Karos Advancing Its Small Molecule Drug Candidate to Treat PAH, KAR5585, in Clinical Testing

Karos Pharmaceuticals announced that is advancing its small molecule drug candidate, KAR5585, in clinical testing as a treatment for pulmonary arterial hypertension (PAH) and other rare diseases characterized by fibrosis.

A number of agents have recently been introduced as therapeutic drugs for PAH. Among them, KAR5585 is a first-in-class, selective inhibitor of an enzyme called tryptophan hydroxylase 1 (TPH1) involved in the production of the neurotransmitter serotonin (5-HT). It works by reducing the levels of peripheral 5-HT and 5-HT-associated vascular remodeling and fibrosis that are involved in the development of PAH.

“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 the 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,” said Lewis J. Rubin, MD, emeritus director of Pulmonary and Critical Care and Professor of Medicine, University of California, San Diego, School of Medicine, in a press release.

A Phase 1 study of single and multiple ascending doses, which incorporates biomarkers aimed to clarify KAR558’s mechanism of action, is ongoing in an estimated 120 healthy volunteers. Results are expected to be reported in mid-2016, and Karos is planning to then initiate a double-blind and randomized Phase 2 study of KAR5585 as a once-a-day treatment in PAH patients.

“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, MD, Karos’ chief medical officer.

In PAH patients, blood flow from the heart to the lungs is constricted due to the narrowed and congested pulmonary arteries. This results in an increase of blood pressure in the lungs, necessitating extra efforts by the heart to pump blood through the arteries, and can gradually lead to exhaustion and heart failure.