Patients living with primary biliary cholangitis (PBC), a rare chronic and gradually progressive liver disease, have gained a new second-line therapy with FDA approval for Intercept Pharmaceuticals Inc.'s Ocaliva (obeticholic acid). The accelerated approval covers the treatment of PBC in adults with an inadequate response to ursodeoxycholic acid (UDCA) and as a monotherapy in those unable to tolerate that common therapy.

Although UDCA treatment can yield significant clinical improvements for many patients, those who don't fully respond or are intolerant have a significantly increased risk of needing a liver transplant.

Ocaliva, Intercept's first approved medicine, will have an annual list price of $69,350, independent of the dosage selected by physicians. Intercept said the drug would be available through its specialty pharmacy network within seven to 10 days, but that it could take several months to gain broad formulary coverage.

Lisa Bright, Intercept's chief commercial and corporate affairs officer, said Tuesday that the company considered several important factors in pricing the therapy, including "the consequences of an inadequate treatment in this progressive liver disease, including compensated and decompensated cirrhosis, hepatocellular carcinoma, liver transplant and death, and the savings associated with slowing disease progression."

There are three warnings and precautions noted in the drug's label. One notes the risk of liver-related adverse events that have been observed in a dose-dependent fashion. Further cautions note a heightened risk of intense or widespread itching at certain doses, as well as a dose-dependent reduction from baseline in mean high-density lipoprotein-cholesterol levels seen in patients during the phase III Poise trial.

Per the accelerated approval, Intercept will also need to provide further data to establish claims of improved survival or disease-related symptoms. To fulfill that obligation in service of achieving a full approval, it's conducting the phase IV Cobalt trial. The company is discussing modifying the Cobalt trial to potentially include a broader cross-section of PBC patients with early, moderately advanced and advanced disease. It is also considering evaluating the safety and efficacy in patients with more advanced Child-Pugh B and C hepatic impairment and as a monotherapy for patients with PBC.

PBC, which has until recently been referred to as primary biliary cirrhosis, mainly affects middle-aged women. There are an estimated 130,000 patients in the U.S. Incidence of the disease varies widely across European countries, but there has been some suggestion that the prevalence of PBC is increasing over time.

The U.S. approval is a triumph for Intercept, which had faced questions from both FDA reviewers and gastrointestinal experts who grappled with the adequacy of reduction in alkaline phosphatase (ALP) as a surrogate endpoint in the company's pivotal trial.

It also opens the door to a potential later approval for the treatment of nonalcoholic steatohepatitis (NASH), a liver condition that can lead to liver failure and affects as many as 3 percent to 4 percent of all Americans.

The drug could generate revenue of nearly $109 million next year, according to a consensus forecast compiled by Thomson Reuters Cortellis. Furthermore, it triggers a milestone payment of up to $5 million from Intercept's Asian licensee, Sumitomo Dainippon Pharma Co. Ltd.

Shares of Intercept (NASDAQ:ICPT) gained $6.59, or 4.7 percent, to close at $148.36 on Tuesday.

Obeticholic acid, or OCA, is a bile acid analogue, a chemical substance that has a structure based on a naturally occurring human bile acid. It selectively binds to and activates the farnesoid X receptor, or FXR, a nuclear receptor expressed in the liver and intestine and a key regulator of bile acid, inflammatory, fibrotic and metabolic pathways. It has been tested in five placebo-controlled clinical trials, including the phase III trial in patients with PBC, called Poise, and two phase II trials in patients with nonalcoholic fatty liver disease, or NAFLD, and NASH. It met the primary efficacy endpoints in each trial with statistical significance.

In addition, in October 2015, Intercept released results from a phase II dose-ranging trial of OCA in 200 patients with NASH in Japan, conducted with Sumitomo. The trial did not meet its primary endpoint of histological improvement with statistical significance, an outcome that Intercept chalked up to differences in the baseline characteristics between Japanese and Western patients.

Ocaliva was granted orphan drug designation in both the EU and U.S. and gained the support of the FDA's Gastrointestinal Drugs Advisory Committee on April 7. Despite the ALP controversy, that meeting led to a unanimous vote in favor of recommending accelerated approval for Ocaliva. (See BioWorld Today, April 6, 2016, and April 8, 2016.)

Although Ocaliva is first to the finish line at the FDA, several other candidates are also in the running as potential second-line treatments for OCA. The corticosteroid budesonide and the fibrate drug bezafibrate have both been explored in phase III trials in Europe. Lille, France-based Genfit SA has also been active, saying in March it would begin a phase II study testing elafibranor for the treatment of PBC before the end of 2016.

In the shadow of the Ocaliva approval, Intercept also hit another milestone on Friday, putting to rest securities class action litigation with a $55 million settlement. The case, a consolidation of two shareholder suits in which investors claimed that the company had misrepresented and/or omitted material facts regarding certain lipid abnormalities seen in the Flint trial, was settled with an order preliminarily approving the agreement issued on May 23.

ZINBRYTA APPROVED

The FDA also approved Zinbryta (daclizumab) on Friday, a once-monthly, self-administered, subcutaneous treatment for relapsing forms of multiple sclerosis (MS) co-developed by Biogen Inc. and Abbvie Inc.

The therapy was approved primarily on the basis of two trials. One trial compared Zinbryta and Avonex (interferon beta-1a) in 1,841 participants who were studied for 144 weeks. Patients on Zinbryta had fewer clinical relapses than patients taking Avonex. The second trial compared Zinbryta with placebo and included 412 participants who were treated for 52 weeks. In that study, those receiving Zinbryta had fewer relapses compared to those receiving placebo.

The approved label contains a black-box warning highlighting the increased risk of hepatic injury, including autoimmune hepatitis and other immune-mediated disorders. Because of those risks, access to the therapy in the U.S. will be restricted to prescribers, pharmacies and patients enrolled in the Zinbryta Risk Evaluation and Mitigation Strategy Program, which includes required monthly liver function tests.

While the precise mechanism of action of Zinbryta is unknown, the companies said, it is thought to work differently from other disease-modifying therapies by binding to CD25, a subunit of the interleukin-2 receptor found on activated lymphocytes, cells believed to underlie the biology of MS.