Karos advances development of KAR5585 into clinic to treat pulmonary arterial hypertension

KAR5585 is being developed for the treatment of pulmonary arterial hypertension (PAH) and other rare diseases marked by extensive fibrosis.

KAR5585 is a first-in-class, selective inhibitor of tryptophan hydroxylase 1 (TPH1) designed to reduce peripheral serotonin (5-HT) and 5-HT-associated vascular remodeling and fibrosis that are the hallmarks of PAH. Karos has completed the single ascending dose portion of its 120-patient Phase 1 clinical trial in healthy volunteers and is now conducting the multiple ascending dose portion of the study, with the goal of reporting results from the Phase 1 program in the middle of this year.

Biomarkers incorporated into the multiple-dose portion of the study are expected to provide insight into the mechanism of action of the drug and the dose-range needed for reduction of peripheral 5-HT. Based on this progress, the Company anticipates commencing a Phase 2 study of KAR5585 as a once-a-day treatment in patients with PAH.

Lewis J. Rubin, MD, Emeritus Director of Pulmonary and Critical Care and Professor of Medicine, University of California, San Diego School of Medicine, stated, "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."

Peter U. Feig, MD, Karos’ Chief Medical Officer, commented, "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."

About KAR5585

KAR5585 is designed to selectively modulate peripheral serotonin biosynthesis, reducing disease-related vascular remodeling, vasoconstriction, and inflammation. Discovered at Karos, KAR5585 has been shown in preclinical studies to reduce vascular remodeling and vascular occlusions in a dose-dependent manner when used for treatment or prevention of the disease pathophysiology in in vivo models of PAH.

KAR5585 delivered orally either in a preventive or in a therapeutic modality, reduced pulmonary arterial hypertension in the preclinical models. KAR5585 also has been studied in preclinical models in combination with agents currently used as standard-of-care (SOC) therapies for PAH, demonstrating substantial lowering of pulmonary arterial hypertension and improvement of pulmonary arterial remodeling both as compared to SOC treatments and in conjunction with those treatments,

The ongoing first-in-human Phase 1 clinical program for KAR5585, expected to enroll a total of 120 healthy volunteers, is designed to evaluate safety and tolerability as primary endpoints and measure biomarkers as proof of mechanism.

Following completion of both single and multiple dose ascending portions of the Phase 1 study, Karos expects to initiate a double-blind, randomized Phase 2 trial. In October 2015 Karos received U.S. FDA Orphan Disease Designation for KAR5585 in PAH.