Richter’s Uterine Fibroid Drug Esmya Hit By Liver Safety Concerns In EU
Executive Summary
EU safety restrictions relating to liver toxicity concerns are likely to lead to changes to the labeling of Richter’s uterine fibroid product Esmya and to a sharp drop in the product’s sales. The moves could also affect the product in the US, where it was filed for approval last year.
Changes are likely to be made to the labeling of Gedeon Richter’s uterine fibroid drug Esmya (ulipristal acetate) as a result of the ongoing EU review of reports of hepatic injury in women taking the product. The company also predicts a sharp drop in sales of the product as a result of temporary restrictions recommended by the European Medicines Agency's Pharmacovigilance Risk Assessment Committee earlier this month. It says that no causal relationship has yet been established between its product and liver damage.
A total of five reports of serious liver injury, including four cases of hepatic failure needing liver transplantation, have now been reported worldwide in women Esmya for uterine fibroids, according to the UK regulatory agency, the MHRA.
National regulators have been writing to health professionals informing them of the safety restrictions. “The new temporary safety measures have been introduced pending completion of the review following receipt in February 2018 of a further report of hepatic failure requiring liver transplant with Esmya,” the MHRA noted.
The PRAC recommended on Feb. 8 that while the review is under way, women taking Esmya should undergo liver function tests at least once a month, and if the test is abnormal (liver enzyme levels more than twice the upper limit of normal) treatment should be stopped, with liver tests repeated two to four weeks later. It added that no new patients should be started on Esmya and that those who have completed a course of treatment should not start another one pending the outcome of the review.
The Esmya review began in December and is expected to result in a PRAC recommendation to the EMA’s key advisory committee, the CHMP, in March. The CHMP is scheduled to issue an opinion by the end of May, the EMA confirmed. This will then go to the European Commission for a binding EU-wide decision.
Richter Disputes Link To Liver Reports
Gedeon Richter PLC expects the EU moves to hit Esmya hard. A spokesperson told the Pink Sheet the company expected sales of the product to fall by more than 50% this year. It also said it foresaw some changes to the Esmya labeling as a result of the review.
“Based on presently available information, the most likely scenario is that there will be some changes in the product information, liver tests might be introduced, but we would like to refrain from further speculations regarding the output of the authorities’ decision-making process while the investigation is still ongoing,” the spokesperson said.
“We believe that all available data support a favourable benefit-risk profile of Esmya” - Gedeon Richter
But the company disputes the liver damage link to Esmya, noting that no causal relationship has yet been established. “We believe that all available data support a favourable benefit-risk profile of Esmya,” the spokesperson commented. During the “extensive” pre-clinical and clinical development program, involving 1,556 subjects in five European Phase III studies and two US Phase III studies, “no signs of liver toxicity were identified.”
The spokesperson said it was important to note that in all reported cases to date, no causality relationship has been established between liver toxicity and Esmya because of co-founding factors such as the use of other medications, viral infections and potential underlying liver conditions.
“Currently, we are aware of sporadic cases of serious hepatic injury of which some led to liver transplantation. All transplant cases occurred in the post marketing use of Esmya 5mg. No cases of hepatic impairment have been observed during the clinical development program of Esmya. In addition, no serious adverse events have been reported on any of the current investigator initiated trials being conducted with Esmya.”
The Review
Esmya was first authorised in the EU in 2012 for intermittent or pre-operative and intermittent treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age. It is given as a 5mg tablet daily for up to three months before women undergo surgery to remove the fibroids, and can also be used longer term, but with treatment breaks, in other women.
The review of Esmya began in December under Article 20 of Regulation (EC) No 726/2004 – which concerns safety or manufacturing issues with pharmaceutical products – after the European Commission notified the EMA in November of a case of fulminant hepatitis in one patient treated with Esmya reported to the French medicines agency (ANSM) on Sept. 22, 2017. More such reports subsequently came to light.
The commission asked Gedeon Richter to submit a cumulative review of the risk of drug-induced liver injury “as reflected in the Esmya Risk Management Plan,” covering “all relevant data sources including clinical studies, literature and post marketing reporting.” The company provided this review in November 2017.
The commission also noted that while there was uncertainty over background incidence and the information in the reported cases, the PRAC’s view was that these cases, with “at least” a possible causal relationship with Esmya, were of concern.
As part of the review, the PRAC sent Richter an additional list of questions covering available safety data relevant to the evaluation of the potential risk of hepatic failure with Esmya. Richter said it had submitted its responses to the committee, noting that it expected “further questions from the PRAC to be raised to which we shall provide the answers in a timely manner.”
US FDA Filing
The EU action could have a knock-on effect in the US, where Gedeon Richter’s partner Allergan announced in October 2017 that the Food and Drug Administration had accepted a New Drug Application filing for ulipristal acetate for the treatment of abnormal uterine bleeding in women with uterine fibroids. The company said at the time that it expected a PDUFA action date sometime in the first half of 2018.
Allergan told the Pink Sheet that it and Richter continued to believe that the totality of the data for Esmya supported a positive benefit-risk profile. It said the FDA would make an independent decision based on all the available data.
Analyst Edward Thomason from Datamonitor Healthcare’s PharmaVitae unit said that the timing of the EMA investigation before Esmya’s PDUFA in May 2018 threatened to jeopardize its approval and the launch of one of Allergan’s star R&D programs. “Even if approved, a warning on [Esmya's] label for liver toxicity would severely dent its commercial potential, and Allergan will hope the investigation is tied up before a FDA decision.”
Nevertheless, Thomason pointed out that at present an association seemed "improbable, with over 700,000 patients having already been exposed to Esmya worldwide, clean studies and only five cases of liver injury reported as yet.”
This chimes with the MHRA’s statement in its letter that while some 20,400 treatment courses of Esmya were dispensed in the UK between Oct. 1, 2016 and Sept. 30, 2017, the agency has to date “received 1 suspected adverse drug reaction report of hepatitis with the use of Esmya in the UK.”
No Effect On Emergency Contraceptive
Ulipristal acetate is also the active substance of a single-dose medicine authorized for emergency contraception, HRA Pharma’s ellaOne, but this product appears to have escaped scrutiny. “No cases of serious liver injury have been reported with ellaOne and there are no concerns with this medicine at this time,” the European Commission said.
From the editors of Scrip Regulatory Affairs.