Nektar Therapeutics (NASDAQ: NKTR) today announced updated results from the first-in-human Phase 1a study of NKTR-358, a novel T regulatory (Treg) cell stimulator in development for the treatment of autoimmune and other chronic inflammatory conditions.
The data, which were presented at the 2019 Annual Meeting of the American College of Rheumatology in Atlanta, show that treatment with NKTR-358 led to a marked and selective dose-dependent expansion in the numbers and proliferative capacity of FoxP3+CD25bright Treg cells, and a measurable activation of Treg cells. These data are a continuation of initial results reported at 2019 Annual European Congress of Rheumatology (EULAR) in June 2019.
NKTR-358 is designed to treat autoimmune and inflammatory conditions by correcting the immune system imbalance that results from reduced numbers and impaired function of immune-regulating Treg cells. NKTR-358 works by targeting the interleukin-2 receptor complex to stimulate the proliferation and activation of Treg cells. NKTR-358 was discovered by Nektar and is being co-developed and commercialized in partnership with Eli Lilly and Company.
"We're pleased to report that final results from our first-in-human Phase 1a study continue to support the positive safety and tolerability profile of NKTR-358, while reinforcing its selective and measurable impact on the numbers, expansion and activation of regulatory T cells or Tregs," said Brian Kotzin, M.D., Senior Vice President, Clinical Development and NKTR-358 Program Lead at Nektar Therapeutics. "Autoimmune and inflammatory diseases are marked by an imbalance in the body's self-tolerance and self-regulatory immune pathways, and the ability of NKTR-358 to expand functional Tregs could help restore normal balance. The results support further studies into the potential of NKTR-358 as a treatment for several types of immune-mediated disorders."
The data were presented today in a poster titled "Selective induction of functional regulatory T-cells in healthy volunteers by NKTR-358, a novel IL-2 conjugate Treg stimulator, in development for the treatment of autoimmune diseases", by Dr. Christie Fanton of Nektar Therapeutics during the T Cell Biology & Targets in Autoimmune & Inflammatory Disease poster session being held from 9:00 a.m. to 11:00 a.m. Eastern Standard Time.
The double-blind, single-ascending dose Phase 1a study evaluated 100 healthy volunteers who received subcutaneous doses of NKTR-358 ranging from 0.3 to 28.0 µg/kg and were followed for 50 days after dosing.
Key highlights from today's data presentation include:
NKTR-358 was safe and well tolerated in this first-in-human study consistent with prior reported results.
No anti-drug antibodies were detected.
Final data show dose-proportional pharmacokinetics, with maximal concentrations reached in 5-7 days and prolonged exposure with an estimated half-life of 8-11 days.
New data confirm that single-ascending doses of NKTR-358 led to marked dose-dependent and sustained increases in the absolute numbers, percentages and proliferation of circulating FoxP3+CD25bright Treg cells. In addition,
At the highest dose tested of NKTR-358, 28.0 µg/kg, the mean percentage of Ki67+ CD25bright Tregs was 6-fold above baseline.
NKTR-358 increased the expression of Treg activation markers.
Epigenetic analysis of immune cells demonstrated a significant increase in demethylated FOXP3 gene following NKTR-358 treatment at 28.0 µg/kg, further reinforcing that NKTR-358 is expanding true Tregs.
NKTR-358 induced dose-dependent changes in other genes associated with Treg regulation.
NKTR-358 was not associated with any measurable changes in numbers and percentages of conventional CD4+ and CD8+ T cells (Tcons) at all doses and low-level increases of natural killer (NK) cell numbers was observed at highest doses tested.