-- Durable, dose-dependent and selective expansion of CD25bright Tregs, reaching a 117-fold increase over baseline at the highest dose --
-- Single dose of XmAb564 well-tolerated with no reported serious adverse events --
-- First patient dosed in Phase 1b, multiple-ascending dose study in patients with atopic dermatitis or psoriasis --
-- Phase 1a results to be presented in a webcast today at 4:30 p.m. ET --
MONROVIA, Calif.--(BUSINESS WIRE)-- Xencor, Inc. (NASDAQ:XNCR), a clinical-stage biopharmaceutical company developing engineered antibodies and cytokines for the treatment of cancer and autoimmune diseases, today announced topline clinical data from its Phase 1a single-dose, healthy volunteer study of XmAb®564, in development for patients with autoimmune diseases. XmAb564 is a wholly owned, monovalent interleukin-2 Fc fusion protein (IL-2-Fc), engineered with dramatically lowered potency and heightened binding affinity for the IL-2 alpha receptor (CD25), resulting in selective activation of regulatory T cells (Tregs). Tregs combat autoimmunity by suppressing other immune cells from attacking normal tissue; however, in many autoimmune diseases, Tregs become dysregulated.
“The goal of an IL-2 therapy for autoimmune disease is to provide sustained low-intensity activation of Tregs while avoiding the pro-inflammatory systemic activation of effector T cells,” said John Desjarlais, Ph.D., senior vice president and chief scientific officer at Xencor. “We engineered XmAb564 with heightened affinity for IL-2’s alpha receptor (CD25) over its beta receptor to selectively target Tregs and with 400- to 1000-fold reduced potency to improve the half-life of XmAb564 and reduce its toxicity compared to wildtype IL-2. Fusion to our modular XmAb heterodimeric Fc domain with Xtend™ technology provides a stable protein scaffold and further enhances half-life. XmAb564’s design gave dramatic Treg increases and unprecedented durability for a single dose, with high levels of Treg populations sustained for at least 3 weeks.”
“We have rapidly advanced XmAb564 through a first-in-human study and have now dosed the first patient in a newly initiated Phase 1b, multiple-ascending dose study in patients with atopic dermatitis and psoriasis,” said Allen Yang, M.D., Ph.D., senior vice president and chief medical officer at Xencor. “XmAb564 is the second potency-tuned XmAb cytokine program showing marked target cell expansion and good tolerability in human studies, following XmAb306, our potency-reduced IL-15 in oncology. In addition, XmAb306 showed accumulation of target immune cells upon repeat dosing, which allows study of further extended dosing intervals and helps inform our development of XmAb564.”
The Phase 1 single ascending-dose study of XmAb564 was designed to characterize its safety, tolerability and pharmacokinetics in healthy volunteers, and the study included an analysis of key immunomodulatory biomarkers. The study enrolled 48 subjects, with six dose-level cohorts each randomizing six subjects to XmAb564 and two subjects to placebo. Single doses ranged from 0.003 mg/kg to 0.065 mg/kg.
XmAb564 was well-tolerated across all dose levels. Adverse events (AE) were Grade 1 or Grade 2 and resolved without intervention, and no serious AEs were observed. The most common AE was injection site reaction. Laboratory tests indicated some subjects had transient increases in eosinophils, though no eosinophil-related AEs were observed. This laboratory increase may be related to the mechanism of action of CD25-targeting IL-2 drug candidates.
Dose-dependent and selective expansion of CD25bright and total Tregs was observed throughout the study. The expansion of CD25bright Tregs with at least 10-fold increases over baseline began at the third dose level and reached a 117-fold increase over baseline at the highest dose. Total Tregs increased 8-fold over baseline at the highest dose. An important metric for selectivity, the ratio of Tregs to conventional T cells (which include effector T cells) increased consistently in a dose-dependent manner, with a ratio of 0.14 at the highest dose compared to