Biological Activity and Safety of Low Dose IL2 in Relapsing Remitting Multiple Sclerosis

Biological Activity and Safety of Low Dose IL2 in Relapsing Remitting Multiple Sclerosis. Multicentric Randomized Study

Interleukin-2 (IL-2) was initially discovered and used as a stimulator of effector T lymphocytes (Teffs), but is now viewed as a very promising immunoregulatory drug having the capacity to stimulate regulatory T cells (Tregs). At low dose, Il-2 tips the Treg/Teff balance towards Tregs. Recently, it has been shown that Tregs of MS patients have reduced proliferative potential. MS-IL2 will assess the safety and biological efficacy of low-dose IL2 as a Treg inducer in a Relapsing-Remitting Multiple Sclerosis (RRMS), with the aim to stimulate Treg and define potential clinical benefits

In MS-IL2, 30 RRMS patients will be treated in a randomized, double-blind, placebo controlled clinical trial. IL-2 will be administered first as an induction course of IL-2 or placebo each day for 5 days, followed by a maintenance course at the same dose or placebo every two weeks over 6 months.

The primary efficacy criteria will be the % change from baseline in Treg at day-5, which is indicative of the biological response to IL-2.

The secondary efficacy criteria will be (i) the maintenance of regulatory T cells during the 6 months of treatment with IL-2 vs. placebo and (ii) the stabilization or regression of the disease as determined by disease activity parameters assessed by MRI (cumulative number of new lesions in T1 enhanced by gadolinium after 6 months) in the groups treated with IL-2 compared to placebo.

Expected impact: MS-IL2 will define which patient respond to IL2 and which doses prevent relapses in RRMS. In addition, the deep phenomics studies will further provide the foundation for a clinical phase II to define clinical efficacy.

Inclusion Criteria:

• Age 18-65 years old ;
• Male and Female;
• Presenting relapsing remitting multiple sclerosis as determined by revised McDonald criteria (2010) ;
• On MRI : 1) Presenting 1-2 lesions enhanced by gadolinium (Gd+) (T1) without clinical expression of the disease clinique upon inclusion or 6 months prior to inclusion or 2) presenting one new lesion T2
• Expanded Disability Status Scale (EDSS) score comprised between 0 and 6;
• No flare (with or without any corticosteroid therapy) for the past 2 months
• Under β-Interferon treatment for ≥ 6 months ; or any other first-line treatment of the Relapsing-Remitting Multiple Sclerosis (RRMS): Dimethyl fumarate or teriflunomide treatment for ≥ 6 months or glatiramer acetate for ≥ 9 months
• For women of childbearing age, contraception for more than 2 weeks upon confirmation of inclusion criteria and negative Beta HCG on inclusion visit (D-30 to D-7);
• Patient informed consent should be signed by the patient and investigator before performing any clinical examination required for the study.
• Affiliation to the French Social Security Regimen

Exclusion Criteria:

• Number of lesions enhanced by gadolinium (Gd+) on MRI in T1 > 2 upon inclusion;

• Known intolerance to IL2 (see SPC):

  • Hypersensibility to active substance or one of the excipients ;
  • Signs of evolving infection requiring treatment
  • Other clinically significant chronic disorders (beside RR-MS)
  • History of organ allograft

• Administration of a non-authorized treatment; bolus of corticosteroids in the last 2 months, or treatment with cyclophosphamide, mitoxantrone, or rituximab in the last 6 months;

• Heart failure (≥ grade III NYHA), renal insufficiency, or hepatic insufficiency (transaminase>5N), or lung failure

• White blood cell count <3000 /mm3, lymphocytes< 1000 /mm3, platelets <150 000 /mm3

• Poor venous access not allowing repeated blood tests

• Vaccination with live attenuated virus in the months preceding the inclusion or planned during the study

• Surgery with general anaesthesia during the last 2 months or surgery planned during the study

• Participation in other biomedical research in the last one month or planned during the study

• Concomitant psychiatric disease or any other chronic illness or drug-abuse that could interfere with the ability to comply with the protocol or to give informed consent

• Cancer or history of cancer cured for less than five years (except in situ carcinoma of the cervix or basocellular carcinoma)

• Pregnant or lactating women;

• Men and women of childbearing potential without effective contraception for the duration of treatment

• Patients under a measure of legal protection