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on september 3, advanz pharma announced that the european commission hadwithdrawal of the conditional marketing authorization of obeticholic acid in europe.this marks the end of the drug's eight-year journey to market in europe.

obeticholic acid is a farnesoid x receptor (fxr) agonist. it was first approved by the fda for marketing with conditions in may 2016 and was approved for marketing in the european union in december of the same year. it is not only the first drug approved for the treatment of primary biliary cholangitis (pbc) in nearly 20 years, but also the only drug approved for the second-line treatment of pbc in europe. it is worth mentioning that obeticholic acid was also the first new drug product to survive the phase iii clinical trial of nash, but was ultimately rejected. according to data from yaozhi.com,in 2022, global sales of obeticholic acid tablets were close to 2 billion yuan.

last october, the european committee for medicinal products for human use (chmp) began to re-evaluate the clinical risk-benefit ratio of obeticholic acid, and finally concluded after reviewing the phase iv clinical data that the existing data could not confirm the clinical benefits of obeticholic acid and recommended its withdrawal from the market. however, as there are still no alternative products on the market, on september 5, the european court of justice ordered a suspension of the implementation of this decree.

the fate of obeticholic acid is also uncertain in the united states.on september 13, the fda will also fulfill the conditions for accelerated approval and convene an expert advisory committee to discuss its clinical benefits, using the same data set as the chmp.

this delisting storm may also affect the domestic market.although the original drug was not launched in china, in 2020, the national health commission released the "second batch of encouraged generic drugs catalogue", and obeticholic acid was one of the 17 drugs encouraged by the country for generic drugs. no less than 10 domestic companies have successively applied for generic drugs. in february this year, zhengda tianqing announced that its obeticholic acid tablets had submitted an application for listing to nmpa and were accepted, and it is expected to become the first generic drug.

if the original research drug is delisted overseas, what will happen to the generic drugs? this is an unprecedented new problem for the domestic pharmaceutical industry.

other second-line drugs are coming soon

pbc is a relatively rare autoimmune liver disease that can eventually progress to cirrhosis and liver failure.ursodeoxycholic acid is the first-line treatment for pbc, but about 40% of patients do not respond well to it, so the clinical status of obeticholic acid as a second-line drug is more prominent.

this makes the forced withdrawal from the market today quite unexpected. the european committee for medicinal products for human use (chmp) said that this conclusion was based on the data from the phase iv clinical study 747-302 (cobalt), which showed that obeticholic acid and placebo were significantly different in the primary composite endpoint of death, liver transplantation or liver decompensation.no statistical difference was shown (hr 1.01, p value: 0.954).

this is obviously difficult for advanz to accept. in 2022, advanz acquired most of the subsidiaries and product rights of intercept, the original developer of obeticholic acid, outside europe, canada and the united states with an advance payment of more than us$400 million.it has only been less than two years since it was sold. if it is withdrawn from the market, the huge investment will be wasted.

advanz tried to resist and publicly stated that "chmp's analysis has many limitations." first, some patients were still classified as placebo group after switching to other treatments; second, its judgment was "unfair" and failed to adopt all available data, especially the real-world evidence of more than 7 years of clinical use of obeticholic acid, which represented more than 47,000 patients' years of treatment experience.advanz's ceo also protested that "obeticholic acid is the only approved and available second-line treatment option in europe."

this protest temporarily delayed the withdrawal of obeticholic acid from the market.on september 5, the european court of justice ordered a suspension of the european commission's decision.advanz later stated that the drug "remains available to new and existing patients across europe."

however, this situation may change soon. recently, the fda conditionally approved two new second-line pbc treatment drugs, ipsen's iqirvo (elafibranor) and gilead sciences' livdelzi (seladelpar). iqirvo was recommended by chmp for conditional approval in the eu in july, and livdelzi has also submitted a marketing application to the ema in march this year.it remains to be seen how the european court of justice will decide after second-line alternative drugs are launched on the market.

where are generic drugs headed?

at present, in addition to europe, obeticholic acid has been launched in the united states, canada and other countries; generic drugs have been launched in india, bangladesh and other countries.the industry believes that if obeticholic acid is withdrawn from the market in europe, it may trigger a series of chain reactions in these regions.

compared with europe, the united states and other countries, the prevalence of pbc in my country is lower, but it has also shown an upward trend in recent years, reaching 21.05/100,000 in 2022.in the 8th batch of national centralized procurement, the oral sustained-release formulation of ursodeoxycholic acid, a first-line drug for pbc, was included.according to the zhongkang kaisi system, the sales of ursodeoxycholic acid in graded hospitals reached 2.178 billion yuan in 2023, and sales in the first quarter of 2024 reached 475 million yuan.

obeticholic acid has not been marketed in china, but for a long time,as the only second-line drug, it is well-known among doctors and patients in relevant departments, and many doctors and patients mention it during online consultations.there are also many global drug search platform websites that advertise obeticholic acid.

since 2017, pharmaceutical companies such as hengrui, sinopharm tianqing, and fudan zhangjiang have successively launched generic research on obeticholic acid.in 2020, the national health commission included obeticholic acid in the list of drugs encouraged for generic development, which further boosted this research and development boom.pharmaceutical companies such as yangtze river pharmaceutical, kelun pharmaceutical research institute, beite pharmaceutical, china resources sanjiu, kanghong pharmaceutical, and minsheng pharmaceutical have successively entered the market. in addition, in 2020, zejing biopharma also applied for approval of obeticholic acid magnesium tablets as a class 2.1 improved new drug, which has been approved for clinical trials.

according to incomplete statistics,in the race for obeticholic acid generics, zhengda tianqing is the fastest, with its application for listing already accepted; fudan zhangjiang and minsheng pharmaceutical are closely behind, both having entered the phase iii clinical trial stage.if the original research product is withdrawn from the market, what will be the fate of these generic drugs waiting to be launched?