LOW-DOSE INTERLEUKIN-2 THERAPY IN ACTIVE SYSTEMIC LUPUS ERYTHEMATOSUS (LUPIL-2): A MULTICENTER, DOUBLE-BLIND, RANDOMIZED AND PLACEBO-CONTROLLED PHASE 2 TRIAL
Notice bibliographique
Résumé
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).
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,003 | 0,002 |
| Méta-épidémiologie (sens strict) | 0,002 | 0,001 |
| Méta-épidémiologie (sens large) | 0,003 | 0,001 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,001 | 0,001 |
| Communication savante | 0,001 | 0,001 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,002 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,006 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».