biological activity and safety of low dose il2 in relapsing remitting multiple sclerosis

Conditions: Relapsing Remitting Multiple Sclerosis

Summary: 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.

Eligibility criteria:
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

Keywords: interleukin 2, il2 relapsing remitting multiple sclerosis autoimmune diseases regulatory t cells, tregs