Dalazatide, A First-In-Class Blocker Of The Kv1.3 Potassium Channel On Effector Memory T Cells: Safety, Tolerability And Proof Of Concept Immunomodulation In Patients With Active Plaque Psoriasis

Background: Effector memory T cells of both CD4 and CD8 lineages are key drivers of autoimmunity and are pathogenic in several autoimmune diseases including psoriasis, atopic dermatitis, lupus nephritis, and inflammatory bowel disease. Kv1.3 is a voltage-gated potassium channel required for sustained intracellular calcium influx, proliferation and activation of effector memory T cells. Dalazatide (ShK-186) is a potent, highly specific, first-in-class peptide blocker of Kv1.3 and effector memory T cell activation. Here we report safety, tolerability, pharmacodynamics and immunomodulating proof-of-concept data for dalazatide from a phase 1b clinical trial in patients with active plaque psoriasis. Methods: A double blind, placebo controlled trial was conducted in patients with active mild to moderate plaque psoriasis. Subjects were randomized to receive doses of 30 mcg (n=10) or 60 mcg (n=10) of dalazatide or placebo (n=4) twice weekly by subcutaneous injection for 4 weeks with 4 weeks of follow up. Skin lesion biopsies were collected at baseline and at week 4 for gene expression and immunohistological analyses. Plasma, serum and peripheral blood mononuclear cells were collected at baseline and at several times throughout the study for cytokine and immunophenotyping studies. Target psoriatic plaques were evaluated at baseline, on day 32 following the last dose, and again on day 57 (end-of-study visit). Results: The treatment was well tolerated with all subjects completing the study and reporting only mild adverse events. Target lesion responses were noted in subjects enrolled in both the 30 mcg and 60 mcg groups. 50% of subjects in 60 mcg group achieved a clinical improvement in their target lesion. Improvements were observed as early as day 15 and continued for up to 4 weeks following the last dose. Ongoing improvement continued during the follow-up period in some subjects. 90% of subjects in 60 mcg group had reduction in PASI score. Conclusion: These results demonstrate that twice-weekly subcutaneous injection of Kv1.3 channel blocker dalazatide is well tolerated in psoriasis patients. Improvement in clinical disease endpoints provides proof-of-concept data for the immunomodulating mechanism of action of dalazatide in a prototypical T cell mediated autoimmune disease.