DEVELOPMENT OF KV1.3 CHANNEL BLOCKER SHK-186 AS A THERAPY FOR MULTIPLE SCLEROSIS - Multiple sclerosis (MS) affects approximately 400,000 Americans and constitutes a progressive, disabling
disease for which current therapies are inadequate. This application describes the nonclinical development of
ShK-186, a novel Kv1.3 potassium channel inhibitor that targets the effector memory T cell (TEM) population in
MS. TEM cells play a prominent role in the tissue damage associated with autoimmune disease, and
autoreactive Kv1.3-dependent TEM cells have been identified in the CNS, synovial fluid, and peripheral blood of
MS, rheumatoid arthritis, and type 1 diabetes mellitus patients. ShK-186 was discovered by Dr. George
Chandy (co-PI) and his group at the University of California at Irvine. The drug is being developed
commercially by KINETA Inc. of Seattle, WA. ShK-186 inhibits Kv1.3 potassium channel function with
picomolar potency and reduces mitogen-stimulated cytokine production, [3H]-thymidine incorporation, cell
motility, and antigen-presenting cell interaction by TEM cells. In addition, ShK-186 and its closely-related
analog, ShK-170 have been shown to prevent and treat disease in a number of autoimmune animal models
including adoptive-transfer experimental autoimmune encephalitis (EAE), immunization-mediated, chronic
relapsing EAE (CR-EAE), and pristane-induced arthritis. ShK-186 has demonstrated excellent tolerability and
safety in preclinical animal models including in a 28-day, repeat dose toxicity study in rat. The drug
demonstrates excellent specificity for Kv1.3 in receptor profiling studies, and there is no evidence for cardiac
toxicity including in ECG telemetry studies of conscious rats. The present application will undertake: (1) further
preclinical studies in the CR-EAE model to better define the relationship between dose, dose frequency, and
treatment period on drug efficacy, (2) GLP tolerability and toxicology studies in rat to support an Investigational
New Drug application for ShK-186 to the Food and Drug Administration, and (3) preparation of the pre-IND and
IND submission documents. The major milestone of this two-year program is the submission to FDA of an IND
application intended to support first-in-human clinical trials of ShK-186.
