medwireNews: Phase 2 trial results suggest that low-dose interleukin (IL)-2 therapy with aldesleukin (ILT-101) may represent a promising add-on treatment option for systemic lupus erythematosus (SLE).
These findings lend further support to previous findings from the proof-of-concept PRO-IMMUN trial, which suggested that aldesleukin is well tolerated and may restore regulatory T-cell (Treg) homeostasis in this patient population.
David Klatzmann (Sorbonne Université, Paris, France) and co-investigators explain that insufficiency of Tregs due to a shortage of IL-2 “is central to the pathophysiology” of SLE, but there are currently no approved treatments targeting this pathway.
For the LUPIL-2 study, 100 people with moderate-to-severe active SLE from 22 sites across Europe, Mexico, and Mauritius were randomly assigned to receive aldesleukin or placebo alongside stable background therapy with glucocorticoids, antimalarials, and/or immunosuppressive agents. Aldesleukin was administered subcutaneously at a dose of 1.5 million IU, given once daily for 5 days, followed by once weekly from day 8 to week 12.
The researchers report in the Annals of the Rheumatic Diseases that the study’s primary endpoint was not met, as rates of SRI-4 response without treatment failure at week 12 did not significantly differ in the aldesleukin and placebo groups (68 vs 58%). Klatzmann and team attribute this to the “unexpectedly high” response rate in the placebo arm, with a 100% response rate at two sites from the same country (Bulgaria).
“We speculate that this placebo response was driven by better adherence to concomitant background medications, including [glucocorticoids], during the trial period compared with their prior care,” write the investigators.
In light of the “unprecedented” placebo response rate, the team carried out a post-hoc analysis in a per-protocol population (n=53) that excluded patients with major protocol deviations, including those from the two Bulgarian sites. This analysis found significantly higher SRI-4 response rates at week 12 with aldesleukin versus placebo (83.3 vs 51.7%), as well as significantly greater absolute and relative reductions in SELENA-SLEDAI score from baseline.
Klatzmann et al say that in both the intention-to-treat and per-protocol populations, the numbers and proportions of Treg cells “were significantly and persistently increased” with aldesleukin treatment. Moreover, there was a significant increase in Treg cell numbers among participants with an SRI-4 response at week 12, but not among those without, suggesting “that the clinical outcome is associated with the magnitude of the Treg response.”
This observation “adds confidence in the overall concept of a Treg insufficiency in SLE and in its treatment by [low-dose] IL-2,” write the investigators.
They report that aldesleukin was well tolerated in the LUPIL-2 study, with the majority of treatment-emergent adverse events being transient and mild-to-moderate in severity.
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