From Lab to Life

Leveling Up PBC Podcast 1 (00:00.984)
Welcome to leveling up primary biliary cholangitis, optimizing biomarker surveillance, addressing PVC -related Pruritus and application of real -world evidence.

Leveling Up PBC Podcast 1 (00:15.608)
My name is Dr. Ahtusa Rabi. I'm joined today by two of my colleagues, Dr. Hannah Blaney, MD, MPH, Transplant Hepatology Fellow from Med Star Health, Georgetown University, as well as Dr. Anitha Rabi, MD, MHS, who is a transplant hepatologist from Digestive Disease Section, Yale School of Medicine. For full relevant financial disclosure information, please see the iridium .com landing page for this activity.

This is supported by an independent educational grant from Intercept Pharmaceutical. We would like to thank them for their support for this initiative. The learning objective for today's program are to describe factors contributing to low initiation rates of PBC therapy and strategies to address barriers to specialty care. So we realized that it's crucial to differentiate between PBC and other conditions that can present with similar symptoms, specifically conditions that

present with cholestasis. This could be extra hepatic, such as malignancy, stones, or intra -hepatics like autoimmune disease, ocular -related liver disease, drug -induced liver injury, or primary sclerosing cholangitis. Can you tell us a little bit about how best to distinguish PBC from these conditions?

Yes, so PBC is fairly straightforward to diagnose, but we do have to differentiate it from other liver disease that may present similarly. This differentiation can be done with a combination of labs and imaging. The serologic hallmark of PBC is anti -mitoprandrial antibody or AMA positivity. So first, we must consider a diagnosis of extra hepatic cholestasis, including conditions like cholelithiasis, malignancy,

or inflammatory stenosis. Typically, this can be done with imaging, including abdominal ultrasound with evidence of biliary dilation, stones, or masses confirming extra hepatic cholestasis. If an inflammatory stenosis is suspected, the clinician could consider IgG4 -mediated strictures, which can be assessed with serum IgG4. Conditions causing intrahepatic cholestasis should also be considered.

Leveling Up PBC Podcast 1 (02:35.054)
PVC can be differentiated from intra -hepatic colostasis through a solid history labs and then further imaging. So autoimmune hepatitis typically has a more hepatocellular pattern of injury with patients often having an elevated serum IgG and positive anti -smooth muscle antibodies. Alcohol associated liver disease can present with a mixed pattern of liver injury.

With a history in serology playing a key role here in the differentiation. Drug induced liver injury should be assessed with a careful review of all recent medications and over the counter supplements. In patients with an unclear diagnosis, it may be worthwhile to trend liver enzymes with expected improvement with a withdrawal of the offending medication. Primary sclerosing cholangitis can be differentiated with serology and imaging with a positive AMA supported of PBC.

and large duct stricturing on MRCP more consistent with PBC. So now let's shift our focus to comparing the traditional paradigm in treatment of PBC, as well as new treatment paradigms. Can you walk us through both paradigms and also touch on the importance of a multidisciplinary care in managing PBC complications? Absolutely.

The current paradigm is once you diagnose PBC, you start the patients on UDCA and you'll monitor and basically to determine if someone is responding to treatment or not, you'll give them a full year. And then at the end of the year, if they're not meeting the response criteria, then you kind of think about starting second line treatment options and obviously managing symptoms down the line.

However, the new paradigm is more of a personalized care. So once you diagnose the patient, you wanna look at it as kind of a whole and see what is their overall risk, how much liver fibrosis there is, what is their risk of progression, what are the symptoms they currently have, and then you start kind of modifying your treatment.

Leveling Up PBC Podcast 1 (04:53.77)
and mainly evaluation for response to treatment differently if a patient is very high risk for progression. And you try to address symptoms, quality of life and other things kind of at the same time rather than just waiting for that laboratory values at one year to decide if someone is responding or not. And in terms of the kind of multidisciplinary team approach,

know, PBC has systemic complications. So patients can have osteoporosis, osteopenia, high risk for dental infections. They can have vitamin deficiencies specifically with fat soluble vitamins or hyperlipidemia. So, you know, it is not just a disease that only affects the liver. So to be able to kind of manage all of these systemic complications.

you need a multidisciplinary team consisting of primary care physicians, endocrinologists, dentists, obviously gastroenterologists or hepatologists and dieticians. So through that, you hopefully are able to provide a more comprehensive care for these patients. So if I may summarize the current treatment landscape for PBC, as well as some potential new drugs on the horizon.

We know that UDCA is our first line of therapy approved. However, up to 40 % of patients with PVC are unresponsive. Obetalcholic acid was FDA approved in 2016 based on phase three POIS trial, which recruited 216 patients. The primary endpoint for this trial was a combination of reaching a serum level of alkaline possibilities less than 1 .67 times upper limit normal.

with a reduction from baseline greater than 15 % as well as patients with normal bilirubin. 50 % of patients treated with Obetacolic acid met response criteria when followed at months 48, 60, and 72, which support a sustained response. L -epipneuronal was just recently approved this year in June as a PPAR alpha delta agonist.

Leveling Up PBC Podcast 1 (07:13.966)
This was, as I said, very recently approved based on a phase three LVH trial, which recruited 161 patients. The primary endpoint, again, combination of reaching a serum level alkaline phosphatase less than 1 .67 times the preliminary normal with a reduction from baseline greater than 15 % and with normal bilirubium. And in this trial, 51 % of patients treated with L -fibrinole

met response criteria at big 52. There's also five rates that can be used second line therapy. They're off label. Then there are other PVC treatment in phase three clinical trials, such as P bar Delta agonies, cello del par. Now, I would like to transition from theory to practice. We'll try to apply all the data and strategies that we have discussed into real -world context, discussing a patient.

This will help us see how the principles of personalized care and timely advancement to second line treatment can actually directly impact patient outcomes in PBC management. So I want to now discuss a very specific patient with you. This is a hypothetical patient, Meet Sally. She's 55 years old. She has a history of PBC and she has been on UDCA for five years.

she comes to you to establish care, and her alkaline phosphatase on routine check is 220. Based on what we discussed, how would you approach this, Anaita? Basically, with the alkphosphate being at 200, there is concern that this patient is not responding to treatment. Although I would want to know,

how long the patient has not been responding to treatment. Is it just like a recent thing or has been on the medication responding for five years now? But basically once you see a non -response, especially someone who has been on this medication for a long time, you wanna consider switching to second line agents. And it's also important to get a sense of does she have advanced fibrosis?

Leveling Up PBC Podcast 1 (09:39.47)
which you would get that from a transient elastography or getting an MR elastography. And if advanced fibrosis is actually present, are we talking about clinically significant portal hypertension or not? And then lastly, obviously having any decompensation. apart from having advanced fibrosis or having CSPH or

clinical decompensations, if the UDCAs not working for the patient, then we are thinking about second line treatments and a betalcoic acid, again, can be started at five milligram daily and then see if the patient is tolerant. We can increase it to 10 milligram over the next three months or so, or you can consider off -label use of phenofibrate.

again, starting at about 45 milligram per day and then titrating it up based on tolerance. You wanna again reassess in about three to six months based on the alcohol and phosphatase and bilirubin levels to make sure that the patient is responding to the second line. And if the patient doesn't respond to the second line, then you could potentially switch to second line agent or even consider

referral for randomized trials or consider a triple therapy situation. I think that's a very good point that just because medication has been prescribed or as part of the medication list doesn't mean that the patient has been actually taking them. That's important to confirm compliance and it's important to make sure that the dose is appropriate for patients' weight. Those are key points to consider.

So in summary, I may, primary bularic cholangitis is a progressive autoimmune liver disease. As Anaita described, it's linked to genetic, epigenetic, environmental factors. But the diagnosis is usually established with elevation of liver enzymes as well as presence of anti -mitrochondria antibodies. Despite having criteria for diagnosis, challenges remain with poor

Leveling Up PBC Podcast 1 (12:00.982)
adherence to management guidelines, limited physician awareness and insufficient patient education, which all in all can actually impact clinical outcomes. The updated treatment paradigm emphasizes more of a personalized care to enhance patient outcomes. It is important that for those patients who do not respond or do not tolerate the first line, they will be transitioned to a bit of colic acid as a second line therapy.

And at this point, we have reached the end of this episode. I want to thank all of my colleagues for this engaging discussion. We would also like to thank you, Intercept, for their support of this program. You can claim your CME credit by filling out the evaluation and post this. And also make sure to follow Iridium on X, Facebook, LinkedIn to see the corresponding med -ed threats.