FDA Advisory Committee Votes 12-2 Against Accelerated Approval of Obeticholic Acid as First NASH Drug

At the recently concluded FDA Gastrointestinal Drugs Advisory Committee meeting, experts reviewed obeticholic acid (Ocaliva, OCA) for the treatment of patients with pre-cirrhotic liver fibrosis caused by NASH. The advisory committee ultimately voted 12-2 (with 2 abstentions) against the accelerated approval of obeticholic acid as the first NASH drug. Additionally, by a vote of 15-1, the committee recommended that the FDA defer the approval of obeticholic acid to await further pivotal data.

The recent meeting of the FDA Gastrointestinal Drugs Advisory Committee has drawn significant attention, not only because its outcome may signal whether obeticholic acid will become the first approved therapy for NASH, offering hope to affected patients, but also because it represents a long-anticipated milestone for companies engaged in NASH drug development.

The meeting reviewed two key issues regarding the drug’s approval and ultimately concluded that the benefits of obeticholic acid for patients with stage 2 or 3 fibrosis due to NASH do not outweigh the risks.

The voting outcome was not surprising. On May 17, the FDA released briefing documents ahead of its Advisory Committee meeting scheduled for May 19 to discuss the resubmitted application for obeticholic acid by the biopharmaceutical company. These documents revealed that the FDA had expressed concerns about the drug’s potential risks of liver injury and diabetes, appearing poised to deny approval. Intercept Pharmaceuticals’ stock price plummeted by more than 20% that day.

Prior to the meeting, Jerry Durso, President and Chief Executive Officer of Intercept Pharmaceuticals, stated, “We look forward to the opportunity to discuss our clinical trial data with the Advisory Committee, which demonstrate the robust and confirmed antifibrotic effects of OCA, as well as its manageable safety profile in NASH.”

Although there are unmet clinical needs in the NASH field, it now appears that the Advisory Committee will retain significant concerns regarding both efficacy and safety.

The FDA cited a long list of safety risks and practical barriers to patient acceptance of liver biopsy, noting that drug-induced liver injury is a “serious signal.” The document stated that, coupled with “modest” efficacy, this “does not justify the use of OCA in patients with NASH and stage 2 or 3 fibrosis.”

On January 19 this year, Intercept Pharmaceuticals announced that the U.S. Food and Drug Administration (FDA) had accepted its New Drug Application (NDA) for obeticholic acid in the treatment of patients with pre-cirrhotic non-alcoholic steatohepatitis (NASH) accompanied by liver fibrosis. The Prescription Drug User Fee Act (PDUFA) date is June 22, 2023. The FDA’s review timeline for the NDA remains subject to change.

This NDA submission is primarily based on the positive interim analysis data from two cohorts in the Phase III REGENERATE study. The REGENERATE study is a randomized, double-blind, placebo-controlled, multicenter international trial evaluating the clinical safety and efficacy of obeticholic acid in patients with pre-cirrhotic liver fibrosis due to NASH.

In November 2022, Intercept presented the latest data from the Phase III REGENERATE trial on obeticholic acid for the treatment of NASH-related liver fibrosis at the AASLD Liver Meeting. The results were positive: the response rate for reduction in liver fibrosis with obeticholic acid 25 mg was twice that of placebo, without worsening of NASH symptoms. Obeticholic acid 25 mg demonstrated more robust anti-fibrotic efficacy in patients with advanced fibrosis but without cirrhosis. Regarding safety, Intercept conducted a robust safety assessment in 2,777 patients, including 1,000 patients who received the drug for up to four years, supporting the safety profile and potential for long-term use of obeticholic acid.

Obeticholic acid is a farnesoid X receptor (FXR) agonist. FXR, which is typically expressed in the intestine and liver, is a key regulatory molecule in bile acid, inflammatory response, fibrosis, and metabolic pathways; activation of FXR can reduce bile acid concentrations within hepatocytes. Non-alcoholic steatohepatitis (NASH) is a severe, progressive liver disease caused by chronic inflammation resulting from excessive fat accumulation in the liver, leading to progressive fibrosis (scarring), which can result in cirrhosis, ultimately liver failure, cancer, and death. In patients with NASH, advanced fibrosis is associated with a high risk of liver-related morbidity and mortality.

In January 2015, obeticholic acid was granted Breakthrough Therapy designation by the FDA for the treatment of patients with nonalcoholic steatohepatitis (NASH) accompanied by liver fibrosis. In May 2016, it received initial FDA approval for the treatment of primary biliary cholangitis. Furthermore, obeticholic acid was the first NASH drug globally to enter Phase III clinical trials. In September 2019, Intercept Pharmaceuticals submitted a marketing application based on the results of the first interim analysis. In June 2020, the FDA declined to grant accelerated approval for the treatment of NASH-related liver fibrosis, citing uncertainty regarding the benefits indicated by the interim histological endpoint data. The FDA recommended that Intercept Pharmaceuticals submit additional interim efficacy and safety data from the REGENERATE Phase III clinical study.

It is not only Intercept Pharmaceuticals that has been affected by this news; the industry is also closely watching the results of the advisory committee. As there are currently no approved drugs for the treatment of non-alcoholic steatohepatitis (NASH), the industry needs a milestone event—a bellwether—to restore some confidence.

In the field of NASH, where no new drugs have been approved, the stance of the FDA as the regulatory authority is crucial to the industry's development. A clear example is that in December 2018 and June 2019, the FDA consecutively released two draft guidance documents on NASH drug development, which significantly promoted industry progress. Major advancements by multiple companies, including Intercept Pharmaceuticals, Madrigal Pharmaceuticals, Akero Therapeutics, and 89bio, have all occurred since 2018.

“The design of clinical trial protocols for NASH is critical; every aspect—from the selection of patient stages, choice of endpoints, sample size, and trial duration, to the standardization of pathological specimen analysis methods—can influence the final outcomes. Currently, the FDA has issued guidance on NASH clinical trials, with clear requirements particularly regarding the determination of endpoints,” said Dr. Li Jiakui, Vice General Manager of Xuanzhu Biopharma, in a previous interview with VCBeat New Medicine.

The results indicate that the advisory committee remains highly cautious about approving the first NASH therapy, particularly with regard to drug safety issues. The capital market is eagerly awaiting the good news of the first NASH drug approval. For practitioners committed to rigorous drug development, while the launch of the first drug is significant, efficacy and safety are the keys to achieving long-term success.

Potential competitors to obeticholic acid are close on its heels. Not long ago, Madrigal Pharmaceuticals’ lead candidate, resmetirom, received Breakthrough Therapy Designation from the U.S. Food and Drug Administration (FDA) and is set to file for marketing approval this quarter. Previously, resmetirom met the primary endpoint of liver histology in its Phase III trial for the treatment of non-alcoholic steatohepatitis (NASH).

Currently, in the NASH therapeutic area, GLP-1R, FXR, and PPAR are the drug targets with the highest number of clinical trial applications. These targets have already been approved for marketing in other indications such as type 2 diabetes, and they have also spurred the development of highly promising new NASH therapies. Notable examples worth close monitoring include the PPAR agonist lanifibranor and Novo Nordisk’s widely recognized semaglutide.

"Second-generation targets," such as THR-β represented by Madrigal and FGF21 represented by Akero, have begun to demonstrate impressive results in recent clinical trials.

“Madrigal did not disclose clinical endpoint data at last year’s EASL Congress or AASLD Liver Meeting. It was not until the end of last year that the company officially announced the primary endpoints from its Phase III clinical trial. At previous EASL and AASLD meetings, many assessments of efficacy were based on metabolic markers, leading to a general perception that the drug was indeed quite effective. The efficacy of Resmetirom lies in its ability to meet two key endpoints: improving steatohepatitis and alleviating liver fibrosis. More importantly, Resmetirom has a favorable safety profile with low incidence of side effects,” said Professor Wu Jian from the School of Basic Medical Sciences at Fudan University, in a previous exclusive interview with VCBeat News.

In short, industry insiders have reached a consensus that the approval of the first-generation NASH drugs this year is all but certain. The turning point in the NASH field has arrived, but China’s domestic industry remains in the early exploratory stage, with no investment consensus yet formed.

“At this stage, many investors are still unwilling to take on significant risks with such early-stage projects. The NASH sector in China has not yet reached a peak of investor enthusiasm; market participants are waiting for greater clarity or seeking opportunities in later-stage projects,” Chen Haigang, Managing Partner at Xingze Capital, previously stated in an interview with VCBeat New Medicine. “While clear domestic demand has not yet materialized, the large patient population ensures substantial long-term growth potential.”

Xingze Capital is one of the earliest venture capital firms in China to recognize the potential of metabolic diseases and non-alcoholic steatohepatitis (NASH). When investing in Yachuang Pharma in 2019, Chen Haigang predicted that the period before 2023 would be the optimal window for VC investment in NASH.

Of course, changes have been quietly underway. Under the impact of a series of positive developments in late last year, China’s primary market has shifted away from its previous stance of “keeping at arm’s length,” with investment institutions once again conducting thorough due diligence on the NASH sector. Since December 2022, multiple venture capital firms have proactively approached Yachuang Pharma.