant further investigation into their eventual therapeutic impact on slowing ALS disease progression.

Funding: The French Health Ministry (PHRC-I-14-056), EU H2020 (grant #633413), and the Association pour la Recherche sur la SLA (ARSLA).

Keywords: Amyotrophic lateral sclerosis; Biomarkers; Low dose interleukin-2; Neuro-inflammation; Randomised clinical trial; Regulatory T cells.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Aged, 80 and over
  • Amyotrophic Lateral Sclerosis / diagnosis
  • Amyotrophic Lateral Sclerosis / drug therapy*
  • Amyotrophic Lateral Sclerosis / etiology
  • Amyotrophic Lateral Sclerosis / metabolism
  • Antineoplastic Agents / administration & dosage*
  • Biomarkers
  • Chemokines
  • Cytokines
  • Female
  • Humans
  • Immunophenotyping
  • Interleukin-2 / administration & dosage
  • Interleukin-2 / analogs & derivatives*
  • Interleukin-2 / metabolism
  • Male
  • Middle Aged
  • Recombinant Proteins / administration & dosage
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism
  • Treatment Outcome

Substances

  • Antineoplastic Agents
  • Biomarkers
  • Chemokines
  • Cytokines
  • Interleukin-2
  • Recombinant Proteins
  • aldesleukin

Associated data

  • ClinicalTrials.gov/NCT02059759