Cymabay Therapeutics Inc. said positive interim phase II results for its primary biliary cholangitis (PBC) treatment, seladelpar, won FDA support for extended dosing of the drug, a key go-ahead enabling the company to plan its phase III program. Data on two low doses of the drug suggest it can drive down serum levels of alkaline phosphatase (ALP), a biomarker correlated with reduced need for liver transplant and risk of death, while avoiding elevation of another biomarker, transaminase, that is tied to severe liver damage and was raised in a few cases during tests of higher doses.

H.C. Wainwright & Co. analyst Ed Arce said the results "provide the answer to two key questions that we (and the Street) have been waiting for, with a resounding affirmative: 1) do much lower doses still deliver meaningful efficacy, while 2) avoiding transaminase elevations?" Positive answers to both questions seemed to satisfy Cymabay backers, who drove company shares (NASDAQ:CBAY) to a 52-week high of $7.77 Monday, before ending the day at $5.98, for a gain of 33 cents.

PBC is a rare disease usually treated first with the generic drug ursodeoxycholic acid (UDCA). Sujal Shah, Cymabay's interim president and CEO, said the phase II results detailed Monday put seladelpar "on a trajectory to potentially have superior efficacy and better tolerability than existing second-line treatments."

Firmly in the crosshairs, no doubt, is Intercept Pharmaceuticals Inc.'s Ocaliva (obeticholic acid), which won accelerated approval as a second-line therapy for PBC last year, making it the first new treatment for PBC in two decades. Analyst forecasts for Ocaliva sales compiled by Cortellis project 2017 revenue of $123 million, and the potential for it to broach the $1 billion mark by 2021, presumably incumbent on Intercept gaining regulatory approval to market the drug in the much larger nonalcoholic steatohepatitis (NASH) market, a goal for seladelpar as well. (See BioWorld Today, June 1, 2016.)

On Monday, Cymabay said in the first part of the phase II study, patients at high risk of disease progression and with an inadequate response to UDCA received either 5 mg or 10 mg of seladelpar once daily. A planned interim analysis of the first 24 patients enrolled in both dose groups demonstrated, after 12 weeks of treatment, a significant ALP reduction from baseline of 39 percent for the 5-mg group and 45 percent for the 10-mg group. On seladelpar, 45 percent of patients in the 5-mg and 82 percent of patients in the 10-mg dose groups had ALP values less than 1.67 times the upper limit of normal — an important achievement because reaching that mark is a key component in the composite endpoint used for regulatory approval of drugs in the space.

The ALP reductions seen in the study "compared favorably" to the 24 percent decrease in alkaline phosphatase seen at 12 weeks for Ocaliva 10 mg in a phase II study with a similar patient population, Shah said.

A pivotal phase III study leading to Ocaliva's approval had a primary composite endpoint defined as a responder rate comprising the percentage of patients with ALP less than 1.67 times the upper limit of normal with a decrease in ALP of at least 15 percent and total bilirubin less than or equal to upper limit of normal.

Alongside reductions in ALP, patients in both dose groups experienced decreases in gamma glutamyl transferase and total bilirubin – all markers of cholestasis, a condition in which the flow of bile from the liver is slowed or blocked. Seladelpar also improved metabolic and inflammatory markers with patients experiencing decreases in low-density lipoprotein-C and high sensitivity C-reactive protein.

No serious adverse events and/or transaminase signals were observed at either dose. Instead, mean transaminase levels decreased during the 12 weeks of treatment reported so far, further supporting seladelpar's anti-inflammatory activity, the company said. There was no signal for drug-induced pruritus. Based on the interim results, Cymabay won't run an optional 25-mg arm of the phase II study.

Piper Jaffray analyst Edward Tenthoff said the latest PBC results and preclinical data have led to FDA discussions supporting clinical development for seladelpar in NASH, too, for which he anticipates plans this year.

Seladelpar is a peroxisome proliferator-activated receptor (PPAR) delta agonist, formerly known as MBX-8025. It could have applications for the treatment of homozygous familial hypercholesterolemia, severe hypertriglyceridemia and NASH. In PBC, Cymabay has secured both the EMA's Priority Medicines, or PRIME, status for it as well as FDA orphan status. While both designations will help ease its regulatory path, the company will face no shortage of potential competition. Chief among them will likely be Genfit SA, which in May enrolled the first patient in a 12-week phase IIa trial evaluating elafibranor, a PPAR alpha and delta agonist, in PBC. Other entrants in the race include Fast Forward Pharmaceuticals BV's FFP-104, Albireo Ltd.'s A-4250, Glaxosmithkline plc's GSK-2330672, Gilead Sciences Inc.'s GS-9674, and four more phase II programs in various stages of advancement. (See BioWorld Today, March 21, 2016.)

All compounds like seladelpar and elafibranor that work by interacting with the PPAR class of receptors are subject to an FDA partial clinical hold, which limits clinical studies to durations of less than six months until the two-year rodent carcinogenicity studies are completed and evaluated. With the arrival of the interim data, Cymabay now has permission to dose patients for 52 weeks, an important next step in proving the drug can treat the growing number of people diagnosed with PBC early in the chronic disease's course, with treatment continuing for the rest of their lives.