PO.6.127 Efavaleukin alfa, a novel IL-2 mutein, selectively expands regulatory t cells in patients with SLE: final results of a phase 1b multiple ascending dose study

• Published in: Lupus science & medicine 2022-10, Vol.9 (Suppl 2), p.A96-A97
• Main Authors: Tchao, N, Sarkar, N, Hu, X, Zhang, R, Milmont, C, Shi Jin, Y, Chow, V, Kroenke, M, Gorski, K, Furie, R, Alan, K, Stanley, C
• Format: Article
• Language: English
• Subjects: Friday 07 October 2022 from 13:00 to 14:10; Lymphocytes
• ISSN: 2053-8790
• DOI: 10.1136/lupus-2022-elm2022.148

PurposeDefects in regulatory T cell (Treg) number and function are associated with autoimmune diseases including SLE. Interleukin (IL)-2 is essential for the development and suppressive function of Treg, and therapies that exploit the ability of IL-2 to expand Treg have shown disease-modifying potential in SLE (1). Efavaleukin alfa, a novel IL-2 mutein Fc fusion protein with greater Treg selectivity and longer half-life than recombinant IL-2, was well tolerated and led to robust, selective Treg expansion in healthy subjects (2). This analysis presents the results of a phase 1b, multiple ascending dose study (NCT03451422) of efavaleukin alfa in SLE patients.MethodsThe study included 5 ascending dose cohorts (cohort 1=lowest dose; cohort 5=highest dose). A total of 35 SLE patients (24–71 y; 85.7% female) were randomized to receive efavaleukin alfa or placebo (5:2 for cohorts 1–3; 3:1 for cohorts 4–5) SC every 2 wk (Q2W; cohorts 1, 2, 4, and 5) or every wk (QW; cohort 3) in addition to standard of care therapy for a total of 12 wk, with 6 wk of follow-up. The primary endpoint was the incidence of treatment-emergent adverse events (TEAEs). Additional endpoints included serum PK and changes in numbers of Treg, CD4+ Tcon, CD8+ T cells, and NK cells in peripheral blood.ResultsThe most commonly reported TEAEs (≥25% of efavaleukin alfa-treated subjects) included non-serious, mild or moderate (grade 1–2) injection site reactions. No grade 4 TEAEs or deaths occurred. Two serious AEs were reported in efavaleukin alfa-treated subjects: one event of syncope (grade 3) was observed in cohort 2 and was not considered related to treatment, and one case of eosinophilia (grade 2) was observed in cohort 5 and was considered related to treatment. Efavaleukin alfa PK was generally linear and dose-proportional, with a terminal half-life ranging from 18–30 h. Peak Foxp3+ Treg expansion was observed at 8 d post-dose, and the magnitude of the peak was generally sustained after multiple QW or Q2W doses. Mean peak increases in Foxp3+ Treg were 14.8-, 17.4-, 5.7-, 2.4-, and 1.1-fold above baseline for efavaleukin alfa Q2W dosing cohorts 5, 4, 2, 1 and placebo, respectively. At the final study assessment (42 d after the last dose), the mean Treg count was 1.3-fold above baseline (95% CI, 0.9–1.9). Treatment with efavaleukin alfa also expanded CD25bright Treg (peak 53.8-fold change) and CD31+ recent thymic emigrant, naïve, and memory Treg subsets. At the highest dose (cohort 5), low-leve