Obeticholic acid, used for years to control the progression of primary biliary cholangitis (PBC), a rare liver disease that mainly affects women, risks no longer being available to patients throughout Europe. Last September 3, in fact, the European Commission revoked the conditional marketing authorization (MA), ratifying the recommendation of the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA). This recommendation – as stated in a note – does not concern safety aspects, but is based, in large part, on the evaluation of the overall risk/benefit ratio in a single randomized placebo-controlled study (Cobalt), which has multiple limitations and does not adequately take into account a large amount of evidence collected in clinical practice (Real World Evidence, RWE) and the consensus of experts.
On September 5, the European Court of Justice temporarily suspended the EC’s decision. Until further notice, therefore, the drug can continue to be prescribed to new patients and to those who were already using it under the reimbursement regime, which, in Italy alone, concerns 1,400 people followed in over 150 hepatology centers. If the EC’s decision were to be confirmed in the near future, the drug could no longer be accessible not only to new patients, but also to those already undergoing treatment. This prospect worries patients with CBP who are asking to use this suspension period to find a solution that at least protects therapeutic continuity for patients who benefit from the treatment. This was discussed this morning in Rome – close to World CBP Awareness Day, which was celebrated on September 8 – in a press conference organized by Omar, Osservatorio Maladie Rare, in collaboration with Amaf Aps Ets – Associazione Maladie Autoimmuni del fegato and Associazione EpaC Ets and with the unconditional contribution of Advanz Pharma.
Obeticholic acid has been authorized in Italy since 2017, as the only second-line therapeutic option for patients who do not have adequate disease control with the first-line treatment based on ursodeoxycholic acid. Furthermore, it has been successfully used in clinical practice for 7 years and post-marketing data have been collected on the safety of more than 40 thousand patients/year, confirming a well-defined safety profile. At the moment there is no second-line alternative and, if they were available, they would act with different mechanisms of action from obeticholic acid. No study has been done on the effects and responsiveness of patients treated with obeticholic acid in the case of switch.
“Primary biliary cholangitis is a rare, severe and progressive autoimmune liver disease that predominantly affects women with a female-to-male ratio of 9 to 1 and causes chronic liver disease with the possibility of progressing to cirrhosis and liver transplantation,” explains Annarosa Floreani, senior scholar at the University of Padua and scientific consultant at the IRCCS in Negrar, Verona. “If a solution is not found immediately, the risk is to go back more than 7 years. Other treatments are in development, but are not yet available to patients and have not been demonstrated in clinical practice. Furthermore, they have different mechanisms of action and are therefore not interchangeable with obeticholic acid.”
One of the possible solutions discussed, already emerged from two parliamentary questions presented by Senators Elisa Pirro and Ignazio Zullo, members of the Commission X “Social Affairs, Health, Public and Private Employment, Social Security”, filed on 8 August, is to apply art. 117.3 of Directive 2001/83 EC, implemented in Italy by art. 43 of the Decree of the Ministry of Health of 30 April 2015. “The rule, which has never been applied to date – clarifies Senator Pirro – provides that, in the event of revocation of the marketing authorization for a drug, the competent national authorities may, in exceptional circumstances, continue to allow its supply to patients already undergoing treatment. It would seem to be applicable to this situation and I hope it can be taken into consideration”. Senator Zullo adds: “Applying art. 117 would be desirable, also considering the fact that the revocation did not concern drug safety reasons and that for these people there is no alternative today. I am available to support the Cbp community in bringing this solution, or any others, to the attention of the institutions”.
The president of the Association of Autoimmune Liver Diseases (Amaf), Davide Salvioni, asks that “all those people who are currently being treated with obeticholic acid and are benefiting from it be protected, at least until new therapies become available”. According to Ivan Gardini, president of the EpaC Ets Association, “this case presents several anomalies: in the United States it is regularly on the market and on the one hand EMA recommends its withdrawal, but at the same time” guarantees it for the continuity of care in those who use it “through compassionate use programs. Furthermore, the opinion of patients is not taken into due consideration. I expect the Italian Medicines Agency to decide to carry out further investigations independently, listening to the Italian scientific community and patient associations before carrying out a possible therapeutic interruption measure”. This is the second case, in a few months, of withdrawal from the market of a drug for rare diseases following a review of the conditional approval and subsequent suspension of the decision.
“It is clear and normal that patients are very concerned,” comments Ilaria Ciancaleoni Bartoli, director of Omar. “Although randomized, double-blind, placebo-controlled studies are considered the gold standard of clinical research, they can be difficult to conduct in rare diseases, especially when this occurs after marketing authorization and product availability, as in the case of the Cobalt study. For ethical reasons, greater consideration of Real World Evidence data would be desirable, which in this case are available (Recapitulate study).”
In this regard, Vincenza Calvaruso, national secretary of the Italian Association for the Study of the Liver (AISF), observes that “the CHMP seems not to have taken into consideration the data from the Recapitulate study, the first data of which were published in March 2023 and further results were presented at the international congress of the EASL (European Association for the Study of the Liver) in June 2024. The Italian data collected since 2018 on 759 patients treated with obeticholic acid in 66 centers have demonstrated a clinical benefit of the drug in reducing the progression of the disease and the development of irreversible liver damage”. The results of the Cobalt study “cannot be interpreted correctly – underlines Pietro Invernizzi, director of the UOC Gastroenterology and Autoimmune Liver Disease Center (Maf), Fondazione Irccs San Gerardo dei Tintori in Monza – To do so, it would have been necessary to also take into account the supporting studies and data from Real World Evidence. Furthermore, the Cobalt study was designed with a placebo arm when the drug was already available as part of routine clinical care, an aspect that played a decisive role in the failure of the study itself. The entire international scientific community therefore agrees in asking European and national authorities to protect people who are already being treated with obeticholic acid by guaranteeing their therapeutic continuity”.
“The therapies available to date have also allowed patients who did not respond to the first line of treatment to keep alkaline phosphatase and bilirubin parameters under control – remarks Umberto Vespasiani-Gentilucci, associate professor of Internal Medicine at the Campus Bio-Medico University of Rome, PhD in Experimental and Clinical Hepatology – To demonstrate the impact of these effects” one should consider the data “of the Recapitulate study which highlights a 60% improvement in liver transplant-free survival and in the reduction of liver-related events for patients treated with Oca, while a further sub-analysis demonstrates a significant reduction in liver stiffness over time, a key indicator – he concludes – of the fibrotic progression of the disease”.
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