Purpose 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 multi-center, double-blind, randomized, placebo-controlled phase-2 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 endpoint, and of (2) relative and (3) absolute changes in the SELENA-SLEDAI scores as key secondary endpoints. Trial registration: NCT02955615

Results The primary endpoint 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 at two study sites from the same country. A post-hoc analysis on a pre-specified per-protocol 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 endpoints, accompanied by differences in several secondary exploratory endpoints. ILT-101 was well tolerated and there was no generation of anti-drug antibodies.

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