Purpose Defects 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.
Methods The 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.
Results The 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-level increases in numbers of CD4+ Tcon (peak 2.3-fold), CD8+ T cells (peak 2.1-fold), and NK cells (peak 2.9-fold) were observed.
Conclusion Multiple ascending doses of efavaleukin alfa were safe and well tolerated and led to selective and prolonged Treg expansion in SLE patients. Results at the highest dose suggest a plateau in Treg expansion with low-level increases in other IL-2–responsive cells, although interpretation is limited due to small subject numbers. The highest tested dose may be outside the therapeutic window and thus will not be assessed in phase 2 clinical studies. These findings support the ongoing phase 2b adaptive randomized controlled trial in SLE patients.
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