Hello, my name is David Assise and I'm an adult hepatologist with a clinical and research interest in autoimmune liver diseases. I practice at Yale School of Medicine. I'm here today with my colleague, Dr. Craig Lambert, who is also an adult hepatologist with an interest in autoimmune liver diseases and who practices at Indiana University. Dr. Lambert is also the vice chair for the cholestatic and autoimmune liver disease SIG at the AASLD and the executive director for Autoimmune Hepatitis Association. We are here to discuss new treatment paradigms in primary biliary cholangitis, or PBC, as part of the New Treatment Paradigm video series for the AASLD. The treatment of PBC has evolved substantially over the last decade. The recent back-to-back FDA approval of two new second-line agents for challenging PBC patients introduces a rapidly moving treatment paradigm for gastroenterologists and hepatologists. Therefore, our goals today are to discuss the treatment landscape of PBC with new second-line agents, Elifibranor and Celadelpar. We'll be discussing the clinical approach to prescribing PPAR agonists for patients with incomplete response to ursodiol or UDCA. We'll be discussing the approach to modifying existing second-line therapy regimens that may benefit from PPAR agonist therapy. And then we'll conclude with a discussion of special populations and other relevant considerations. Why don't we get started with a discussion of a real-world case, and for this I'll turn it over to Craig. Thank you, David. We'll start with this 53-year-old black female with a past medical history of hypothyroidism, and she is referred by her primary care physician with a finding of abnormal liver tests for the past two years. She complains of progressive fatigue and intermittent nighttime itch that has dramatically reduced her quality of life over the past six months. Labs that are collected at the liver office reveal an AST of 54, ALT of 62. Her alkaline phosphatase, or ALP, is 296. Total bilirubin 1.0, hemoglobin, and platelet count are both normal. Her anti-mitochondrial antibody has a positive titer of 1 to 80. Her smooth muscle antibody is negative, and on a subsequent liver biopsy that's completed, we see primarily a lymphocytic predominant infiltrate with portal hepatitis and granulomatous destruction of bile ducts. Now even without a biopsy, this patient has met the criteria to establish a diagnosis of primary biliary cholangitis. And just as a reminder, PBC is a chronic cholestatic disease with a progressive course that often extends over many years, and the rate of disease progression can vary greatly among individuals. More patients are even being recognized at earlier stages of disease. The reassuring thing is patients do respond well to medical therapy, yet this disease is clearly increasing in prevalence. There are still many areas of unmet needs, one of these being optimal treatment. So on this slide, I want to realize that we, hepatologists, are still using 2018 PBC Guideline Statement from ASLD, as well as a published update from 2021 to help steer the management of PBC patients. But let's be very clear, we have two key goals. Prevent disease progression in these patients, and attempt to ameliorate the substantial burden of disease-related symptoms. Modifying treatment remains very important, and ursodioxycholic acid, or UDCA, was the first and only drug approved by the FDA for the treatment of PBC in the U.S. until 2016. And there is numerous data that show UDCA not only improves biochemical indices, but delays histologic progression and improves survival without transplantation. Accordingly, UDCA remains the initial drug of choice for PBC at the dose of 13 to 15 milligrams per kilogram per day. To define biochemical response in UDCA, we assess lab values after 12 months, focusing on ALKFOS and bilirubin values in a number of binary as well as continuous models now. One such model shown here, the Toronto Criteria, was founded on disease progression assessed by paired liver biopsies over time. This actually set the stage for the POIS criteria, a commonly used primary outcome in many clinical trials in PBC today, which we'll talk about later. POIS is currently defined as reaching alkaline phosphatase at less than 1.67 times upper limit normal, with a 15% reduction in alkaline phosphatase from baseline and a normal bilirubin at one year. And unfortunately, despite UDCA's impact on PBC globally, still 40% of PBC patients just don't meet biochemical remission criteria, thus they remain at risk of disease progression. So let's return to our case. Treatment with UDCA was initiated at dose-appropriate amounts, and our patient had good tolerance and compliance. Alkaline phosphatase levels at six months, as you can see, were 265, and by 12 months was 278. Because she was a non-responder, according to Toronto Criteria, she was in subsequent place on the first FDA-approved medication beyond UDCA for non-responders or those intolerant to UDCA as well, specifically abetacolic acid, or OCA. In 2016, the landscape changed for patients not exhibiting any biochemical remission. This is when OCA received its conditional approval for PBC treatment in those patients with poor response or intolerance. And just as a reminder, OCA is a semi-synthetic hydrophobic bile acid that acts as an agonist for farnesoid X receptor, or FXR. This is a nuclear bile acid receptor. It's thought that FXR activity may regulate bile acid activity as well as triglyceride synthesis, possibly fibrosis as well, and maybe other metabolic pathways. In a very critical 2016 study, the POIS trial, OCA was administered to UDCA as a monotherapy or as monotherapy for 12 months in patients with poor response or those with intolerance. The findings are highlighted here on the left side of this bar graph. OCA treatment resulted in decreases from baseline ALKFOS and total bilirubin set differed significantly from placebo that are identified there with the white bars. Further in follow-up, real-world studies that are seen here on the right side from patients from the POIS trial as well as its open-label extension versus real-world non-OCA taking controls both from the UK PBC group and the global PBC group showed patients were statistically different and that OCA patients had significantly greater transplant-free survival than these comparable external control patients that were not taking OCA. Yet we should take a step back and consider the road for OCA. It's been a little bit bumpy. It's been clear that OCA can exacerbate pruritus, which in the eyes of PBC patients is really not advantageous at all. And this is exemplified by the observation that nearly half of patients stopping OCA in the first year of therapy is typically related to itch. Even more concerningly, in May of 2021, OCA was given a black box warning regarding its use in advanced cirrhosis. Further, more data has revealed that between 50 and 70% of patients with poor response to UDCA are not rescued and even more fail to normalize their liver tests as well. Another issue is in June 2024, the European Medicines Agency Human Medicines Committee concluded with its review of OCA and has recommended that the medicines marketing authorization be revoked because its benefits may be no longer outweighing its potential risks. Now, we don't know currently where this will go in Europe nor what its pathway will be like here in the US, but these disease-related shortcomings had set the stage for a new line of other therapeutics, specifically peroxisome proliferator activated receptor agonism or PPARs as seen here on the next page. PPARs are nuclear receptors that were first identified and cloned in 1990, and they were found to have a key role in the regulation of transcription of genes involved in everything from inflammation, carcinogens, metabolic pathways, and after binding to the ligands, PPARs interact with specific DNA sequences, thus regulating target genes. There are three different isotypes of PPARs that are relevant for today, PPAR alpha, delta, and gamma, each of them encoded by different genes and characterized by specific tissue allocation and actions. For instance, agonism of all subunits may help mitigate inflammatory pathways, and yet delta and alpha may directly impact cholestasis and lipid metabolism, for instance. The first use of the pan-PPAR agonist benzofibrate in PBC patients was reported in Japan in 1999. This study was performed by Iwasaki, and encouraging results from the Benzero trial subsequent to this in 2018 led to a 24-month double-blind placebo-controlled base-3 trial where multiple centers across France that included 100 patients who had inadequate response to UDCA were randomized to receive benzofibrate at 400 milligrams by mouth per day, or placebo. The primary outcome being normal serum levels of ALKFOS, AST, ALT, total bilirubin, as well as a normal prothrombin index, was actually observed in 31% of the patients assigned to benzofibrate and 0% in placebo, as you can see here from the bar graph. Now in this same study, there was a small drug-induced liver injury signal that was observed as there was an increase in aminotransferase levels more than five times upper limit normal range that were reported in three patients in the benzofibrate group. There was also a moderate asymptomatic rhabdomyolysis that developed at three months in one patient in the benzofibrate group, too, and this is relevant because we saw myalgias were reported in approximately 20% of the benzofibrate group as well. The one that developed rhabdomyolysis was actually concurrently receiving statin-based therapy. So phenofibrate is a tenfold more specific alpha PPAR isoform rather than the gamma and further different from benzofibrate as it is only currently available in the U.S. Now benefits of add-on off-label therapy with phenofibrate and PBC emerged from several small cohort-based studies, as well as a large monocentric retrospective studied by Chung et al. in 2015, where we saw 41% of treatment arm patients meeting the primary endpoint. In 2021, the PBC guideline update reconciled that fibrates could be considered as off-label alternatives for patients with PBC in inadequate response to UDCA, although fibrates were discouraged in patients with decompensated liver disease. And really the success of PPAR agonism in PBC has heralded other non-fibrate PPAR agents as well. Specifically here, elefibrinol, PPAR delta, and some alpha subunit agonism was granted accelerated approval recently in June. And similarly, celadelpar, a PPAR delta agonist, in August of this year. And maybe Dr. Assiz can tell us more about the studies that led to both of these agents' approval. Happy to do it, Craig. Thank you very much. So building on the studies that Craig had discussed, we're excited to report and review with you some of the studies that led to the accelerated approval for elefibrinol and celadelpar. Let's start with elefibrinol. In a study that was published in the New England Journal in February of 2024, you can see on the graph to the left that, borrowing on the POIS criteria to indicate response to therapy in PBC, that patients who received elefibrinol compared to placebo had a significantly higher response by POIS criteria, with 51% of those patients receiving elefibrinol having response compared to 4% of those on placebo. You can also see on the upper right-hand corner that normalization of alkaline phosphatase increasingly seemed to be a goal in PBC, was found in 15% of patients receiving elefibrinol and zero in those on placebo. Furthermore, you can see on the graph to the bottom right that the percentage change in alkaline phosphatase was very rapid and very robust, detectable and clearly significant already by four weeks. Similarly, celadelpar was studied and published in the Phase III Pivotal Trial in the same issue of the New England Journal in 2024, and you can see the results of the primary endpoint on the left. Biochemical response by POIS criteria was identified in 61.7% of those receiving celadelpar compared to 20% of those receiving placebo. Furthermore, full normalization of alkaline phosphatase occurred in 25% of patients on celadelpar compared to zero in placebo. And on the graph to the right, you can see a similar early, robust and sustained improvement in the serum alkaline phosphatase level in patients receiving celadelpar. This then, as Craig had mentioned, led to the accelerated approval for elefibrinol on June 10th of 2024 with an indicated dosing of 80 milligrams once daily. And on August 14th of 2024, accelerated approval for celadelpar with a dosing of 10 milligrams once daily. I should highlight then that these drugs were both approved based on accelerated pathway, which does require ongoing confirmatory studies using real-world harder endpoints. Therefore, these studies are continuing in real-world settings that are necessary for the confirmatory approval as per FDA guidelines. If we return then to our patient who had received then, perhaps two years ago, therapy with UDCA, which Craig had reviewed and then started beta-colic acid, let's check in to see how this patient is doing. And perhaps similar to some cases around the country that you or your colleagues may have been dealing with, you can see that after one year of concurrent therapy with UDCA and beta-colic acid, the alkaline phosphatase had some further reduction compared to the pre-therapy values. However, it did not reduce to less than 1.6 times upper normal, much less normalization. And furthermore, this patient now on a beta-colic acid for up to a year started to experience mild and progressively more moderate degrees of pruritus that has been requiring increasing antipyretic medications, including hydroxyzine. And this leads us to perhaps a discussion of some additional key properties of the PPAR agonist, which we think will be highly beneficial to patients as well as, of course, to clinicians. We should start by then reviewing the Fitch study, which was published out of a multicenter study in Netherlands in gastroenterology in 2021 publication date. You can see that this study included patients with cholestatic itch. And on the graph to the left, you can see here that the primary endpoint, which is a greater than or at least a 50% reduction of pruritus by visual analog scale was found in 45% of patients who received Bezafibrate for about 21 days compared to only 11% of patients in placebo. You can see that the subgroup of patients who had PBC was up to 55%, indicating a clearly statistically significant improvement in pruritus. And you can see in the middle graph that after discontinuation, pruritus did worsen again to baseline levels. Therefore, there's a strong effect on pruritus in those who received Bezafibrate. Furthermore, you probably know from your clinical practice of patients with cholestasis and PBC that although alkaline phosphatase is not a completely accurate biomarker of pruritus, patients with worsening cholestasis often have worsening itch. You can see in the graph all the way to the right that Bezafibrate significantly reduced alkaline phosphatase, and this had a correlation with improvement in pruritus by the visual analog scale. This key study really suggested through a rigorous randomized controlled trial that PPAR agonisms have the potential to have an impact for the better on pruritus in patients with PBC. Let's review then the data for pruritus modification in the two pivotal studies that were published earlier this year in the New England Journal. Well, you can see that for Elafribinor, while there was some reduction in the degree of moderate to severe pruritus by least squares means change in the worst itch NRS scale, this score did not achieve statistical significance from comparing baseline to week 24 or from baseline through week 52. By contrast, the study of Seladelpar from the New England Journal article in which there was a slight difference in methodology, but the patients with a baseline pruritus of NRS score were about least four, the least squares mean difference was minus 1.5 points, and this did achieve statistical significance at six months, which was the pre-specified secondary endpoint. Furthermore, one interesting feature of the Seladelpar study was that there was a measurement of serum interleukin-31 or IL-31 levels in these patients, data which we will not have time to review today, indicates some emerging data that IL-31 might be one key marker and perhaps even participate in the pathophysiology of cholestatic itch, and as you can see in the graph to the right on the bottom, that there was a reduction in IL-31 levels in patients who received Seladelpar. Whether this indicates an ultimate difference in the improvement in pruritus between these two drugs, we should first caution that this was not a head-to-head study, and so there is further need to understand the impact of different PPAR agonists in regards to pruritus amelioration. However, as a drug category, I think it is very fair to say that there is big promise not only for the improvement in cholestatic markers, which led to the clear accelerated approval, but also the expectation of improvement in pruritus, which is of course a very important aspect from quality of life that patients and clinicians can share together. So this is in part the reason for our enthusiasm as to the paradigm shift in the treatment of patients with PBC. What we'd like to do next then is just conclude with a few discussion points about special populations and other relevant considerations for clinicians out there that might be eager to get started with therapy with PPAR agonism for their patients with PBC. We'll first start with two topics that often come up in the clinic about the questions of potential impact of these drugs on fatigue or in patients with more advanced liver disease, and I'll pass it over to Craig for this discussion. Thank you, David. These are both very important questions, specifically the first question being at the minds of every PBC patient that I see in clinic. As we know, fatigue is considered to be one of the most frequent and debilitating symptoms in PBC, affecting over 50% of patients, and one in five patients, as we all know, may suffer from severe fatigue, which really dramatically impairs quality of life. Unfortunately, in these phase three studies, a direct swipe at fatigue was not necessarily made, despite some of the messages about pruritus, as Dr. Assise has highlighted for us. So I wanted to steer our direction more about a published study in 2021 by Dr. Kramer and friends that reported the effects of Celadelpar treatment over a one-year, open-label, uncontrolled phase two study on patient-reported measures of pruritus fatigue and other metrics of quality of life. Really, what we saw was that this improvement of PBC 40 fatigue scores was observed in 50% of patients treated. Now, this was 55% and 64% in kind of a low and higher dose group of Celadelpar, and after one year of Celadelpar treatment, PBC 40 scores were reduced in three times more patients than increased in the higher dose group. Now, other important phenomena here is that the correlation between pruritus, the visual analog score, and the PBC 40 domain was quite significant, indicating that actually itch may continue to be contributing to fatigue in PBC patients, and this may be one mechanism that these new agents may dramatically improve fatigue. More data and more study is certainly warranted. Now, in regards to drugs and these being utilized in decompensated cirrhosis, the bottom line is it's not considered safe, and I think we need to step back to think about the label, and what we've seen is, in the elifibrinol studies, patients have been excluded if they had other liver disease or decompensated cirrhosis, and in Celadelpar, patients were excluded from trial if they had other chronic liver disease, but also clinically important hepatic decompensation, including portal hypertension and or cirrhosis with complications, including a MELD score of 12 or more. Therefore, these labels both suggest elifibrinol and Celadelpar are not recommended in patients who have or develop decompensated cirrhosis, thus including child class B or C patients, and one last point about this, David, is that as we monitor these patients with cirrhosis that are using these agents, if there is evidence of decompensation, as clinicians, we should take very great care to consider the discontinuation of these medications moving forward, particularly as they move into maybe severe hepatic impairment. Which brings up other important questions, and again, paramount to the population as whole, particularly a large percentage of patients being within the realm of childbearing age, what about pregnancy and breastfeeding, David? It's a good question, Craig, thank you. I will highlight and perhaps direct our viewers to the actual label, of course, for these recently approved medications. There are some differences in how the labels are written up. I can tell you as somebody who has prescribed off-label phenofibrate for a number of years for my patients as second-line therapy for PBC, for a subset of those patients, the question of safety and pregnancy and breastfeeding does come up, so it is relevant. We know that the label for phenofibrate, for example, indicates that the benefits of this therapy really need to be thought through and must outweigh the potential harms, although they're poorly defined for women who are becoming pregnant as well as breastfeeding, as there is a potential impact on lipid-altering effects of the drug on the fetus as well as the newborn. Therefore, it's worth examining and being mindful of how the labels address these topics in the case of our new PPAR-approved agonists. The label for elefibrinol says that based on findings from animal reproduction studies, elefibrinol may cause fetal harm when administered during pregnancy, and you can see there that there's a specific note that for females of reproduction potential that one is encouraged to verify that the patient is not pregnant prior to initiation of therapy and that non-hormonal contraceptives or barium method should be added for the duration of therapy and certainly discontinued three weeks before the last dose. Celadelpar has a little bit more of a lack of granularity in terms of advice, but highlighting that there is insufficient data on the human pregnancies exposed to celadelpar, which really does not allow for an assessment. I think that both Craig and myself would defer to the basic scientists as to the ultimate data in this regard, but it's worth highlighting that PPAR agonists in other settings including phenofibrate are often thought to be potentially harmful. Therefore, I think it's a note of caution that our patients should be mindful of, and in my routine practice, I often ask patients to abstain from these drugs until after they're finished with lactation. What I'll pass on to Craig next is obviously a very important discussion about drug interactions and monitoring for adverse effects as our clinicians and colleagues around the country and around the world get more familiarized with these two new drugs. Absolutely, David. In terms of interactions, there's a number of things that we should consider when we think about the PPAR classification, particularly the first line highlighting the co-administration with hormonal contraceptives may actually reduce systemic exposure to estradiol and progesterone or any other CYP3A4 substrates, which obviously compared to what you just highlighted with us regarding pregnancy risk is critically important. As you'll find in the label that hormonal contraceptives use, we should have females consider switching to an effective non-hormonal contraceptive or add a barrier method when considering hormonal contraceptives and really for at least three weeks after the last dose of the PPAR utilized. Other interactions, particularly in Celadelpar, it's also noted to avoid concomitant use of strong CYP2C9 inhibitors as well. Now, these are but not limited to amiodarone and fluconazole, but also 3A4 inhibitors such as clarithromycin, ketoconazole, and protease inhibitors. Beyond this, you know, co-administration of things that we also use in this patient class, particularly for pruritus, namely rifampin, may reduce systemic exposure of PPAR agonists and therefore may culminate in reduced effects or efficacy in this patient population. Then finally, another really important point and story that's come out of the works of study, we've seen that myalgias have been present in some of the clinical trials to date, but also a risk of true myopathy has been reported, and particularly may be increased when these drugs are co-administered to HMG-CoA reductase inhibitors, specifically statins. And therefore, moving to this next point, that there is a monitoring of adverse effects that's probably warranted from the clinical setting. And as of right now, when we look at the label, monitoring for myalgia myopathy prior to elefibrinol's initiation is critical with periodic assessment, potentially asking about myalgias, but also then taking an extra step in checking the CPK during treatment, especially, again, with those that have signs and symptoms, or if they have worsening pain or myopathy as well. Now, David, we've highlighted PPARs, and again, they do seem to have some efficacy in terms of helping to rescue some of our at-risk PBC patients. But I've also noted from our tables, we don't see that everybody responds to PPAR agonists. What does the future hold for those patients that still have that unmet need? Thanks, Greg. It's a great question. Building on what you had reviewed earlier, if up to 40% of patients will not have a complete response to UDCA, which of course sets up the need for second-line therapy, which we're reviewing today with the new paradigm. But if you go back to the phase three studies that were published in the New England Journal, likewise, Boyce criteria were met in up to 50% to 60% of patients who received PPAR agonist therapy, depending on the study, and normalization was found in 15% to 25%. You can just therefore assume that there still is a lingering subpopulation that is not deriving sufficient benefit from PPAR agonism. This brings us to just a peek into potentially future avenues to deal with this problem. You can see here in this one study from about three years ago, that triple therapy is now actively being evaluated. Triple therapy entailing, therefore, UDCA, PPAR agonists, as well as beta-cholic acid. You can see in this one study, again, a multi-center data collection and analysis, that the triple therapy was more successful than baseline dual therapy in achieving alkaline phosphatase reduction, as well as normalization. If you look at the bar graph to the right, you can see that this also had an incremental but substantial benefit for removing pruritus from the quality of life of these patients. Therefore, while not really ready for a full indication, I would stay tuned for this potential avenue for patients who do not have sufficient response to PPAR agonist therapy. Craig, how about the moving goalposts of how stringent to get when treating patients with PBC overall, whether with first-line or second-line therapy? Great question, David. We may be finding that PBC is getting in line with other liver diseases, specifically hepatitis B, or maybe even autoimmune hepatitis for that, that maybe lower is better. In fact, when we look at some data that's been recently published from a few years ago from a patient cohort from the Global PBC Study Group that comprises of long-term follow-up data from both European and North American centers, this figure here highlights that alkaline phosphatase normalization was actually optimal in terms of overall survival. And the data suggests that 10-year survival rates were about 93% in patients with alkaline phosphatase less than one times the upper limit normal, whereas it was only 86% in those patients with alkaline phosphatase meeting Toronto, but were between 1 and 1.67 times upper limit normal. As you can see on the next slide, there may even be a step down in looking at the bilirubin threshold as well. And the authors actually concluded that the bilirubin that actually could predict the best overall outcomes in regards to need for liver transplant or death at one year was 0.6 times the upper limit normal total bilirubin. And in fact, what we see here from these different quartiles is that the 10-year survival rates of patients with the bilirubin of less than 0.6 times upper limit normal and those greater than 0.6 times upper limit normal were 91% and 79% respectively in terms of overall survival, and it's quite statistically significant. So therefore, we've really kind of highlighted that bilirubin levels lower than 0.6 in alkaline phosphatase within the normal range are associated with the lowest risk of liver transplant and death in PBC patients. And I think this has really important implications, particularly as we design future clinical studies and outcome-based trials that maybe there's more room for improvement and potentially what we see as change in that dogma, time will tell. So David, we've covered a lot of information today and told the story about PPARs and the evolution, but also now the utilization of these now in clinical practice. But maybe we could stop here and you could highlight a few of the most important take-home points for our viewers today. Absolutely, happy to do it. I do think, and I know Craig agrees with me, that these do represent, these new accelerated approvals do represent a significant paradigm shift in the approach to treatment of cholestasis in PBC. Currently, they are approved for second line therapies, and you can see that based on the phase three studies that we reviewed today, there is a significant reduction in cholestatic markers and also, and particularly for siladelpar, significant reduction in pruritus, again, with the most likely class effect. So I think what we're really starting to see in the take-home here is that there is a nice union between biochemistries and the biochemical goals that clinicians have had for a number of years with the prospect and the expectation, frankly, of improvement in quality of life from these patients. This is a nice alignment of goals between the clinician and the patient that we should all take note of, and I think this is really ushering in an area of synergy that we can really aim for with our treatment of patients. I think it's important to be mindful, of course, of the special populations that we reviewed today, and experience with any new drug really is important to be familiar and to read the label carefully, but also to bear in mind that there is work still to be done, whether it is through evaluating new strategies for those who do not respond, predicting those who aren't going to respond to people or agonists, and to look for what our targets for therapy should be for biochemistries in the future. So while we know that this is an accelerated approval for these drugs, then confirmatory studies are necessary as per protocol for the regulatory agencies. This is a wonderful area of progress in the therapy of PBC, and we hope that these innovations and others can really become known to and make an impact for patients' lives all around the country and around the world. This concludes the Paradigm Treatment video series from the ASLD. Thank you for your attention, and we hope to see you again soon. Thank you.

Primary Biliary Cholangitis

autoimmune liver diseases

treatment paradigms

second-line agents

Ursodeoxycholic Acid

PPAR agonists

triple therapy

Elifibranor

Celadelpar

Ursodiol

Clinical trials

Drug interactions