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Abstract Number: 2738

Shk-186, a Kv1.3 channel inhibitor That Targets Effector Memory T Cells: Safety and Tolerability in Humans and Its Evaluation in a Model of Rapidly Progressive Glomerulonephritis

Ernesto J. Muñoz-Elías1, Kayla Norton1, John B. Grigg1, Liz Bromley1, David W. Peckham1, Eric J. Tarcha1, Jared Odegard2, James Qin2, Megan Yuasa3, Anne Stevens4, Wayel H. Abdulahad5, Galina Schmunk6, K. George Chandy6 and Shawn P. Iadonato1, 1Kineta Inc., Seattle, WA, 2Benaroya Research Institute at Virginia Mason, Seattle, WA, 3Seattle Children's Res Institute, Seattle Children's Research Institute, Seattle, WA, 4Seattle Children's Res Inst, Seattle Children's Hospital, Seattle, WA, 5Rheumatology and Clinical Immunology, University Medical Center Groningen, Groningen, Netherlands, 6Department of Physiology, Biophysics, and Surgery, UC Irvine, Irvine, CA

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: Lupus nephritis, safety and vasculitis, T cells

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Session Information

Session Title: T cell Biology in Lupus, Vasculitis, Myositis and Other Autoimmunity

Session Type: Abstract Submissions (ACR)

Background/Purpose:

The voltage-gated potassium channel Kv1.3 is a novel target for the treatment of autoimmune disorders including psoriatic and rheumatic diseases. ShK-186 is an exquisitely specific, highly potent peptide inhibitor of Kv1.3 on activated effector memory T cells that has just entered clinical development.  Here, we report on ShK-186’s safety and tolerability in phase I trials and on the evaluation of its therapeutic potential in an autoimmune kidney disease model.

Methods:

To evaluate the safety, tolerability and pharmacokinetics (PK) of ShK-186, we conducted single ascending dose and multiple ascending dose doubled-blind, placebo-controlled phase I trials in healthy volunteers. In the single ascending dose trial, individuals were given increasing doses of ShK-186 subcutaneously and characterized after a single dose of drug; in the multiple ascending dose trial, individuals were given 9 doses of drug twice weekly over 4 weeks and characterized throughout. To investigate ShK-186’s potential therapeutic application in autoimmune kidney disease, we evaluated the drug in a glomerular basement membrane animal model of autoimmune glomerulonephritis. Moreover, we have begun evaluating peripheral blood and urine samples from patients with autoimmune kidney disease for expression of Kv1.3 and production of cytokines in the presence and absence of ShK-186.

Results:

ShK-186 was well tolerated with no serious adverse events reported.  PK analysis revealed that the doses and dose regimens evaluated provided drug exposure in plasma surpassing the predicated therapeutic range based on therapeutic drug exposures in preclinical models of disease.  Supporting the therapeutic potential of ShK-186 to treat chronic autoimmune kidney diseases, we showed that ShK-186 could lower kidney disease parameters such as urine protein and creatinine in a model of autoimmune glomerulonephritis, as well as significantly reduced histopathological changes associated with disease such as crescent formation and inflammatory cellular infiltrate. Ex vivoimmunophenotyping and functional studies of blood and urine from autoimmune kidney disease patients showed that Kv1.3 is present in effector memory T cells.

Conclusion:

This first-in-human clinical trial suggests that ShK-186 is a well-tolerated drug when given at doses expected to provide a therapeutic benefit. In addition to previously described indications where Kv1.3 has been implicated including multiple sclerosis and rheumatoid arthritis, we provide evidence to support extending its therapeutic scope to the treatment of chronic kidney autoimmune diseases.


Disclosure:

E. J. Muñoz-Elías,

Kineta Inc,

3;

K. Norton,

Kineta Inc,

3;

J. B. Grigg,

Kineta Inc,

3;

L. Bromley,

Kineta Inc,

3;

D. W. Peckham,

Kineta Inc.,

3;

E. J. Tarcha,

Kineta Inc,

3;

J. Odegard,
None;

J. Qin,
None;

M. Yuasa,
None;

A. Stevens,
None;

W. H. Abdulahad,
None;

G. Schmunk,
None;

K. G. Chandy,

Kineta Inc.,

1;

S. P. Iadonato,

Kineta Inc,

3.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/shk-186-a-kv1-3-channel-inhibitor-that-targets-effector-memory-t-cells-safety-and-tolerability-in-humans-and-its-evaluation-in-a-model-of-rapidly-progressive-glomerulonephritis/

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