The FDA has lifted all the clinical holds it placed on seladelpar from Cymabay Therapeutics Inc. for INDs in nonalcoholic steatohepatitis (NASH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis, giving the company new hope.
Meanwhile, after several weeks of reviewing data, Genfit SA decided to discontinue its phase III NASH and fibrosis study of lead candidate elafibranor, which failed to meet its predefined primary surrogate efficacy endpoint. The company said it is focusing on launching a phase II trial of elafibranor for treating PBC by year-end.
Cymabay’s brush with near failure was shocking and became a personal struggle for CEO Sujal Shah, who found the company on life support while data were sifted through and the FDA pondered.
“When it’s seemingly taken away from you in what feels like the blink of an eye, you struggle to find your daily purpose,” Shah told BioWorld. “It’s become our life’s work in the last few years. Then you wake up one day and completely out of the blue you can’t do that anymore.”
Cymabay stopped all studies of seladelpar, a PPAR-delta agonist, in November when atypical histologic findings created doubts about the phase II NASH study. The FDA then placed all the seladelpar INDs on hold.
“Sometimes we come across science we can’t fully grasp or understand,” Shah said. “You pick yourself back up and get back to work.”
Shah said the highest probability outcome from an independent panel reviewing the data was that results would remain in a gray zone and that “we might not ever understand the biology.”
The panel identified a subset of patients in the study with an “unexpected pattern of histological findings overlaid on NASH pathology,” Shah told investors on a conference call mid-evening May 11. The findings were predominantly characterized as an interface hepatitis with or without bile duct injury or cholangitis, presence of plasma cells and eosinophils, and, in some cases, vascular lesions, Shah said.
The FDA lifted the restrictions after reviewing the findings that showed no clinical, biochemical or histological evidence of seladelpar-related liver injury in the study.
H.C. Wainwright & Co. analyst Ed Arce wrote Thursday that this “is the result we had hoped for and expected, though this decision comes much quicker than we had anticipated, especially given the current restrictive pandemic environment.”
Shah also was surprised by the FDA’s speed. Cymabay “heard back from the agency more quickly than the average of 30 days.”
The next step, Shah said, will be to re-initiate seladelpar’s clinical development by focusing on the phase III PBC study.
SVB Leerink analyst Thomas Smith wrote Thursday that PBC is “where we believe seladelpar has a competitive profile on both efficacy and safety/tolerability in the second-line setting relative to the currently approved second-line option, Intercept's (ICPT, MP) Ocaliva (obeticholic acid).”
The FDA update, Smith added, should alleviate investor concerns. That was indeed the case as lifting the clinical holds lifted Newark, Calif.-based Cymabay’s shares (NASDAQ:CBAY) on Thursday. They rose 25% and closed at $4.39.
Genfit moving ahead in PBC
Now that it has set NASH aside, Genfit will concentrate on developing elafibranor for treating PBC and on the commercial growth of NIS4, a blood-based diagnostic technology designed to identify patients with NASH and significant fibrosis. Elafibranor’s phase II study of PBC brought in favorable results and the company said it is focused on initiating a phase III trial.
Wainwright’s Arce wrote Thursday that he anticipates Lille, France-based Genfit to initiate the phase III pivotal trial of elafibranor for PBC by year-end, as elafibranor’s phase II met the primary endpoint of serum alkaline phosphatase change compared to placebo at week 12 from baseline.
PBC is a chronic autoimmune disease that destroys the liver’s bile ducts. The FDA granted elafibranor breakthrough therapy designation in the indication.
Genfit stock (NASDAQ:GNFT) closed flat on Thursday, with shares selling for $5.49.