Rezpegaldesleukin showed durable dose-dependent improvements in physician-assessed disease activity and patient-reported outcomes in patients with atopic dermatitis (AD) and psoriasis (PsO), according to two Phase 1b studies in Nature Communications.
Under development as a self-administered injection, rezpegaldesleukin is a first-in-class interleukin-2 receptor (IL-2R) agonist that enhances the activity of regulatory T cells (Tregs). It is wholly-owned by Nektar Therapeutics.
Results from the Phase 1b studies showed that rezpegaldesleukin safely and dose-dependently increased Tregs and rapidly improved measurable exploratory disease outcomes that are largely durable for at least 36 weeks after ceasing treatment.
“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,” says study author Jonathan Silverberg, MD, PhD, Professor of Dermatology at George Washington University School of Medicine in Washington, DC, in a news release. “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.”
Key findings include:
- Rezpegaldesleukin was evaluated in two randomized, double-blind, placebo-controlled Phase 1b trials in patients with moderate-to-severe atopic dermatitis (AD) (NCT04081350) or chronic plaque psoriasis (PsO) (NCT04119557)
- Rezpegaldesleukin is safe and well-tolerated and demonstrates consistent pharmacokinetics in participants receiving subcutaneous doses of 10 to 12μg/kg or 24μg/kg once every 2 weeks for 12 weeks, meeting the primary and secondary objectives of each study
- AD patients receiving high dose rezpegaldesleukin demonstrate an 83% improvement in Eczema Area and Severity Index (EASI) score after 12 weeks of treatment EASI improvement of ≥ 75% (EASI-75) and vIGA-AD responses are maintained for 36 weeks after treatment discontinuation in 71% and 80% of week 12 responders, respectively
- The clinical improvements are accompanied by sustained increases in CD25bright Tregs
- Serum proteomic biomarkers demonstrated rezpegaldesleukin’s ability to engage multiple immunoregulatory mechanisms to facilitate immune homeostasis, which may indicate a potential mechanism of attenuating Th1, Th2, and Th17 responses by restoring the balance of Tregs.
- Results validate the role of IL-2-induced Treg proliferation and activation in the AD treatment paradigm, and support the advancement of rezpegaldesleukin in the Phase 2b study in AD.
- The delayed-type hypersensitivity (DTH) mouse model and the profound reduction in serum IL-15 levels in atopic dermatitis patients treated with rezpegaldesleukin provides mechanistic insight for the durable efficacy that persists for months following treatment.
“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” adds Jonathan Zalevsky, PhD., Chief Research & Development Officer at Nektar. “These findings further validate our therapeutic approach of using a Treg stimulator to dampen inflammatory responses and simultaneously restore immune balance in patients with chronic inflammatory skin diseases. We look forward to reporting topline data next year from our two Phase 2b rezpegaldesleukin studies in atopic dermatitis and alopecia areata.”
