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A randomized double-blind placebo-controlled trial of low-dose interleukin-2 in relapsing–remitting multiple sclerosis

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Abstract

Background

Multiple sclerosis (MS) is associated with regulatory T cells (Tregs) insufficiency while low-dose interleukin-2 (IL2LD) activates Tregs and reduces disease activity in autoimmune diseases.

Methods

We aimed at addressing whether IL2LD improved Tregs from MS patients. MS-IL2 was a single-center double-blind phase-2 study. Thirty patients (mean [SD] age 36.8 years [8.3], 16 female) with relapsing–remitting MS with new MRI lesions within 6 months before inclusion were randomly assigned in a 1:1 ratio to placebo or IL-2 at 1 million IU, daily for 5 days and then fortnightly for 6 months. The primary endpoint was change in Tregs at day-5.

Results

Unlike previous trials of IL2LD in more than 20 different autoimmune diseases, Tregs were not expanded at day-5 in IL2LD group, but only at day-15 (median [IQR] fold change from baseline: 1.26 [1.21–1.33] in IL2LD group; 1.01 [0.95–1.05] in placebo group, p < 0.001). At day-5, however, Tregs had acquired an activated phenotype (fold change of CD25 expression in Tregs: 2.17 [1.70–3.55] in IL2LD versus 0.97 [0.86–1.28] in placebo group, p < 0.0001). Regulator/effector T cells ratio remained elevated throughout treatment period in the IL2LD group (p < 0.001). Number of new active brain lesions and of relapses tended to be reduced in IL2LD treated patients, but the difference did not reach significance in this trial not powered to detect clinical efficacy.

Conclusion

The effect of IL2LD on Tregs in MS patients was modest and delayed, compared to other auto-immune diseases. This, together with findings that Tregs improve remyelination in MS models and recent reports of IL2LD efficacy in amyotrophic lateral sclerosis, warrants larger studies of IL2LD in MS, notably with increased dosages and/or modified modalities of administration.

Trial registration information

ClinicalTrials.gov: NCT02424396; EU Clinical trials Register: 2014-000088-42.

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Data availability

A deidentified dataset will be archived and upon request will be available from Assistance Publique Hôpitaux de Paris.

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Acknowledgements

We thank the personnel from the Biotherapy Department, and particularly Michele Barbié, Nathalie Ferry and Cornelia Degbé, for their excellent work. We thank the personnel from the Neuroscience Clinical Investigation Center, and particularly research nurses Carine Lefort and Marie-France Le Labousse. We also thank Olivia Tran for the monitoring of the study. We thank all patients for their commitment in participating in this study.

Funding

This study was funded by a grant from the AFM/ARSEP. It was performed in the Clinical Investigation Centers of the Pitié-Salpêtrière Hospital which receive recurrent support from the DGOS and INSERM. Immune investigations were supported by an ANR grant iMAP (ANR-16-RHUS-0001). ILTOO pharma provided the investigational drug and the placebo.

Author information

Author notes

  1. C. Louapre and M. Rosenzwajg contributed equally.

  2. C. Lubetzki and D. Klatzmann co-senior authors.

Authors and Affiliations

  1. Sorbonne University, Paris Brain Institute - ICM, Assistance Publique Hôpitaux de Paris, Inserm, CNRS, Hôpital de la Pitié Salpêtrière, Department of Neurology, CIC neurosciences, Paris, France

    C. Louapre, M. Golse, C. Papeix, E. Maillart, A. Ungureanu, J. C. Corvol & C. Lubetzki

  2. Immunology-Immunopathology-Immunotherapy (i3)-UMRS_959, Sorbonne Université- INSERM, Paris, France

    M. Rosenzwajg, A. Roux, F. Pitoiset, L. Adda, N. Tchitchek & D. Klatzmann

  3. Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Clinical Investigation Center for Biotherapies (CIC-BTi) and Immunology-Inflammation-Infectiology and Dermatology Department (3iD), Paris, France

    M. Rosenzwajg, A. Roux, F. Pitoiset, L. Adda & D. Klatzmann

  4. Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Pharmacie à Usage Intérieur, Reqpharm Unit, Paris, France

    F. Charbonnier-Beaupel

  5. Neuroradiology Department, Sorbonne University, Assistance Publique Hôpitaux de Paris, Paris, France

    D. Galanaud

  6. Assistance Publique Hôpitaux de Paris, Lariboisière Hospital, Clinical Trial Unit, Paris, France

    E. Vicaut

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  1. C. Louapre
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Contributions

DK contributed to the concept of the study. CLo, MR, EV, JCC, CLu and DK contributed to the design of the study. All authors contributed to the acquisition, analysis, or interpretation of data. CLo, MR, CLu and DK drafted the first version of the manuscript. All authors contributed to critical revision of the manuscript for important intellectual content. Statistical analysis was performed by EV. CLu and DK had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Prof Alain Créange, Prof Jean Pelletier, Prof Sandra Vukusic, Dr Silvy Laporte were members of the Data Safety Monitoring Board.

Corresponding author

Correspondence to D. Klatzmann.

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Conflicts of interest

DK and MR are inventors of a patent application owned by their institutions that protects the use of low-dose IL2 in autoimmune diseases. This patent has been licensed to ILTOO pharma in which they hold shares.

Ethical approval

The study was approved by the institutional review board of Pitié-Salpêtrière Hospital (CPP Ile de France VI) and was conducted in accordance with the Declaration of Helsinki and good clinical practice guidelines. The study protocol is registered on ClinicalTrials.gov (NCT02424396). Written, informed consent was obtained from all participants before enrolment in the study.

Ethical standard

The study was approved by the institutional review board of Pitié-Salpêtrière Hospital (CPP Ile de France VI) and was conducted in accordance with the Declaration of Helsinki and good clinical practice guidelines. The study protocol is registered on ClinicalTrials.gov (NCT02424396).

Informed consent

Written, informed consent was obtained from all participants before enrolment in the study.

Supplementary Information

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Supplementary file1 (DOCX 1004 KB)

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Louapre, C., Rosenzwajg, M., Golse, M. et al. A randomized double-blind placebo-controlled trial of low-dose interleukin-2 in relapsing–remitting multiple sclerosis. J Neurol 270, 4403–4414 (2023). https://doi.org/10.1007/s00415-023-11690-6

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