Advances in Treatment of Primary Biliary Cholangitis (PBC) - Episode 14

Real-World Data on OCA in PBC

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Hepatology experts review the real-world studies of obeticholic acid for management of PBC, highlighting data that show obeticholic acid could improve clinical outcomes in PBC.

Kris Kowdley, MD, FACP, FACG, AGAF, FAASLD: I’m going to switch gears and talk about the long-term, real-world evidence that is now accumulating about the potential efficacy of obeticholic acid as a second-line treatment. We already have data from Japan with bezafibrate, which is not available in the United States but was first introduced for managing PBC [primary biliary cholangitis] as second-line treatment in Japan. They showed, in a large registry of over 8000 patients, that the hazard ratio for needing a liver transplantation or liver-related death occurring in patients with PBC was about 0.18, so an 82% risk reduction, showing that second-line treatment can be significantly additive in terms of ursodiol for preventing adverse outcomes in terms of events such as transplant or death.

There’s a study called HEROES, which is a real-world, evidence-based study using a large database comparing patients who were on obeticholic acid with patients who were not on obeticholic acid, showing a very similar risk reduction, with a hazard ratio of about 0.3 to 0.34, similar to the long-term safety extension of POISE. We have similar data from COBALT, which is the confirmatory trial of outcomes in PBC, which was stopped because of futility. One of the concerns in COBALT was what we called informative discontinuation: patients getting their alkaline phosphatase level checked, realizing that they may be on placebo, and then crossing over to active treatment. The patients who were on obeticholic acid had a very similar risk reduction of about 68% and a hazard ratio of about 0.3 to 0.34. So we have accumulating real-world evidence showing that long-term treatment with obeticholic acid in patients could improve clinical outcomes, not just blood test results. Ed, what are your comments about that, and how do you react to these kinds of data?

Edward Mena, MD: I agree with it all, and it’s an exciting time for patients in that we can halt the progression of disease with these drugs, with ursodiol as second-line therapy. When patients use them, I see a normalization of alkaline phosphatase level in most patients. I wouldn’t say 100% of patients but the majority of patients.

Kris Kowdley, MD, FACP, FACG, AGAF, FAASLD: Sonal, any comments about real-world evidence, and how does that convince you in terms of efficacy in comparison with a phase 4, traditional, randomized, placebo-controlled trial? Do you think that these are valid and useful or don’t replace a confirmatory trial?

Sonal Kumar, MD, MPH: They’re valid and useful for the patient to see that there are real-world data out there. Not that I go over all the data with them, but I tell them that we have findings from real-world studies that show that these therapies we’re using can halt disease progression. It’s very reassuring for a large number of patients. When we see them in our practice, they’re very reassured.

Kris Kowdley, MD, FACP, FACG, AGAF, FAASLD: Steve, any comments?

Steven Flamm, MD, FAASLD, FACG: These data are extremely important, Kris. When obeticholic acid was approved for this patient population, we were following surrogate markers, such as alkaline phosphatase and bilirubin levels, hoping that this conferred a clinical outcome benefit over the long term. It wasn’t at the beginning 100% clear, but as these data continue to come in, real-world data for the Global PBC Study [Group study] POISE and the longer-term trials, all are showing us that the surrogate markers, alkaline phosphatase and bilirubin levels, seem to predict more optimal clinical outcomes. It lends credence to what we do in practice: trying to optimize and lower those laboratory values to have real clinical outcomes that benefit patients.

David Victor III, MD: This is one of the reasons I talk to my patients about why you need to be on second-line therapy, even if there are adverse effects, because you do better. You undergo transplant less, and you do not want to have this disease slowly progress. So, it’s another motivation for my patients to continue to be adherent and manage this disease when, largely, they have no symptoms, because they don’t want to reach the point of symptomatology. In thinking like that, patients are more apt to understand the gravity of their disease if they don’t manage it optimally.

Transcript edited for clarity