Nektar Therapeutics' rezpegaldesleukin, a first-in-class interleukin-2 receptor (IL-2R) agonist, has shown promising results in Phase 1b studies for atopic dermatitis (AD) and psoriasis (PsO). The data, published in Nature Communications, highlight the drug's efficacy, safety, and tolerability in patients with these inflammatory skin conditions. The studies demonstrated that rezpegaldesleukin enhances the activity of regulatory T cells (Tregs), leading to dose-dependent clinical improvements.
Clinical Trial Results
The Phase 1b trials, which were randomized, double-blind, and placebo-controlled, evaluated rezpegaldesleukin in patients with moderate-to-severe AD (NCT04081350) or chronic plaque PsO (NCT04119557). Patients received subcutaneous doses of 10 to 12 μg/kg or 24 μg/kg once every two weeks for 12 weeks. The studies met their primary and secondary objectives, demonstrating that rezpegaldesleukin is safe, well-tolerated, and exhibits consistent pharmacokinetics.
In AD patients receiving the high dose of rezpegaldesleukin, an 83% improvement in the Eczema Area and Severity Index (EASI) score was observed after 12 weeks of treatment. Furthermore, EASI-75 (≥75% improvement in EASI score) and vIGA-AD responses were maintained for 36 weeks after treatment discontinuation in 71% and 80% of week 12 responders, respectively. These clinical improvements were accompanied by sustained increases in CD25bright Tregs.
Mechanism of Action and Biomarker Analysis
Serum proteomic biomarker analysis revealed that rezpegaldesleukin engages multiple immunoregulatory mechanisms, facilitating immune homeostasis. This suggests a potential mechanism of attenuating Th1, Th2, and Th17 responses by restoring the balance of Tregs. The drug's effect on serum IL-15 levels in atopic dermatitis patients also provides mechanistic insight into the durable efficacy observed, which persists for months following treatment.
Expert Commentary
"These promising findings clinically validate, for the first time, the Treg hypothesis – that restoring Treg function through a central pathway of IL-2R-driven Treg rescue can have disease remittive potential across a variety of chronic inflammatory skin diseases," said Jonathan Silverberg, M.D., Ph.D., Professor of Dermatology at George Washington University School of Medicine and lead study author. He added, "Newer evidence suggests that diseases like atopic dermatitis are not exclusively Th2-mediated. These results show that rezpegaldesleukin can act on multiple disease-driving pathways and is uniquely poised to address a diversity of immunopathologies."
Jonathan Zalevsky, Ph.D., Chief Research & Development Officer at Nektar, stated, "The exciting clinical cross-indication efficacy here is buttressed by serum biomarker analysis demonstrating that rezpegaldesleukin can modulate multiple immunoregulatory pathways to provide rapid onset and duration of efficacy." He further noted the validation of their therapeutic approach of using a Treg stimulator to dampen inflammatory responses and restore immune balance. Nektar anticipates reporting topline data from their two Phase 2b rezpegaldesleukin studies in atopic dermatitis and alopecia areata next year.
About Rezpegaldesleukin
Rezpegaldesleukin is being developed as a self-administered injection for various autoimmune and inflammatory diseases. It aims to restore immune system balance by stimulating the proliferation of regulatory T cells. Nektar Therapeutics wholly owns the drug.
