Introduction

Coeliac disease (CeD) is a chronic inflammatory disorder triggered and maintained by ingestion of gluten and which has no approved therapeutic treatment. KAN-101 is an investigational therapy composed of a liver-targeting glycosylation signature conjugated to a gliadin-derived peptide designed to induce tolerance as a therapeutic approach to the treatment of CeD. Previously KAN-101 was shown to be safe and tolerated and demonstrated induction of functional tolerance of gliadin-specific T cells in CeD patients in the Ph1 clinical trial (Murray et al, Lancet Gastro Hep in press).

Aims & Methods

The Assessment of KAN-101 in CeD (ACeD) study evaluated PK and immune biomarker responses following a GC to assess induction of immune tolerance in CeD patients who received multiple doses of KAN-101 or placebo (NCT04248855). DQ2.5+ CeD patients on a gluten free diet were randomized 3:1 to receive three intravenous (IV) infusions of KAN-101 at 0.15, 0.3, or 0.6 mg/kg or placebo on days 1, 4 and 7, followed by a 3-day oral GC (9 grams/day) starting on day 15. Samples were collected on day 1 and 7 for pharmacokinetic analysis of KAN-101. Samples collected pre-dose, day 15 pre-GC and day 21 were analyzed by flow cytometry for HLA-DQ2.5 α-I and α-II gliadin-tetramer positive T cells and surface phenotype markers. Plasma samples collected pre- and post-GC were analyzed for cytokines using multiplex immunoassays.

Results

Following IV infusion, KAN-101 was cleared rapidly from systemic circulation within approximately 6 hours across all dose levels. KAN‑101 exhibited non-linear PK behavior with increasing dose, consistent with target-mediated drug disposition. Following KAN-101 administration, an increase in tetramer positive (Tet+) CD4+ T cell populations was observed on day 15 prior to GC in KAN-101-treated patients, however, the Tet+ T cells exhibited a surface phenotype consistent with T cell anergy, including programmed cell-death 1 (PD-1, or CD279) and lymphocyte activation gene 3 (LAG-3, or CD223) and restimulation of samples did not result in activation. Placebo patients experienced an increase in Tet+ cells following GC (day 21) while most KAN-101-treated patients showed no increase. Profiling of plasma samples taken within 6 hours of the GC demonstrates a dose-dependent modulation of cytokines, including IL-2, by KAN-101 but not placebo.

Conclusion

KAN-101 was found to be safe and tolerated in CeD patients and reduced gliadin-specific T cell responses after GC in a Ph1 study. While the clearance of KAN-101 after administration occurs within hours, the pharmacodynamic effects can be observed for at least 3 weeks after the start of treatment. Gliadin-specific T cells are increased following KAN-101 treatment but display an exhausted phenotype, are functionally anergic and do not expand further after GC. In patients receiving placebo, Tet+ CD4+ cells are only observed following GC and respond upon antigen re-stimulation. Furthermore, KAN-101 modulated the plasma cytokine response to GC.

References

Murray JA, Wassaf D, Dunn K, et al. Safety and tolerability of KAN-101, a liver-targeted immune tolerance therapy, in patients with coeliac disease: a first-in-human, open-label single dose escalation and randomised, placebo-controlled repeat dose study. Lancet Gastroenterol Hepatol 2023 (in press)

Disclosure

JM reports grants (to institution) from Nexpep/ImmusanT, National Institutes of Health, Immunogenix, Takeda Pharmaceutical, Allakos, ProventionBio, Oberkotter Foundation, and 9Meters, Inc.; contract (to institution) from Kanyos Bio (a wholly owned subsidiary of Anokion); and consultancy fees from Johnson and Johnson, Bristol Myers Squibb, Intrexon Corporation, Dren Bio, Neoleukin, Reistone pharma, Immunic Therapeutics, Senda Biosciences, Brightseed Bio, Chugai Pharma, Alimentiv, Equillium, Ukko, Medibeacon, Precigen, and has received royalties from Torax Medical and Evelo. DW, SM, TT and KMG are employees and have stock options in Anokion. At the time of the study SK and KEG were employees of Anokion and have stock options.