LOW-DOSE INTERLEUKIN-2 THERAPY IN ACTIVE SYSTEMIC LUPUS ERYTHEMATOSUS (LUPIL-2): A MULTICENTER, DOUBLE-BLIND, RANDOMIZED AND PLACEBO-CONTROLLED PHASE 2 TRIAL
Bibliographic record
Abstract
PV181 / #691 Poster Topic: AS20 - Precision Medicine Background/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 an international, multicenter, double-blind, randomized, placebo-controlled phase 2 proof-of-concept trial to evaluate the safety and efficacy of low-dose IL-2 therapy in patients with SLE having moderate-to-severe disease activity while receiving standard-of-care 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 (2) of relative and (3) of absolute changes in the SELENA-SLEDAI scores as key secondary endpoints. Multicolor flow cytometry was applied at defined time points to assess changes in Treg and other immune cells. Results Although the primary endpoint was not met in the intention-to-treat population (ILT-101: 68%, placebo: 58%; p=0.3439), which was due to a 100% SRI-4 response rate in placebo-treated patients at 2 study sites from the same country (n=14 in total), a post hoc analysis on a prespecified per-protocol population that also excluded patients from these 2 sites (n=53) revealed a statistically significant difference at week-12 in favor of ILT-101 for the SRI-4 response rate (ILT-101: 83.3%; placebo: 51.7%; p=0.0168) and for the 2 key secondary endpoints (p<0.05). This was accompanied by significant differences (p<0.05) in several secondary and exploratory endpoints, such as proportions of SRI-6 and SRI-8 responders, patients in remission and changes in glucocorticoids. Notably, a significant and robust difference in the SRI-4 response rate was already evident at week-8 (ILT-101: 79.2%; placebo: 41.4%; p=0.0051). ILT-101 was safe and well tolerated and no generation of anti-drug antibodies was observed. Treatment with ILT-101, but not with placebo, led to a selective and sustained expansion of the CD25hi Treg population and clinical benefit was associated with the magnitude of the Treg response. 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, consistently support that low-dose IL-2 therapy is beneficial in active SLE. Our data also imply that clinical efficacy of low-dose IL-2 therapy is driven by the activation and expansion of the Treg population, which adds confidence in the pathophysiological concept of an impairment of the Treg-IL-2 axis in SLE. The results of this trial[1] in conjunction with encouraging data from several other studies[2] warrant the further development of low-dose IL-2 therapy as precision medicine for SLE and other autoimmune diseases, and provide a valuable scientific basis for the design of confirmatory phase 3 clinical trials in SLE. References: [1.] Humrich JY. Ann Rheum Dis 2022;81(12):1685-94. [2.] Akbarzadeh R. Curr Opin Rheumatol 2023;35(2):98-106. Trial registration number: NCT02955615 . Funding: Funding was provided by ILTOO Pharma (trial sponsor) and the French National Research Agency (ANR-16- RHUS- 0001, RHU IMAP).
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.002 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.003 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.006 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".