Communication to our Primary Biliary Cholangitis (PBC) patients – especially those receiving treatment with Ocaliva

On 28 June 2024, the European Medicines Agency (EMA) recommended revoking Ocaliva’s marketing authorization, citing that its risks outweigh the benefits.

This message probably comes as a big surprise for many PBC patients, who have been and are taking this drug with the hope to slow or even stop the progression of their chronic liver disease and will raise worries on their future perspectives. The European Reference Network for Hepatological Diseases, ERN RARE-LIVER, acknowledges these worries and wants to send this message to patients and their doctors. We want to put this recommendation into perspective, we want to reassure patients about presently available treatment options, and we want to install hope for better treatments already being foreseeable for the near future.

1. Why does the EMA make this recommendation?
In 2016 Ocaliva was given a “conditional marketing authorization” based on the results of clinical trials showing that treatment with obeticholic acid, the active drug component of Ocaliva, can effectively reduce the level of alkaline phosphatase (AP).
An elevation of AP is a characteristic of PBC, and epidemiological studies had shown that lower levels of AP are associated with a better prognosis. It had also been shown previously that a good treatment response to the standard therapy of PBC, ursodeoxycholic acid (UDCA), measured as a lowering of AP, is also associated with a better prognosis. Therefore, it was believed that lowering of AP by Ocaliva would probably also be associated with a better prognosis. However, with the data available now, the benefits of this effect have now been called into question.

Looking for the long-term overall health of the patients, the EMA therefore requested the company to perform a longer-term study to answer this question. This long-term study was now carefully evaluated by experts of the EMA, and it was concluded that such benefits could not be convincingly demonstrated. When reassessing the effects of Ocaliva overall, the agency did not only diligently investigate these data themselves, but they also consulted various experts and patient representatives.. Furthermore, the company producing the drug, Advanz Pharmaceuticals, its own experts and other experts appointed by them were given the opportunity of a detailed discussion of the evidence as well as the provision of data from additional studies that have in the past years been performed across the world.

Most experts will agree that it is very difficult to assess the risks and benefits of a drug targeting a slowly progressive chronic disease, and weighing risks and benefits can be a very complex process. Detailed long-term data are therefore essential in assessing the potential benefit of a drug for an individual patient. As the long-term follow-up study now failed to show that Ocaliva was more effective than placebo in terms of the number of patients whose disease worsened or who died, both in the overall population and in a group of patients with early stage PBCEMA has decided to recommend withdrawal of market authorization.

In addition to the hard data on disease progression and survival it should also be noted that a considerable number of patients experience worsening of one of the key symptoms of the disease, that is itching. Even though detailed analyses to this aspect are missing it is thus very unlikely that the drug improves quality of life. Therefore, it appears wise to call into question the use of this drug despite its apparent effect on lowering the levels of AP in the blood.

2. Will I have to stop the drug immediately?
This EMA recommendation at this time is just a “recommendation”, the actual final decision is taken by the European Commission. Up until this decision has been taken, Ocaliva will still be available to patients. 

More importantly, as on the basis of this careful EMA analysis there is no sufficient evidence of more benefits of the drug than risks, it may be sensible to stop the drug even before market removal. However, this should be an individual medical decision for each single patient concerned, and we strongly agree with the press statement by the EMA that patients should consult with their treating physician on if, and if yes when, to stop the drug and what alternative treatments to consider.

The ERN RARE-LIVER member centres and affiliated partners offer expert advice for patients with rare liver diseases, including PBC, which is the most common among the rare liver diseases. Patients and their treating doctors are invited to consult with experts from the ERN member centres either directly or via the Clinical Patient Management System (CPMS).

3. Which alternative treatments are there for patients using Ocaliva?
Standard therapy of PBC consists of UDCA at a daily dose of 13-15mg / kg body weight. Almost all patients tolerate this treatment well, and the benefit of this therapy has been convincingly demonstrated, it is the cornerstone of PBC therapy. UDCA can sometimes induce mild digestive problems. The very few patients not tolerating UDCA well should consult their doctors, in order to try to find ways to apply UDCA nonetheless, for example supportive therapy, individual UDCA doses divided more evenly across the day, or a lower overall dose could perhaps help – it appears that even lower doses of UDCA are better than no UDCA.

It should furthermore be stressed that for the large majority of patients PBC runs a very benign course with stable disease, or only very, very slow progress, for many years and decades. Therefore, the need for additional therapy on top of UDCA has to be weighed carefully against the possible risks.

Encouragingly, we have very strong data for fibrates being beneficial for patients not responding sufficiently to UDCA therapy, in particular Bezafibrate, usually at a dose of 400mg / day. Bezafibrate not also influences the overall disease course, it often has a very beneficial effect on itching. However, also fibrates have possible side-effects and risks, and treatment with fibrates should be guided by experts. Furthermore, even though fibrates are old, well-known and well-tested drugs, they are not licensed for PBC. As these are relatively cheap drugs with no patent protection, licensing for PBC by a pharmaceutical company is unlikely to be forthcoming. Thus, application of these drugs in PBC may not be universally available and depends on local prescription and reimbursement rules.
Some patients with a more aggressive course of PBC, or the PBC-autoimmune hepatitis (AIH) variant syndrome, may benefit from immunosuppressive therapy similarly to AIH patients. This again being a rare condition is best guided by experienced specialists.

4. Which new therapies are coming up?
New drugs likely to be effective and better tolerated for PBC are foreseeable. Recently two large studies for the drugs Elafibranor and Sedalpar were published with very encouraging results. We very much hope that the scientific community will drive these efforts for better, more effective and better-tolerated drugs forward.

There are indications that options for “compassionate use” of Ocaliva will be possible and can thus be considered in strictly selected patients, who together with their doctors request this.In view of the long-term trial data such a decision should be weighed very carefully. The same applies to the eventual possibility of early access to one of the above mentioned new substances, whose long-term efficacy still needs to be carefully assessed. As a community, we have to cooperate in investigating and testing new drugs, which not only address the liver in this disease, but also address the important aspects of disease associated symptoms and quality of life of PBC patients.