Fresh off presenting positive new mechanistic data on its lead candidate, seladelpar, at the 2018 International Liver Congress in Paris, Cymabay Therapeutics Inc. said patient screening for a phase IIb proof-of-concept study of the drug in nonalcoholic steatohepatitis (NASH) is now underway. Enrollment is estimated to take about 12 months, with a top-line readout expected in the second half of 2019, Cymabay's CEO and president, Sujal Shah, told BioWorld.

News of the trial's start arrived just ahead the company's first-quarter earnings report on Tuesday, and in the midst of ongoing progress toward a phase III test of seladelpar in primary biliary cholangitis (PBC) in the second half of this year. PBC remains the major focus both internally at the company and externally among investors. But there have been plenty of signs pointing to potential benefits to be investigated in NASH, Shah said, including both earlier data from a mixed dyslipidemia study and preclinical data in a mouse model of NASH published last year demonstrating reductions in liver fat content, inflammation and fibrogenesis.

The Newark, Calif.-based company, formerly known as Metabolex Inc., has undergone "quite a transformation" in recent years, Shah said, noting the completion of its second financing in February, an offering that raised about $135.5 in net proceeds.

Research and development expenses at the company have, of course, grown. They were $9.5 million in the first quarter vs. $4 million in the same period of 2017, primarily due to higher PBC and NASH clinical trial expenses and seladelpar drug manufacturing expenses. But so too has the company's financial strength increased. Cymabay raised $96.85 million in July 2017 and now has about $229.5 million in cash and equivalents, enough to fund its current operating plan into 2021, it reported Tuesday — a significantly more solid foundation than the $13.7 million it had at the end of the first quarter of 2017.

Other major changes have included Shah's ascent to CEO from chief financial officer in the wake of former chief Hal Van Wart's retirement about a year ago and the licensing of the company's former lead candidate, arhalofenate, to Kowa Pharmaceuticals America Inc., which is continuing to develop it for the potential treatment of gout. (See BioWorld Today, Dec. 3, 2013, and July 18, 2017.)

By broadening its focus to NASH, the progressive form of nonalcoholic fatty liver disease, it has taken on a growing global health issue that, without an approved therapy, has drawn considerable efforts from a host of drug developers such as NGM Biopharmaceuticals Inc., Madrigal Pharmaceuticals Inc. and Intercept Pharmaceuticals Inc.

Seladelpar, a peroxisome proliferator-activated receptor (PPAR) delta agonist formerly known as MBX-8025, is licensed to Cymabay from Johnson and Johnson's Janssen Pharmaceutical NV.

"What we're really excited about with seladelpar is that it has impacts on both the metabolic elements of the disease as well as inflammation and fibrosis," Shah said. With the randomized, placebo-controlled phase IIb study, to be run in close consultation with Pinnacle Clinical Research, his team will look to prove that out in a fairly broad patient population, including those with minimal liver scarring (F1) to severe fibrosis (F3).

About 175 patients with biopsy-proven NASH are expected to enroll, many with co-morbidities, such as diabetes. They'll be randomized to seladelpar at doses of 10 mg/day, 20 mg/day and 50 mg/day or placebo in a 2-to-2-to-2-to-to-1 fashion. The primary efficacy outcome will be the change from baseline in liver fat content at 12 weeks as measured by magnetic resonance imaging using the proton density fat fraction method (MRI-PDFF).

Among the secondary measures of efficacy, most notable is the evaluation of histological improvement in NASH and fibrosis as assessed by comparing liver biopsy samples taken at baseline and 52 weeks. Additional planned assessments include MRI-PDFF measurements at 26 and 52 weeks of treatment, as well as the use of the latest available additional technologies for biochemical markers and non-invasive imaging which reflect inflammation, fibrosis and liver health.

In January, the company enrolled the first patients in a long-term open-label phase II/III extension study, designed to generate long-term safety and efficacy data to support approval. The study continues to provide access to long-term seladelpar treatment for patients enrolled in a previous, ongoing or future study evaluating seladelpar for the treatment of PBC.

Shares of Cymabay (NASDAQ:CBAY) closed 13 cents lower on Tuesday, at $12.30.

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