Listed Company's 125 Million Yuan Generic Drug Application Rejected as Original Drug "Crashes": Withdrawn from European and US Markets Due to Safety Issues

Listed Company's 125 Million Yuan Generic Drug Application Rejected as Original Drug "Crashes": Withdrawn from European and US Markets Due to Safety Issues, All Related Clinical Trials Suspended

On October 13, Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co.,Ltd. (688505.SH) announced that its wholly-owned subsidiary Taizhou Fudan-Zhangjiang Pharmaceutical Co., Ltd. recently received a "Drug Marketing Application Disapproval Notice" from the National Medical Products Administration. The obeticholic acid tablets for treating primary biliary cholangitis (PBC) were not approved for registration as they did not meet relevant drug registration requirements.

The main reason for the regulatory authority's disapproval was that the imported original drug for Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co.,Ltd.'s obeticholic acid tablets had "crashed" overseas due to safety issues and was withdrawn from European and US markets. In the announcement, Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co.,Ltd. explained that as a domestic generic drug, its obeticholic acid tablets' overseas reference formulation did not receive conventional approval abroad. Given that post-marketing studies of the original drug clearly showed lack of confirmed benefits and serious risks, existing data cannot adequately support the drug's approval under Class 3 generic drug conventional approval technical requirements.

The announcement also revealed that Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co.,Ltd. has cumulatively invested approximately 125 million yuan in research and development for this obeticholic acid tablets project. The company stated that the drug registration application's disapproval will not have a significant impact on the company's current financial status.

Original Drug Withdrawn from European and US Markets Due to Safety Issues

Public information shows that the original obeticholic acid drug (trade name: Ocaliva) is a farnesoid X receptor (FXR) agonist developed by Intercept Pharmaceuticals.

Obeticholic acid first received accelerated approval from the FDA (US Food and Drug Administration) in May 2016 for treating primary biliary cholangitis (PBC) patients who are unresponsive to or intolerant of ursodeoxycholic acid (UDCA). This was the first innovative drug to receive PBC indication approval in nearly 20 years at that time. In December of the same year, the drug received conditional approval for marketing in Europe, filling the gap in second-line PBC treatment.

PBC is a rare autoimmune liver disease that can ultimately progress to cirrhosis and liver failure. With improved understanding of PBC and enhanced clinical diagnostic capabilities, the prevalence of PBC in China has shown an upward trend, reaching 21.05 per 100,000 in 2022.

Industry data shows that obeticholic acid's global sales from 2016-2021 demonstrated steady growth followed by stabilization: approximately $250 million in 2019; increasing to $310 million in 2020, a 25.3% year-over-year growth; climbing to $363 million in 2021, then stabilizing around $300 million in subsequent years.

However, since 2017, safety alerts regarding obeticholic acid have been continuous. The FDA received multiple reports of serious liver injury and even deaths related to obeticholic acid, subsequently adding the drug to "black box warning" and restricting its use in PBC patients with cirrhosis. The FDA announced that in post-marketing clinical trial evaluations of obeticholic acid, patients receiving obeticholic acid had higher risks of liver transplantation and death compared to those receiving placebo.

In October 2023, the European Medicines Agency (EMA) assessed that existing data for obeticholic acid could not confirm its clinical benefits and recommended revoking its marketing authorization. In September 2024, the European Commission (EC) formally revoked obeticholic acid's marketing authorization in Europe. On September 11 this year, Intercept Pharmaceuticals announced its voluntary withdrawal of obeticholic acid sales in the US market at the FDA's request. Simultaneously, the FDA suspended all clinical trials involving obeticholic acid.

Domestic Generic Drugs Affected

As of now, no obeticholic acid has been marketed domestically. In fact, the "Second Batch of Encouraged Generic Drug Catalog" formulated by the National Health Commission and other departments in 2021 clearly identified 17 encouraged generic drugs and dosage forms, including obeticholic acid tablets.

However, with the exposure of safety risks of the original drug and its successive withdrawals from European and US markets, its domestic generic prospects also face tremendous uncertainty.

The announcement shows that Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co.,Ltd. completed obeticholic acid human bioequivalence study trials in July 2020, received clinical trial approval notification in July 2021 and completed enrollment of the first patient in confirmatory clinical trials in December of the same year. The company submitted the drug's marketing application to the National Medical Products Administration in October 2024 and received acceptance, completing on-site inspection for marketing application registration in June 2025.

Checking the National Medical Products Administration's Center for Drug Evaluation database reveals that besides Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co.,Ltd., multiple other domestic pharmaceutical companies have obeticholic acid generics in development, including well-known pharmaceutical companies such as Hengrui Medicine, Zai Lab, Chia Tai Tianqing, Kelun Pharmaceutical, and Yangzijiang Pharmaceutical.

These companies have similarly encountered setbacks in the marketing progress of obeticholic acid generics. As early as December 2020, Hengrui Medicine submitted marketing applications for obeticholic acid and received acceptance, but approval has not been granted to this day. In February 2024, China Biologic Products Holdings announced that its subsidiary Chia Tai Tianqing Pharmaceutical Group Co., Ltd. had submitted marketing applications for developed obeticholic acid tablets and received acceptance. On September 1 this year, drug notification delivery information released by the National Medical Products Administration showed that Chia Tai Tianqing's reported obeticholic acid tablets were not approved. Additionally, according to Zai Lab's 2023 annual report, in the research project status section, after cumulative investment of 36.0027 million yuan in research and development funding, obeticholic acid magnesium (ZG5266) tablets showed status as "discontinued."

(Disclaimer: Article content and data are for reference only and do not constitute investment advice. Investors operate at their own risk.)