Experts reviews the current treatment landscape for management of PBC, highlighting ursodeoxycholic acid (UDCA) and obeticholic acid (OCA), as well as liver transplant.
Kris Kowdley, MD, FACP, FACG, AGAF, FAASLD: How is PBC currently treated? Ed, why don't you kick us off? You alluded to fenofibrate, which is the fibrate that is available in the US for off-label treatment. Second-line obeticholic acid, which is approved as a second-line treatment, also deoxycholic acid. Tell us a little bit about how these drugs may change the natural history of the disease and how they work.
Edward Mena, MD: I think our goal, like we said earlier, is to get that normalization of our alkaline phosphatase. As second-line agents, the first one that was FDA approved for second line would be obeticholic acid. Usually, I like to start off at a 5-milligram dose depending on how much side effects they're getting. The number one side effect I see with obeticholic acid is pruritus. If their pruritus isn't too bad at 3 months, I'd like to reevaluate them, and then I increase the dose to 10 milligrams to make sure that their alkaline phosphatase is getting to goal. Another agent that I also like to use, depending if I have coverage on obeticholic acid, is fenofibrate. I usually start off at a low dose and work my way up depending on side effects. I like to see these patients at least every 3 to 6 months to not only evaluate their alkaline phosphatase, but evaluate any side effects that they may be having with those second-line agents.
Kris Kowdley, MD, FACP, FACG, AGAF, FAASLD: David, how about you?
David Victor III, MD: I follow basically the same pathway. The one caveat I do with ursodiol is I have to make sure they can afford it and find the medicine. This has been one of the things that I think is better now. There are more options on the internet with some internet-based pharmacies that provide opportunities for patients to afford Urso. I think, that's one of the things that when you really drill down, is one of the reasons people fail urso, being that they don't buy it. I think that's a really key point, is to identify compliance and if they are taking the medicine before you start a second line agent. Otherwise, I follow the exact same pathways to monitor, carefully discuss, discuss side effects and expectations. At each point, I really do talk to the patient about why we're doing this, and that you can have a normal life if this disease is treated well, and you do not want to go down the pathway of chronic liver disease and progression to cirrhosis.
Kris Kowdley, MD, FACP, FACG, AGAF, FAASLD: That's great. Sonal, can you tell us a little bit about the mechanism of action of these drugs, Urso, obeticholic acid, and fenofibrate? How do you explain it to the patients and to the referring doctors about the rationale for using these drugs?
Sonal Kumar, MD, MPH: When explaining it to the patients and other providers, I try to be as simple as possible. I tell them that what's happening is that you're getting buildup of these bile acids that can cause damage since they're toxic. Urso is another bile acid, but not considered toxic, and it displaces the toxic bile acids and helps reduce damage that way. When talking about obeticholic acid, I always make sure to stress that it's a different mechanism of action and that it's more inhibiting bile and acid synthesis, increasing secretion as opposed to Urso so they understand why it's additive therapy as opposed to switching it over.
Kris Kowdley, MD, FACP, FACG, AGAF, FAASLD: That's great. Steve, you're often leading speaker training and training us to speak about obeticholic acid. Anything further to add to the mechanism of action of any of these drugs?
Steven Flamm, MD, FAASLD, FACG: I don't generally get into a long discussion with patients about the mechanism of action because I don't think they care that much, to be honest with you. They just want to know will it work and will it hurt. That's what they want to know so I don't get into a lot of that, but I do talk to them about the importance of taking these medications, following the plan and thinking of this in a long-term way, because I will say one of the key messages, I think, from the Global PBC Group, which you have been one of the leaders in, in these recent years, has been that we really need to follow these patients closely. As the years go on, we're learning that we really need to drive down the alkaline phosphatase and the bilirubin. We didn't even really know that 10 to 15 years ago. It's relatively new. I try to communicate that to patients that we need to give them the medical therapies that they need to drive those numbers down because we think in the end that they will be much more likely to have a good outcome and not require liver transplantation.
Kris Kowdley, MD, FACP, FACG, AGAF, FAASLD: I think that's a great summary and brings added value and color to what we're talking about. I usually like to describe sort of Urso as a nonspecific flush of the liver. It's sort of a glorified liver flush, going in and getting your pipes cleaned out. There's a lot of debate, of course, about whether Urso increases independent bile flow, changes the pH of the bile, makes it more aqueous, et cetera, but it's nonspecific. Then, when you add OCA or obeticholic acid, you are now adding a more rational drug that binds to specific receptors in the liver. By blocking CYP7A, it is going to both reduce the production of new bile acids and increase the secretion of bile acids, sort of getting that dual effect. Fenofibrate, of course, is a pan-PPAR agonist. This is a group of receptors in the liver where there's a variety of different pleiotropic activities, but fenofibrate is not FDA approved, but is in the guidelines as a second-line therapy as an alternative to obeticholic acid. These fibroids, of which there are a number in development, also have sort of a different mechanism of action. We'll talk a little bit about how each of you—because we all practice in different environments and have different levels of involvement of care with patients with PBC—would think about goals of treatment in a minute.
Then, what about liver transplantation? One of the things that we like to teach is that liver transplantation has reduced in volume as far as PBC, undoubtedly related to Urso, but the average age of the patient undergoing transplant for PBC has not changed. There's a group of patients who are younger, have rapidly progressive disease that need a transplant, and clearly, that's an unmet need. Do you still see patients with PBC in your transplant practice? Can you describe what's unique about them from your average patient?
David Victor III, MD: We do see these typically in younger women with rapidly progressive disease or sometimes younger men. The hard part is because of the way we allocate livers, their disease state is such that they are not prioritized. We don't have an exception that we do for a liver cancer or whatnot. Oftentimes, they are dramatically symptomatic, very, very jaundiced, intensely paralytic, but languish on the list longer than they probably deserve. That's the rules that we play by. We do really try to identify those patients early and seek opportunities because they're typically a little younger and a little bit more robust or healthy to identify ways to find an organ, whether that is an extended criteria or living donation. Then posttransplant, just one word, you do want to monitor for recurrence of PBC and we keep all our patients by protocol, not by science, on urso posttransplant, just hoping that we can prevent any further recurrence after.
Kris Kowdley, MD, FACP, FACG, AGAF, FAASLD: That's a really good point. Obviously, this may not apply to a lot of our audience, but there's now pretty clear data that preemptive Urso is associated with the reduced rate of recurrence of PBC. There's also some data suggesting that depending on the calcineurin, cyclosporine, or tacrolimus that's used, there may be a difference in the rate of recurrent PBC. Do you also, in your practice, routinely start patients on UDCA posttransplant?
Steven Flamm, MD, FAASLD, FACG: Yes, we do.
Kris Kowdley, MD, FACP, FACG, AGAF, FAASLD: Regardless of whether they have recurrence or not?
Steven Flamm, MD, FAASLD, FACG: Yes. Yet, even before this was done on a routine basis from around the country, patients with PBC have done extremely well after liver transplantation. In fact, of all the people that undergo liver transplantation, patients with cholestatic liver diseases, have done the best. This was even before the prophylactic Urso, but yes, we do. We think it optimizes the chance that a patient will remain PBC-free after liver transplant.
I want to echo what David said. Patients with PBC, true PBC, don't really present with acute jaundice with the bilirubin of 24. I just referred a lady for liver transplant that you're mentioning, a youngish lady, she just turned 50, and has had rapidly progressive disease, despite Urso, and is now being referred for liver transplantation evaluation. Her bilirubin was 3 and then 4 and then 5. Now has ascites. These patients get very sick without the profound bilirubin level increases and thus do not often have very high MELD scores. So, they're a little bit, I think, disadvantaged in the MELD scoring system for liver allocation. So, we, too, see that in Chicago, where patients with PBC who need liver transplantation can languish on the list a little bit and it makes finding an organ for them more challenging.
David Victor III, MD: I think, for me, one of the real important pieces in why I'm here today is to make sure that we are optimizing the therapy for everyone that can be treated for PBC. I would like to transplant no one for PBC because of the challenges we have. I think that's why there needs to be continued inertia in identifying and maximizing therapy for these patients.
Transcript edited for clarity