Karos’ Experimental Therapy for PAH and Fibrotic Diseases, KAR5585, Advances in Phase 1 Study


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Karos Pharmaceuticals recently announced that its small molecule drug candidate, KAR5585, has advanced in Phase 1 clinical testing. The drug is being developed for the treatment of pulmonary arterial hypertension (PAH) and other diseases characterized by extensive fibrosis.

KAR5585 received Orphan Drug designation for the treatment of PAH by the U.S. Food and Drug Administration (FDA) in October 2015. It is a first-in-class, selective inhibitor of tryptophan hydroxylase 1 (TPH1), designed to selectively modulate peripheral serotonin (5-HT) biosynthesis, and to reduce disease-related vascular remodeling, vasoconstriction, and inflammation.

The drug’s safety and tolerability is being tested in a Phase 1 clinical trial involving 120 healthy subjects, and the single-ascending dose portion of the study is now complete. A multiple ascending dose test is beginning, and Karos hopes to report results in mid-2016. Biomarkers are being incorporated into the multiple-dose phase to provide insight into KAR5585’s mechanism of action and the dosing range needed to reduce peripheral 5-HT. The company anticipates soon starting a double-blind, randomized Phase 2 trial of the drug as a once daily treatment in PAH patients.

Preclinical studies in in vivo models of PAH have shown that KAR5585 can reduce vascular remodeling and occlusions when administered in a dose-dependent manner. The drug can be delivered orally for preventive or therapeutic action.

“PAH is a uniformly fatal disease if left untreated, and while there are current treatments available, they do not halt or reverse the primary pathophysiology underlying disease progression. Critically important will be to develop new treatments that can alter the course of disease and deliver improvements in patient survival and quality of life. Based on the early evidence to date, I believe that peripheral serotonin modulation holds great potential, and I look forward to the further advancement of Karos’ program,” Dr. Lewis J. Rubin, emeritus director of Pulmonary and Critical Care and a professor of Medicine at the University of California, San Diego, School of Medicine, said in a press release.

“Karos is dedicated to discovering and developing novel therapies that address the role of dysregulated peripheral serotonin seen in diseases associated with tissue fibrosis and inflammation. With PAH as our lead disease target, we are also advancing programs in pulmonary fibrosis unrelated to PAH, other diseases associated with fibrosis, and carcinoid syndrome. Our goal is to have proof-of-concept studies in two or more indications in 2017,” said Peter U. Feig, Karos’ chief medical officer.

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