Introduction

Targeting interleukin (IL)-2 and its ability to expand regulatory T cells (Treg) represents a novel therapeutic mechanism for the treatment of ulcerative colitis (UC). Low-dose recombinant IL-2 (aldesleukin) has shown disease-modifying activity in UC in early clinical studies.^1,2 However, low dose IL-2 has a small selectivity window for Treg over conventional CD4+ T cells (Tcon) and natural killer (NK) cells, with the potential for inflammatory cell expansion and adverse events (AE) related to low selectivity. Efavaleukin alfa is an IL-2 mutein Fc fusion protein with a mutation that decreases binding to IL-2Rβ and increases dependence on IL-2Rα (CD25), which is expressed constitutively at high levels on Treg. Here we evaluated the selectivity of efavaleukin alfa for Treg expansion, using data from preclinical³ and phase 1 (NCT03451422)⁴ studies to support the biologic rationale for a phase 2 clinical study of efavaleukin alfa in UC patients.

Aims & Methods

In vitro activity and selectivity were assessed according to levels of phosphorylated STAT5 (pSTAT5) and proliferation of Treg, Tcon, and NK cells in primary human peripheral blood mononuclear cells (PBMC) cultured with increased doses of efavaleukin alfa or aldesleukin. The in vivo effects on body temperature, C-reactive protein (CRP), proinflammatory cytokine production, and peripheral blood Treg, Tcon, and NK cell numbers were evaluated in cynomolgus monkeys after escalating single SC doses of efavaleukin alfa or 5 consecutive daily SC doses of aldesleukin. Safety, tolerability, and pharmacodynamics of efavaleukin alfa vs placebo were evaluated in a single-dose phase 1a study in healthy subjects and in a multiple ascending dose phase 1b study in patients with systemic lupus erythematosus (SLE).

Results

In human PBMC cultures, efavaleukin alfa led to a more selective Treg response (pSTAT5 and proliferation) than aldesleukin, with lower levels of IL-2 signaling observed in non-Treg (Tcon and NK) cells and proliferation of inflammatory cells only observed at higher doses of efavaleukin alfa vs aldesleukin. Dose-dependent expansion of FoxP3+ Treg in aldesleukin-treated cynomolgus monkeys was accompanied by increased body temperature and levels of CRP and IL-6. However, efavaleukin alfa stimulated Treg expansion with no increases in IL-6 and without significant effects on body temperature or CRP except at the highest dose, suggesting an increased therapeutic window compared with aldesleukin. In phase 1 studies, peak Treg expansion was observed at 8 days post-dose, and mean Treg levels remained above baseline through the end of the follow-up period. The mean peak increases in FoxP3+ Treg were 4.7-fold above baseline after a single dose administered to healthy subjects and 17.4-fold above baseline after multiple doses in SLE patients. In contrast, there were minimal changes in fold-change of Tcon, CD8+ T cells, B cells, or NK cells with efavaleukin alfa. In phase 1 studies, the most common AEs were mild-moderate (grade 1-2) injection site reactions, and no dose-limiting toxicities, treatment-related serious AEs, or deaths were reported.

Conclusion

Efavaleukin alfa is a novel IL-2 therapy that has an increased therapeutic window compared with aldesleukin. Preclinical and phase 1 results with efavaleukin alfa demonstrated highly selective expansion of Treg with minimal effects on pro-inflammatory immune cells. These findings support the rationale and design of an ongoing phase 2b study investigating the safety and efficacy of efavaleukin alfa induction therapy in patients with moderate to severe active UC (NCT04987307).

References

(1) Allegretti J, et al. Gastroenterology. 2021;160(3):S9-S10
(2) Rosenzwaig M, et al. Ann Rheum Dis. 2019;78:209-217
(3) Tchao N, et al. Blood. 2017;130(S1):696.
(4) Tchao N, et al. Ann Rheum Dis. 2022;81:1343-1344 [AB0432]

Disclosure

Farshid Firoozbakht, Nandita Sarkar, and Kevin Gorski are employees and stockholders of Amgen Inc. Nadia Tchao is a former Amgen employee and stockholder.