Sonal Kumar, MD, MPH

Kris Kowdley, MD, FACP, FACG, AGAF, FAASLD: 

We’re comingto the end of this discussion, but I want to talk about unmet needs in PBC [primary biliary cholangitis]. What are some unmet needs? I’m going to have everyone comment, but I’m going to start with you, David.

This was a lead-in to say that transplantation for patients with PBC is an unmet need. They’re not well served by our current allocation system, and I’ve implored some of our UNOS [United Network for Organ Sharing] colleagues to consider itching in the malignant, life-altering aspect of pruritis to be something that we incentivize for transplant. Transplant is supposed to make your life longer and better, and many of these patients with recalcitrant pruritus from PBC deserve quality therapy. That’s where I see the biggest unmet need. I don’t think we do great in our transplant world. That’s a bigger question to answer. I’m hopeful that these new therapies and some of the emerging therapies may be able to treat some of our patients who aren’t candidates for obeticholic acid or second-line therapy as we try to prevent them from progressing to such a stage.

That’s a good point. There’s concern about patients who have decompensated liver disease. Obviously, they can’t receive obeticholic acid. With fibrates, there are some concerns and warnings about liver or kidney toxicity. Clearly, that’s the population where there’s a big need. I’ve had 3 patients in my career who I was able to get either prior to MELD [model for end-stage liver disease] and requiring exception points or during MELD with exception points for refractory life-threatening pruritis, 2 of whom were considering suicide. Those patients would not be eligible for exception points in this era. It’s uncommon, but it’s a huge unmet need. Ed, what do you think are the unmet needs in this disease?

Something we looked at in our clinic is ethnic disparities in PBC. We found that our Latino population who had PBC came at a much later stage of disease. Most of them have cirrhosis. David, you mentioned patients with PBC languishing in clinics. Increasing awareness of PBC and screening using the antimitochondrial antibody in certain ethnic groups or communities would be of value.

Like many things in liver disease, Kris, they’re all out of unmet needs. First, there’s an unmet need regarding the education of practitioners in how to diagnose this early. There’s an unmet need in terms of having more effective primary therapy in the first place for patients with PBC. There’s an unmet need for the treatment of the profound fatigue that some patients have with this disease. Even if they don’t have cirrhosis, it’s a major quality-of-life issue for them. There’s an unmet medical need for the pruritis. The pruritis doesn’t always correlate with the advance, with the stage of the disease. That’s also a misunderstanding. Patients can have moderate pruritis, which does affect their quality of life, but it’s not enough to need a transplant, and their liver disease isn’t so advanced. We know we could do better with therapy. So, there are a lot of unmet needs in PBC.

I agree, and your point about pruritis and symptoms not being correlated with disease severity is important to recognize. Some patients, as they start having more symptoms, are petrified, and their fatigue is getting worse. They think they need to get on a liver transplant list.

For patients with PBC, 1 of the extrahepatic manifestations is they can have very profound and aggressive osteoporosis. The guidance documents are clear that patients should have periodic bone densitometry when they have PBC. This, too, doesn’t correlate necessarily with the stage of their liver disease, and you can’t wait until patients are having spontaneous pathological fractures to identify this. The audience should also know in a patient with PBC that they are or should be recommending periodic bone densitometry to look for osteoporosis or even osteopenia.

At a minimum, your patient with PBC who comes into the office every 6 months or 1 year should have a vitamin D test with their standard labs. That’s a guidance, but it’s often not done. We added it to our standard order set for patients with cholestatic liver disease, so other providers would do it. That’s the best and easiest screening tool to identify higher-risk patients.

That’s an excellent point. Fractal vitamin deficiency isn’t necessarily seen only in patients with jaundice, so we do that routinely when we first see the patient. Sonal, you get the last word on unmet needs for education and for patients or clinicians.

I’ll piggyback on what Steve said. As physicians, we focus on normalization of the alkalis or goals of preventing and disease prevention, which are understandable and obviously important. But from a patient perspective, what affects their day to day is their quality of life. If we can improve that, in combination with these new therapies, that will prevent disease progression. That will be huge.

That’s great. That hour and a half went by fast. I appreciate the chance to share thoughts and clinical experience. Thanks to all of you for this rich and informative discussion. Before we conclude, I’d like to get some final thoughts. Everybody gets 30 seconds. Let’s start with you, Steve.

The practitioners in the audience should understand that although this is an uncommon disease, it’s not so uncommon that you won’t see it. You will, and you need to know how to diagnose it and be comfortable about the diagnosis. Be aggressive in your therapy, even in patients who are asymptomatic. Follow their fibrosis scores, and don’t forget these extrahepatic manifestations, which are more prominent than any of the others in liver disease: osteoporosis, hyperlipidemia, pruritis. Become comfortable with it, understand it, and follow the patients aggressively because you’ll help them.

Steve summed it up well. Disease awareness is a big deal in PBC. Although this is a rare disease, it’s not something you’ll see once in your lifetime or never see. It’s important for practitioners to be aware that this disease exists and recognize that it’s an exciting time for patients with PBC. We have good therapies already in existence but even more exciting therapies in development.

I agree with what everyone said. But let’s not let these patients languish in our clinics. Let’s follow that alkaline phosphatase, and let’s get that alkaline phosphatase to normal.

Having the last name Victor puts me at the end of this. Our panelists have hit on all the issues. To the providers and practitioners watching this, go through your clinic and make sure you’ve optimized the patients you have to make sure they don’t see me for transplant.

That’s very well summed up. Thank you again. To our viewing audience, I hope this 

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Experts in hepatology review the unmet needs in primary biliary cholangitis, commenting on liver transplant, ethnic disparities, management of pruritis, as well as other symptoms.

Unmet Needs in the Treatment of PBC

There are a lot of new things, like new medications in development. Seladelpar is in a phase 3 trial that’s close to enrollment. Elafibranor is in a phase 3 trial that’s close to enrollment. These are PPAR-Δ and PPAR-⍺-Δ dual agonists. Saroglitazar, which is an PPAR-⍺-γ dual agonist, is also in clinical trials. There’s a fixed-dose combination study that’s ongoing with obeticholic acid and bezafibrate. Sonal, what’s your impression about these trials? Have you been involved? What’s the future in terms of these new therapies? Are you excited about them?

We’ve been involved in some of these trials. It’s exciting…. We’re using different mechanisms of action to attack this disease. The more we learn about it and the more drugs we have in our toolbox, it’s better for patient outcomes, especially in patients who are symptomatic. If they’re not a candidate for things like obeticholic acid, PPARs are a great option for them. I’m excited to see the combo with obeticholic acid and bezafibrate. I know it’s still in phase 2 studies, though.

Thanks. Does anybody else participating in these trials want to comment on how our treatment landscape may be changing in the next few years?

We’re participating in some of the trials. The preliminary data from some of them are very impressive. Keep in mind that these studies are in patients who are failing or intolerant to ursodiol. There aren’t new studies, to my knowledge, with these emerging agents looking like primary therapies for primary biliary cholangitis [PBC]. I’d be most excited about that because it wouldn’t be a surprise if these products help patients who are the most difficult, the ones who are failing ursodiol or not having an optimal response. If they’re safe, there’s no reason to believe they wouldn’t also help ursodiol in treatment of PBC as a primary indication. We’re not looking at that yet, but I’m excited for this particular patient population, these new products.

I’m excited that there’s some excitement around PBC. I hope this unearths patients, in primary care and GI [gastrointestinal] practices, who’ve been languishing on ursodiol who we may be able to do more for. The best day of my life would be if we never did another liver transplant. I hope that, with these new agents, we’re moving that way for PBC. It’s an exciting time for a disease state that everyone knew how to treat, but we’re bringing back options and opportunities to treat them better. It’s a great time for PBC and the patients. They’ve been treated fairly, but now we have more.

That’s an excellent point, Steve, about step-up therapy. Steve and I are probably the only 2 individuals old enough to remember the old step-up vs step-down PPI [proton pump inhibitor] debates when we were fellows and doing gastroenterology: start with antacids and then go up to a PPI.

Well, you’re the only individual I can say this to.

Everybody else is the next generation. It’s interesting to think that you start with a more effective therapy, you could potentially withdraw ursodiol. This is a real issue for patients. The cost is not a trivial matter. It seems to be less of a complaint now, but a lot of my patients, especially those who are on Medicare, will have problems affording UDCA [ursodeoxycholic acid]. I encourage sponsors and individuals doing clinical trials to say you could redraw or have a monotherapy study and see what happens with these therapies.

Sonal Kumar, MD, MPH, and David Victor III, MD, provide an overview of the emerging treatments in the primary biliary cholangitis landscape, highlighting PPAR agonists and combination OCA and bezafibrate.

Emerging Treatment Options in PBC

Speaking of the stage of the disease, that brings us to an interesting discussion among the PBC [primary biliary cholangitis] circles. This is a hot topic, and Ed, you alluded to this in terms of triple therapy. So, have you used triple therapy? When would you use it? If you haven’t used it, when would you consider using it? We have fenofibrate as a guidance recommended treatment off label as well as obeticholic acid approved for second-line treatment, and there are some new agents coming around, which we’ll talk about in a minute.

I start triple therapy when their alkaline phosphatase level is still elevated, and I like to look at about 1.5 times the upper limit of normal. That’s my cutoff, especially for patients who have a high kilopascal value on FibroScan. I use all 3: ursodiol, obeticholic acid, and fenofibrate and the PPARs [peroxisome proliferator-activated receptors].

 I like following Ed because I do what he does most of the time. The only other group is patients who have some pruritus on obeticholic acid of 5 mg. I have added fenofibrate at a low dose to try to accentuate. The group that I’m not sure what to do yet with [is] the patients who are above the upper limit of normal and on 2 agents. Is there benefit as we get more data that normal alkaline phosphatase level is better? I follow the bilirubin level in those groups to decide whether I add a third line or not.

That’s an interesting approach, using fenofibrate to mitigate the itching. Steve, do you use triple therapy and in what case?

I haven’t yet. The majority of patients respond to ursodiol in the first place. I’ve had very good luck when I use OCA [obeticholic acid] in the patients who did not optimally respond to ursodiol. That’s using, as you’ve worded it, the POISE criteria: alkaline phosphatase level 1.67 or less times the upper limit of normal. I have a lot of patients with levels between the upper limit of normal range and 1.67 whom I have considered responders to dual therapy with ursodiol and OCA. I have not yet considered them nonresponders. I will in the near future as more data appear, but I haven’t had the opportunity to use triple therapy, unless there are data on bezafibrate, which we don’t have in the United States. We have fenofibrate, for which there aren’t the same type of data. So, I haven’t used it yet, but I’d be eager to hear what you’re doing.

I have not used triple therapy in many patients. But…if you have a patient who has not achieved your biochemical end point, especially if they are above 1.5 times the upper limit of normal and have low fibrosis stage, I’m probably going to be using triple therapy more. If they have advanced-stage disease, meaning if they have a liver stiffness result greater than 10 kPa or getting closer to 10 vs 8 [kPa], I’m moving in that direction. Sonal, what about you? Have you used triple therapy in routine clinical practice, and do you think that makes sense?

I haven’t in my current population. Though I think that’s the wave of the future. As we’re pushing toward normalization of alkaline phosphatase levels, there are going to be a lot more nonresponders out there who would be potentially eligible for third-line treatment. But I have not done that yet in my practice.

Kris, I have a question. In my patient population, which is in Pasadena, California, I have a large Latino population with primary biliary cholangitis. They also have a little overlap with fatty liver disease. So how do you know? Is it failure of the ursodiol or obeticholic acid that’s not causing you to get to goal, or is it a fatty liver problem because we’re not performing biopsy for these patients the majority of the time?

Kris Kowdley, MD, FACP, FACG, AGAF, FAASLD:

 It’s a good point. Obviously, along with the entire US population gaining weight and up to 40% of our population having some degree of metabolic fatty liver disease, we’re seeing that the patients with PBC are not immune from this either. If you use transient elastography, the CAP [controlled attenuation parameter] score can be helpful. If it’s over 280 [dB/m or] maybe over 260 [dB/m] and the patient has metabolic features, that’s something you might want to consider. That’s an interesting approach where you might consider triple therapy and other types of things with that. I don’t routinely do liver biopsies for patients with that as a question, but if they have aminotransferase levels that remain elevated as the alkaline phosphatase level is coming down and they have a high CAP score, that’s where you would consider that.

Hepatology experts discuss the use of triple therapy in the management of PBC as the wave of the future.

Triple Therapy in PBC

Ed, we have all the trials for second-line treatment that would require the patient to be on a stable dose of ursodiol for a year before you can consider second-line treatment. What is your practice? Do you start the patient on second-line treatment and then wait a year before you decide that they need to have fenofibrate added or something else?

It would depend on the staging of their disease. If I felt that they had a significant amount of fibrosis, especially on a FibroScan showing greater than 10 kPa, I’d probably start them on a third-line agent in this case because they’re on ursodiol or obeticholic acid, probably in 6 months.

So, 6 months for you if they have advanced-stage disease. David?

I’m similar, except there’s one other group of patients. With someone whose FibroScan value has gotten worse in a year or in a short order, I will be more apt to add a third agent or increase obeticholic acid to 10, even if they do have some mild pruritus, in hopes that you can stop the progression of disease. Though the 6-month intervals likely will be adequate moving forward, but all the data are based on a year, so that’s the standard. I am a little more aggressive in adding a second or third agent based on their stage of disease.

Same for me. As time goes on, we are becoming more aggressive and looking at changing our regimens or adding to the medical regimens earlier. Yes, the way the POISE trial was designed was somebody not responding or not having an optimal response to ursodiol after 12 months of therapy. Though when you look back at the data, we’re starting to see that you can tell at an earlier time point whether patients are or are not responding well to therapy and you don’t always have to wait 12 or more months. There are more data coming out for that.

You can tell whether obeticholic acid is working very early on, within 3 months. You don’t have to wait long periods of time to see whether these products work in primary biliary cholangitis. Keeping in mind that we really want to drive down the alkaline phosphatase and total bilirubin levels in these patients, it’s better for us to maintain an aggressive approach and shorten those time points a little when we decide to add additional therapies.

I usually wait 6 months and then start having discussions with the patient about starting second-line therapy. Sometimes we’re prohibited by insurance approval for getting access to drugs, but at the very least, I can start those discussions. This 1-year timeline has been based on a lot of these clinical trial results, but we know by 6 months whether or not a patient is going to respond to therapy.

 I’m in the same camp. There’s a paper, published in 

 from the Global PBC Study Group showing that if your alkaline phosphatase level at 6 months is greater than 1.9 times the upper limit of normal, those patients are very unlikely to reach the POISE criteria of less than 1.67. So, starting alkaline phosphatase is a good point, and then considering the stage of the disease, which is important.

Experts in hepatology comment on how long they keep a patient with PBC on first-line treatment before deciding to switch to another therapy.

Sonal Kumar, MD, MPH

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