Ocaliva (obeticholic acid), which started as a blockbuster liver disease therapy and attracted much attention for its great potential in MASH treatment, will further fade away at the end of 2024. Not only did the "bad" news come one after another, but it also came from the two regulatory agencies covering the European and American markets, the FDA and the EMA. However, looking back at the development history of obeticholic acid, it is actually not smooth. Since it was approved for the treatment of primary cholangitis (PBC) in 2016, Intercept has tried twice to expand the drug to MASH, but both attempts failed. This made Intercept completely abandon the MASH project and lay off one-third of its employees. Later, Intercept was acquired by the Italian pharmaceutical company Alfasigma, but the change of destination did not improve the fate of obeticholic acid. And with the first PPAR agonist Elafibranor approved by the FDA for second-line PBC treatment in June this year, obeticholic acid, which lost its "only" status, is even more embarrassing.

▍Hepatitis drug
Obetocholic acid is an orally available FXR (farnesoid X receptor). FXR participates in maintaining the homeostasis of endogenous active substances and participates in multiple pathological processes. It can negatively regulate bile acid synthesis, bile acid excretion, lipid metabolism and glucose metabolism. In May 2016, obeticholic acid was officially approved by the FDA for the clinical treatment of PBC that is unresponsive or intolerant to ursodeoxycholic acid (UDCA), becoming the only blockbuster drug approved for primary biliary cirrhosis in 20 years.

Seven months later, obeticholic acid also received conditional approval from the EMA for marketing, becoming the first second-line treatment for PBC in the European market.
Although obeticholic acid is prone to cause severe itching symptoms, in addition, higher doses of obeticholic acid may also cause liver function deterioration in patients with advanced liver disease and cirrhosis. In 2018, the FDA issued a "black box warning", but this did not affect the market of obeticholic acid.

In the first year after approval, sales of obeticholic acid were about $18 million; in 2018, they increased nearly 10 times to about $178 million; in 2019, they were $250 million, and in 2020, they were $310 million. In the following years, sales tended to stabilize at around $300 million.

To some extent, this is related to the background of PBC. PBC is an autoimmune disease in which the bile ducts of the liver become inflamed and gradually destroyed, leading to inflammation, scarring, and cirrhosis, and increasing the risk of liver cancer. Data show that the global annual incidence of PBC is estimated to be 1.76 cases per 100,000 population, while the prevalence is 14.6 cases per 100,000 population. The disease mainly affects women, and its incidence increases with age.

Similarly, in the field of MASH, which is almost untreatable and has huge clinical needs, obeticholic acid has also been given great expectations, and was granted breakthrough therapy recognition by the FDA in 2015 for the indication of "treating MASH liver fibrosis." Obeticholic acid was once considered to be the first MASH drug approved for marketing, and the drug also tried to respond to expectations with data.

In February 2019, Intercept announced that the interim analysis of the 18-month REGENERATE study of obeticholic acid for the treatment of MASH patients with liver fibrosis achieved positive results. In July 2022, Intercept announced that the new interim analysis of the key phase III REGENERATE study of obeticholic acid reached the preset primary endpoint. As a result, obeticholic acid became the world's first MASH drug to achieve positive results in phase III clinical trials. But the road to MASH is not easy, and obeticholic acid's highlight this time seems to be a twilight in hindsight.

▍Failure in MASH
Since its launch, obeticholic acid has shown a growing trend in global sales. However, if the industry perspective is included, the gap emerges.

In Evaluate's 2015 forecast, obeticholic acid sales in 2020 would reach US$1.8 billion. As a result, the actual sales are far from the forecast. This also seems to foreshadow the troubled future of obeticholic acid. After achieving the first positive results of the MASH trial in 2019, Intercept submitted an NDA for obeticholic acid to the FDA in September of that year for the treatment of MASH-induced liver fibrosis. But the following year, Intercept was asked by the FDA to provide longer-term efficacy and safety data for obeticholic acid.

In July 2022, after the new mid-term trial reached the preset endpoint again, Intercept resubmitted the application for marketing and successfully determined the PDUFA date-June 22, 2023. However, the branches are rampant again. In May 2023, the FDA Gastrointestinal Drugs Advisory Committee gave an objection. The expert committee ultimately opposed the accelerated approval of obeticholic acid as the first MASH drug with a result of 12:2 (2 abstentions). Intercept subsequently announced that the FDA had issued a CRL for the new drug application for obeticholic acid for the treatment of pre-cirrhotic fibrosis caused by MASH. According to the content of the CRL, obeticholic acid needs to successfully complete at least the long-term results phase of the REGENERATE study.

After this, Intercept was discouraged and stopped all MASH-related projects, refocusing on liver disease and rare diseases, and accelerating profitability from 2024. Unfortunately, before the bell of 2024 was heard, Intercept retreated to the edge of the stage. In September 2023, Intercept announced that it was acquired by Italian pharmaceutical company Alfasigma for $800 million. Obeticholic acid, which was caught in a dilemma, was taken over by Alfasigma. In addition, Advanz Pharma of the United Kingdom acquired the rights of the drug outside the United States for $405 million in 2022.

▍Frustrated in two major markets
Obetocholic acid, which was divided by the two companies, failed to get good luck and suffered setbacks in two major markets in the world. First, in June this year, EMA announced that after review by CHMP, it was considered that the clinical benefits of obeticholic acid did not outweigh the risks, and it was recommended to revoke the marketing authorization of obeticholic acid. The 747-302 study data based on which EMA relied showed that there was no significant difference in the results of the primary composite endpoint between the experimental group and the control group. In September, the European Commission (EC) announced the withdrawal of the drug's marketing application. However, a few days later, the General Court of the European Union announced the suspension of the EC's decision to withdraw the drug from the market.

Advanz had not had time to put its heart back in its stomach, and suffered another fatal blow. In November, the General Court of the European Union officially determined that it would not extend the EC's decision to revoke the conditional marketing authorization of obeticholic acid in Europe. Officially, obeticholic acid has withdrawn from the European market, but Advanz disagrees with this decision. The announcement information shows that it is discussing with relevant national agencies so that patients who need this drug can continue to obtain it.

Also in November, the FDA also showed a yellow card to obeticholic acid. The FDA's CRL showed that according to the Gastrointestinal Drugs Advisory Committee meeting held in September, it was not supported that the benefits of obeticholic acid on the clinical outcomes of PBC outweighed the risks, and the supplementary new drug application was rejected. The second interim analysis data of the REGENERATE study showed that after 18 months of treatment, only 22.4% of the high-dose group of obeticholic acid had achieved statistically significant improvement, and the low-dose group did not achieve statistically significant improvement. As for the side effect of itching, the incidence of itching in the high-dose group was more than half, which would greatly affect patient compliance.

The FDA's recent announcement showed that a post-marketing clinical trial found that patients with PBC without cirrhosis treated with obeticholic acid experienced severe liver injury events. In addition, in patients treated with obeticholic acid - those at low risk of disease progression - the drug appeared to aggravate death or the need for liver transplantation. For example, 7 of 81 treated patients had to undergo a transplant, while only 1 of 68 placebo controls underwent a transplant. Four patients died in the obeticholic acid group and only 1 in the placebo group.
According to the regulator, the risk ratio for liver transplantation and death was 4.77 in patients without advanced cirrhosis and no contraindications to taking the drug. Based on these new signals, the FDA recommends that healthcare professionals "frequently" monitor patients' liver tests for early signs of worsening liver function.

However, the FDA also stated that "based on current data, it is unclear whether this monitoring is sufficient to address the risk of severe liver damage." In addition, if evidence of liver disease progression is found or the efficacy of the drug on the patient cannot be determined, the drug should be discontinued immediately.
At present, although obeticholic acid is still sold in the United States, the future does not seem optimistic. For the star drug that is unparalleled in the world, this has to be said to be a sad ending.

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