Ocaliva down but not out: A timeline of FDA troubles for a once-promising PBC contender
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Eight years ago, Ocaliva was a prospective lifesaver for patients with primary biliary cholangitis who failed to adequately respond to first-line ursodeoxycholic acid. However, the once-promising drug now finds itself struggling to deliver.
When obeticholic acid (Ocaliva, Intercept Pharmaceuticals) was granted accelerated approval for PBC in 2016, the first-in-class selective farnesoid X receptor represented the first significant change in the PBC therapy landscape since ursodeoxycholic acid 19 years earlier.
With this groundbreaking approval in hand, manufacturer Intercept Pharmaceuticals planned to leverage Ocaliva’s unique mechanism of action for other rare liver diseases, such as primary sclerosing cholangitis, and possibly make in-roads into the nonalcoholic steatohepatitis (NASH) market.
Unfortunately, the FDA has not agreed with the company’s outlook for Ocaliva.
Reports of serious liver injury among patients receiving the drug began to surface within the first year following Ocaliva’s approval for PBC. Although the FDA moved quickly to add a black box warning to the label in 2018, cautioning against incorrectly dosing higher-risk patients, concerns for risk-benefit would continue to haunt Ocaliva’s prospects.
In 2023, after two failed attempts to put Ocaliva in a lead position as the first FDA-approved treatment for NASH, Intercept was delivered a final setback when an FDA advisory committee voted that the drug’s benefits failed to outweigh its potential risks.
Intercept ultimately shelved its NASH program that year, opting instead to focus on the progress they had made in rare liver diseases, notably, the orphan drug designation for the fixed-dose combination of Ocaliva and bezafibrate for patients with PBC.
This year brought new complications for the wearied drug contender with a series of costly FDA rulings. Just as two new drugs – Iqirvo (elafibranor, Ipsen/Genfit) and Livdelzi (seladelpar, Gilead) – received accelerated approval for PBC, in September, an FDA advisory committee voted against full approval for Ocaliva, citing “concern for real possible harm”. The FDA officially rejected full approval for Ocaliva 1 month later, but the agency would still allow its use for specific patients with PBC under its original accelerated approval.
Despite its auspicious start in 2016, Ocaliva’s once far-reaching potential has been whittled down to a single indication, sharing space in a narrow market now cramped with two newcomers that lack its concerns for serious liver injury. Can Ocaliva reverse course after this considerable FDA slump?
Healio has closely followed Ocaliva since its initial approval in 2016, reporting on regulatory updates that broke major headlines as well as those that snuck in under the radar. Want to see what you missed? We tallied up the pivotal FDA moves that have shaped the course of Ocaliva development and determined whether the drug will continue to be a serious contender in PBC in 2025 and beyond.
FDA: Ocaliva still linked to ‘serious liver injury’ in PBC, even without cirrhosis
The FDA has issued a safety alert warning that Ocaliva carries an increased risk for “serious liver injury” among patients with primary biliary cholangitis, even those without advanced cirrhosis.
In a recent FDA review of postmarketing data on Ocaliva, the agency received reports on 20 cases of liver injury among patients with noncirrhotic PBC, and “this risk was notably higher for patients taking Ocaliva compared with a placebo.” Read more
FDA denies Ocaliva full approval in primary biliary cholangitis; safety data still in play
The FDA issued a complete response letter to Intercept Pharmaceuticals indicating it cannot grant full approval to the company’s supplemental new drug application for Ocaliva as a treatment for PBC.
In its letter, the FDA noted that it was unable to approve the company’s drug application in its current form. However, the agency stated that it was “continuing to consider safety data” from Intercept’s postmarketing requirement confirmatory trial, 747-302, indicating a potential benefit not found in other available therapies. Read more
FDA advisory panel votes against Ocaliva for PBC citing ‘concern for real possible harm’
An FDA advisory committee voted against approval for Ocaliva in PBC without cirrhosis or compensated cirrhosis with portal hypertension, citing “concern for real possible harm”.
The Gastrointestinal Drug Advisory Committee voted 13 to 1 with no abstentions that the benefits of Ocaliva on clinical outcomes in patients with PBC could not be verified with available data from the postmarketing requirement confirmatory trial, 747-302 and the observational study, 747-405. Read more
Intercept pivots away from NASH following second FDA rejection for Ocaliva
The FDA issued a complete response letter to Intercept indicating it cannot approve the company’s new drug application for Ocaliva as a treatment for pre-cirrhotic liver fibrosis due to NASH.
Already saddled with two FDA rejections for NASH after Ocaliva’s initial rebuff in 2020, Intercept has opted to discontinue its NASH-related investments, reorganize its operations “to strengthen its focus on rare and serious liver diseases” and pivot toward profitability in 2024. Read more
‘Unfavorable benefit-risk’: FDA panel votes against obeticholic acid approval for NASH
An FDA advisory committee voted against approval for obeticholic acid in pre-cirrhotic patients with liver fibrosis due to NASH, citing a “concerning” benefit-risk profile.
The Gastrointestinal Drug Advisory Committee voted 12 to 2 with 2 abstentions that the benefits of 25 mg obeticholic acid do not outweigh its risks among patients with NASH and stage 2 or 3 fibrosis, most notably drug-induced liver injury and quality of life.
Ocaliva plus bezafibrate clears FDA orphan drug hurdle for PBC
The FDA granted Intercept Pharmaceuticals orphan drug designation for the fixed-dose combination of Ocaliva and bezafibrate intended for treatment of patients with PBC.
“We are pleased that the FDA has granted orphan drug designation for the fixed-dose combination of OCA-bezafibrate, an important component of our long-term strategy and ongoing commitment to people living with PBC,” M. Michelle Berrey, MD, MPH, president of research & development and chief medical officer of Intercept, said in the release. “This designation represents a milestone in the development of the OCA-bezafibrate fixed-dose combination, which we believe provides the potential to establish best-in-class clinical benefits and further improve the treatment of PBC.” Read more
FDA issues complete response letter for obeticholic acid for fibrosis due to NASH
The FDA issued a complete response letter for the new drug application for obeticholic acid for treatment of fibrosis due to NASH, according to a press release from Intercept Pharmaceutical Inc.
“Today represents a setback first and foremost for NASH patients with advanced fibrosis who have bene waiting far too long for a therapy to treat their disease,” Mark Pruzanski, MD, president and CEO of Intercept, said during a conference call. “It has been an extraordinarily challenging program to get to this point and we believe that we have convincing data that should support the initial approval of the drug to get it to patients. We will move expeditiously to get approval and get it to patients in need.” Read more
FDA adds boxed warning, requires medication guide for PBC drug Ocaliva
The FDA has added a new boxed warning to Ocaliva to clarify current recommendations, according to a release from the agency. The FDA will also require a medication guide for patients, as incorrect dosage can lead to liver injury.
“Following extensive review of postmarketing data, we remain confident in Ocaliva’s safety profile and the benefit it provides when used as directed in patients with PBC, a devastating disease that is one of the leading causes of liver failure in women,” Mark Pruzanski, MD, president and CEO of Ocaliva’s manufacturer Intercept, said in a company press release. “The focus of our label update is to aid physicians in identifying and appropriately dosing Ocaliva in the most vulnerable PBC patients with advanced cirrhosis.” Read more
FDA: Patients receiving incorrect Ocaliva dosage, reports of liver injury
The FDA released a report today that Ocaliva has been incorrectly prescribed to some patients with moderate to severe liver impairment and may be tied to cases of liver injury and death.
“These patients are receiving excessive dosing, particularly a higher frequency of dosing than is recommended in the drug label for them,” the FDA stated in their report. “Ocaliva may also be associated with liver injury in some patients with mild disease who are receiving the correct dose. The recommended dosing and monitoring for patients on Ocaliva are described in the current drug label. We are working with the drug manufacturer, Intercept Pharmaceuticals, to address these safety concerns.” Read more
FDA approves Ocaliva for PBC
The FDA announced it granted accelerated approval for Ocaliva for the treatment of PBC in combination with ursodeoxycholic acid for adults who failed therapy with ursodeoxycholic acid alone, or as a single therapy in adults intolerable to ursodeoxycholic acid.
“Patients left untreated, or who have not responded to [ursodeoxycholic acid], are at risk for liver failure and death,” Amy Egan, MD, MPH, deputy director of the office of drug evaluation III in the FDA’s Center for Drug Evaluation and Research, said in a press release. “Today’s approval of Ocaliva provides an important treatment option for patients living with PBC who have not responded to the only other approved therapy, [ursodeoxycholic acid].” Read more
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