Efavaleukin alfa Advanced Drug Monograph

Efavaleukin alfa Report

Name: Efavaleukin alfa Name (English): Efavaleukin alfa DrugBank ID: DB16149 Type: Biotech CAS Number: 2049067-94-7

Description: Efavaleukin alfa is a novel interleukin-2 (IL-2) mutein Fc fusion protein. It is designed to selectively expand regulatory T cells (Treg) by preferentially binding to the high-affinity IL-2 receptor alpha chain (CD25), which is constitutively expressed at high levels on Tregs. This preferential binding leads to increased cell surface retention and sustained Treg signaling compared to recombinant IL-2.

Mechanism of Action: Efavaleukin alfa is an IL-2 mutein with an introduced mutation that decreases its binding to IL-2Rβ and increases its dependence on IL-2Rα (CD25). This modification allows for selective binding to the high-affinity IL-2 receptor on Tregs, promoting their expansion and function without significantly affecting other immune cells like conventional CD4+ T cells, CD8+ T cells, or natural killer (NK) cells.

Clinical Development: Efavaleukin alfa has been under investigation for the treatment of inflammatory and autoimmune diseases, including:

• Systemic Lupus Erythematosus (SLE): Phase 1b and Phase 2 clinical trials have evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of efavaleukin alfa in patients with SLE. Initial results showed that the drug was well-tolerated and led to selective and prolonged Treg expansion in these patients. However, Amgen discontinued its Phase 2b study in SLE due to futility.
• Ulcerative Colitis: Efavaleukin alfa is also being evaluated in a Phase 2 long-term extension study for the treatment of moderately to severely active ulcerative colitis.

Safety and Tolerability: In clinical trials, efavaleukin alfa has generally been well-tolerated. The most common adverse events reported were mild to moderate injection site reactions. No dose-limiting toxicities or treatment-related serious adverse events were frequently observed in early-stage trials.

Pharmacokinetics: The pharmacokinetics of efavaleukin alfa have been described as generally linear and dose-proportional, with a terminal half-life ranging from 18 to 30 hours.

Pharmacodynamics: Efavaleukin alfa treatment has been shown to induce a robust and prolonged dose-dependent expansion of Tregs, with minimal changes observed in other IL-2-responsive cell populations, highlighting its pharmacodynamic selectivity. It has also been shown to restore CD25 expression on Tregs in SLE patients to levels comparable to healthy controls.

Current Status: As of late April 2023, Amgen discontinued the Phase 2b study of efavaleukin alfa for SLE due to futility. However, development continues for other indications, such as ulcerative colitis.

Note: This report provides a summary of the available information on Efavaleukin alfa as of May 13, 2025. Clinical development is dynamic, and the current status may be subject to change.