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Low-dose interleukin-2 therapy in active systemic lupus erythematosus (LUPIL-2): a multicentre, double-blind, randomised and placebo-controlled phase II trial
  1. Jens Y Humrich1,
  2. Patrice Cacoub2,3,
  3. Michelle Rosenzwajg3,4,
  4. Fabien Pitoiset3,4,
  5. Hang Phuong PHAM5,
  6. Joel Guidoux5,
  7. David Leroux5,
  8. Thomas Vazquez5,
  9. Gabriela Riemekasten1,
  10. Josef S Smolen6,
  11. George Tsokos7,8,
  12. David Klatzmann3,4
  1. 1Department of Rheumatology and Clinical Immunology, University Hospital Schleswig-Holstein, Lübeck, Germany
  2. 2Service de médecine interne et immunologie clinique, Hopital Pitie-Salpetriere, Paris, France
  3. 3Sorbonne Université-INSERM UMRS959, Immunology-Immunopathology-Immunotherapy (i3) laboratory, Sorbonne Universite, Paris, France
  4. 4Biotherapies Department, Pitié-Salpêtrière hospital, Assistance Publique-Hopitaux de Paris, Paris, France
  5. 5ILTOO Pharma, Paris, France
  6. 6Medical University of Vienna, Wien, Austria
  7. 7Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
  8. 8Division of Rheumatology and Clinical Immunology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
  1. Correspondence to Professor David Klatzmann, Sorbonne Université - INSERM UMRS959, Sorbonne Universite, Paris 75006, France; david.klatzmann{at}sorbonne-universite.fr

Abstract

Objectives A regulatory T cell (Treg) insufficiency due to shortage of interleukin-2 (IL-2) is central to the pathophysiology of systemic lupus erythematosus (SLE). We performed a multicentre, double-blinded, randomised, placebo-controlled phase II proof-of-concept trial to evaluate the efficacy of low-dose IL-2 therapy in patients with SLE having moderate-to-severe disease activity while receiving standard treatment.

Methods We randomly assigned 100 patients in a 1:1 ratio to receive either 1.5 million IU/day of subcutaneous IL-2 (ILT-101) or placebo for 5 days followed by weekly injections for 12 weeks. Clinical efficacy was assessed at week 12 in a predefined hierarchical analysis of (1) the SLE responder index-4 (SRI-4) response as a primary end point, and of (2) relative and (3) absolute changes in the Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index scores as key secondary end points.

Results The primary end point was not met in the intention-to-treat population (ILT-101: 68%, placebo: 58%; p=0.3439), due to a 100% SRI-4 response rate in the placebo group from the two sites from Bulgaria. A post hoc per-protocol analysis on a prespecified population that excluded patients from these two sites (n=53) showed a statistically significant difference for the SRI-4 response rate (ILT-101: 83.3%; placebo: 51.7%; p=0.0168), and for the two key secondary end points, accompanied by differences in several secondary exploratory end points. ILT-101 was well tolerated and there was no generation of antidrug antibodies.

Conclusions The post hoc hierarchical analysis of the primary and key secondary end points in a per-protocol population, complemented by the exploratory analyses of multiple other secondary end points, support that low-dose IL-2 is beneficial in active SLE.

Trial registration number NCT02955615.

  • autoimmunity
  • lupus erythematosus, systemic
  • biological therapy

Data availability statement

Data are available on reasonable request. Data are available on request to the corresponding author: David Klatzmann.

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Data availability statement

Data are available on reasonable request. Data are available on request to the corresponding author: David Klatzmann.

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Footnotes

  • Handling editor David S Pisetsky

  • Contributors All authors contributed to the development of the manuscript, including interpretation of results, substantive review of drafts and approval of the final draft for submission. DK is the guarantor.

  • Funding Funding was provided by the sponsor, ILTOO Pharma and the French National Research Agency (ANR-16-RHUS-0001, RHU IMAP).

  • Competing interests PC, MR and DK are inventors for patents related to the therapeutic use of IL-2, which belongs to their academic institutions and have been licensed to ILTOO Pharma in which they hold interests. HPP, JG, DL and TV are employees of ILTOO Pharma.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.