A Phase II, multi-centre, randomized, double blind, placebo-controlled study to evaluate the efficacy, safety and pharmacokinetics of ILT-101 in patients with active moderate to severe systemic lupus erythematosus (SLE)

INTERVENTION: Product Name: ILT‐101 Product Code: ILT‐101 Pharmaceutical Form: Powder for solution for injection INN or Proposed INN: Aldesleukin CAS Number: 110942‐02‐4 Other descriptive name: INTERLEUKIN‐2 Concentration unit: mg/ml milligram(s)/millilitre Concentration type: range Concentration number: 1.50‐3.00 Pharmaceutical form of the placebo: Powder for solution for injection Route of administration of the placebo: Subcutaneous use CONDITION: Systematic Lupus Erythematosus ; MedDRA version: 19.0 Level: PT Classification code 10042945 Term: Systemic lupus erythematosus System Organ Class: 10028395 ‐ Musculoskeletal and connective tissue disorders Therapeutic area: Body processes [G] ‐ Immune system processes [G12] PRIMARY OUTCOME: Main Objective: The primary objective of the study is the evaluation of the clinical efficacy of ILT‐101 (1.5 MUI of IL‐2 daily for 5 days and then weekly from day 8 to day 162) at week 12 in active SLE patients with moderate to severe disease activity. Primary end point(s): Percentage of patients with a SLE responder index of 4 (SRI‐4) at week 12, SRI‐4 response being defined as (1) a = 4‐point reduction in SELENA‐SLEDAI score as compared to baseline, and (2) no new BILAG A score or = 1 new BILAG B score, and (3) no deterioration from baseline in the physician's global assessment by = 0.3 points Secondary Objective: To assess:; 1/ Maintenance of clinical efficacy (at week 24) within responders (i.e.; those with SRI‐4 at week 12); 2/ Maintenance of clinical efficacy at week 36 within responders; 3/ Safety of ILT‐101 during the treatment period; 4/ Relationship between immunological cell subsets (Tregs) and clinical; endpoints Timepoint(s) of evaluation of this end point: 12 weeks after baseline SECONDARY OUTCOME: Secondary end point(s): Maintenance of clinical response ; ‐ Number and percentage of W12 SRI‐4 responder patients who sustain SRI‐4 response at week 24 ; ‐ Percentage of W12 SRI‐4 responder patients with mild/moderate or severe flares according to SFI at week 24 ; ; Corticosteroids tapering ; • Prednisone‐equivalent CS daily dose at week 12 as compared with baseline, at week 24 compared with week 12 and at week 36 as compared with week 24 ; ‐ Percentage of patients able to reduce oral steroid dose to 15mg daily at week 12, and to 7.5 mg daily prednisone at week 24 ; ‐ Percentage of patients able to reduce oral steroid dose by 25 and 50% at week 12, 16, 20 and 24 as compared to baseline ; ; Biological response ; ‐ Change in anti‐dsDNA at week 4, 8, 12, 20, 24 and 36 as compared to baseline ; ‐ Change in blood Tregs (expressed as percentage of CD4 and absolute numbers) at day 5, week 4, 12, 24 and 36 as compared to baseline ; ; Safety ; ‐ Safety parameters assessed by clinical examination, routine laboratory tests, recording of adverse events and vital signs preceding any study procedure ; ; Maintenance of clinical response from week 12 to 24 ; Number and percentage of W12 SRI‐4 responder patients who sustain SRI‐4 response at week 16 and 20 ; ‐ Number and percentage of W12 SRI‐4 responder patients with mild/moderate or severe flares according to SFI at week 16 and 20 ; ‐ Time to flare between week 12 and week 24 in W12 SRI‐4 responder patients ; ‐ Percentage of patients having a SRI‐4 response at week 4, 8 or 12 and who sustain it for 3 months ; ‐ Percentage of W12 SRI‐4 responder patients fulfilling SRI‐6, SRI‐8, BICLA criteria at week 16, 20 and 24 as compared to baseline ; Maintenance of biological and clinical response at week 36 ; • Number and percentage of W12 and W24 SRI‐4 responder patients who sustain SRI‐4 response at week 36 ; • Number and percentage of W12 and W24 SRI‐4 responder patients with mild/moderate or severe flares according to SFI at week 36 ; • Time to flare between week 24 and week 36 in W24 SRI‐4 responder patients ; • Percentage of W12 and W24 SRI‐4 responder patients fulfilling SRI‐6, SRI‐8, BICLA criteria at week 36 as compared to week 24 ; • Change in anti‐dsDNA at week 36 as compared to week 24 ; • Change in blood Tregs (expressed as percentage of CD4 and absolute numbers) at week 36 as compared to week 24 ; ; Early clinical response ; ‐ Number and percentage of patients responding to treatment according to SRI‐4 at week 4 and 8 as compared to baseline ; ‐ Number and percentage of patients fulfilling SRI‐6, SRI‐8, BICLA criteria at week 4, 8 and 12 as compared to baseline ; ‐ Time to first SRI‐4, ‐6, ‐8 response during the first three months ; ‐ Time to flare during the first three months ; ‐ Number and percentage of patients with mild/moderate or severe flares according to SFI at week 4, 8 and 12 ; ; Other clinical assessments ; ‐ Absolute and relative change in SELENA‐SLEDAI at week 4, 8, 12, 16, 20 24 and 36 as compared to baseline ; ‐ Absolute and relative change in BILAG at week 4, 8, 12, 16, 20, 24 and 36 as compared to baseline ; ‐ Absolute and relative change in PGA at week 4, 8, 12, 16, 20, 24 and 36 as compared to baseline ; ‐ Percentage of patients in remission (SLEDAI=2) at week 4, 8, 12, 16, 20, 24 and 36 ; ‐ Quality of life index: Lupus QoL at week 4, 12, 24 and 36 as compared to baseline ; ‐ Fatigue by VAS and fatigue severity scale at week 4, 8, 12, 24 and 36 as compared to baseline ; Biological response ; ‐ Change in C3/C4 at week 4, 8, 12, 20, 24 and 36 as compared to baseline ; ‐ Quantification of anti‐ILT‐101 antibodies and of their neutralising effect at baseline, week 12 and 24 ; ; Timepoint(s) of evaluation of this end point: Please refer to E.5.2 INCLUSION CRITERIA: ‐‐ Age = 18 years ‐ Male or female ‐ Having a confirmed diagnosis of SLE assessed by the presence of at least 4 of the criteria of American College of Rheumatology (ACR) list or of the Systemic Lupus International Collaborating Clinics (SLICC) list at least at diagnosis. ‐ Having an active SLE characterised by: > SELENA‐SLEDAI score = 6 > Positive for Anti‐nuclear antibody (ANA), titre (=1:80) > Positive for anti‐dsDNA antibody > Low levels (below the laboratory normal range) of C3 or C4 complement components OR a SELENA‐SLEDAI score = 8 ‐ Being on stable background therapy (dose and type) before inclusion including any corticotherapy at dose =7.5mg/day but lower than 30mg/day or 0.5mg/kg/day whichever is the lower. Corticosteroids and antimalarial drug should be stable for 1 month prior to inclusion, immunosuppressant must be stable for 2 months prior to inclusion. ‐ Using highly effective methods of contraception during