Activity Transcript

Chapter 1: Overview of PBC and Its Pathophysiology

Gideon Hirschfield, MB BChir, PhD, FRCP (Lon): Hello. My name is Dr Gideon Hirschfield. I'm a professor of medicine at the University of Toronto, and I direct the Autoimmune Liver Disease Program at the Toronto Center for Liver Disease in Toronto, Ontario. Welcome to this Medscape program titled, "Exploring Data on Emerging Treatments for Primary Biliary Cholangitis." Over the next 30 minutes or so, myself and my colleagues, Dr Marlyn Mayo and Dr Kris Kowdley, will be discussing the exciting topic of emerging treatments in primary biliary cholangitis (PBC), with a particular focus on peroxisome proliferator-activated receptor (PPAR) agonists. I will be getting us started in Chapter 1 with an overview of PBC pathophysiology and therapeutic targets. Then in Chapter 2, Dr Mayo will review clinical data to date on PPAR agonists in PBC. Finally, for Chapter 3, Dr Kowdley will take a closer look at some other therapies under investigation.

Let's start with some background on primary biliary cholangitis -- formerly, of course, known as primary biliary cirrhosis. We'll then look at some of the specific targets for emerging therapies we'll be reviewing in the chapters that follow.

So, I'm sure you're all aware that PBC is the classical and archetypal autoimmune cholestatic liver disease. It's female predominant, 90% of our patients are women, and the onset of disease is in the middle age. It is a common rare disease. Maximum incidence is around 5.8 per 100,000. And of course, it's characterized by antimitochondrial antibodies and a very selective destruction of the intrahepatic cholangiocytes. It's chronic, lifelong, progressive, and frequently symptomatic. And there are many features that suggest it's a mixture of genes and environment as to the etiology of disease for our patients. The first-line treatment is effective but not effective for everyone; that is, ursodiol or ursodeoxycholic acid (UDCA), given in a weight-based manner, usually divided in 2 doses. However, up to 40% of the patients that come to our clinic do not achieve a sufficient biochemical response to UDCA therapy after 1 year.

Because of this, we are very keen to develop second-line treatments. And obeticholic acid (OCA) was FDA approved in 2016 as a second-line treatment. UDCA is well tolerated. We all know that OCA, whilst beneficial, can be associated with exacerbation of pruritus. Furthermore, in May 2021, the FDA adjusted the product label for OCA, such that those patients with cirrhosis and evidence of portal hypertension should not receive obeticholic acid. Therefore, there continues to be a need for new therapies that both improve liver biochemistry and improve symptoms.

Now, the targets that we've focused on in the development of drugs for PBC are selective and very rational. Obeticholic acid is a farnesoid X receptor (FXR) agonist, regulating intrahepatic bile acid homeostasis, reducing inflammation, and reducing fibrosis. The topic we are going to talk about a lot today is PPAR agonists. They regulate bile acid pools, reduce inflammation, and reduce fibrosis. And, of course, we would like to develop antifibrotic agents that may work, in effect, on fibrosis or on chemotaxis and inhibit oxidative stress. And that's really where the current efforts lie: to go beyond ursodeoxycholic acid into the future of PBC therapeutics.

And what that means is that there are a number of drugs approved or under evaluation for PBC, making PBC a very exciting field. I talked about first-line therapy, second-line therapy obeticholic acid, but you are going to hear a lot more about PPAR agonists, fibric acid derivatives, fibroblast growth factor-19 (FGF-19) pathway agonists, the potential for immunomodulation still exists, and NADPH oxidase (NOX) inhibitors, and bile acid transporter inhibitors.

When we think about current clinical development for PPAR-targeted therapies in PBC, what we can see is the off-label use of fenofibrate and bezafibrate with, also, further development in clinical trials. And the fenofibrates are PPAR agonists, alpha-agonists; bezafibrate is a pan-PPAR agonist. Then there are a number of new agents -- elafibranor, seladelpar, and saroglitazar -- and they target the PPAR pathway in different ways. Elafibranor, PPAR-alpha and PPAR-delta; seladelpar, PPAR-delta; and saroglitazar, PPAR-alpha and PPAR-gamma. And they are in phase 3 development, some of the studies ongoing but fully recruited. Therefore, very exciting times in the next couple of years.

There are other therapeutic targets in PBC of course, which are also equally exciting, which I hope you look forward to hearing about. The NADPH oxidases, the NOX enzymes, are overproduced in conditions of excessive oxidative stress, and there is a clinical trial of setanaxib going into phase 2 to phase 3. Ileal bile acid transport (IBAT) inhibitors are under development; they're already approved for treatment in pediatric liver disease. And these block the reabsorption of bile acids, which may reduce pruritus in patients with PBC. And there is a whole theme of drug development around pruritus and cholestasis and IBAT inhibitors. And then, of course, there is always the potential for new FXR agonists.

So, in closing, I hope you can see that this is a very exciting time to be a patient with PBC and in the field of PBC therapeutics. And in the next chapter, my colleague, Dr Marlyn Mayo, will take a closer look for you at the clinical data for PPAR agonists that explains our excitement about the future treatment of PBC. So, I thank you for listening.

Chapter 2: PPAR Agonists in PBC Treatment

Marlyn J. Mayo, MD: Hello, I'm Dr Marlyn Mayo, and I'm a professor of internal medicine at UT Southwestern Medical Center in Dallas, Texas. And in this section I'm going to discuss some of the recent clinical data for PPAR agonists for the treatment of PBC.

Fibrates are potent PPAR agonists, and bezafibrate and fenofibrate are used in parts of Asia and Europe to treat PBC, but bezafibrate's not available in the US and fenofibrate is off-label for use in PBC in the US. One of the largest trials to date was the BEZURSO study that evaluated bezafibrate. It was a phase 3, randomized controlled trial, a multicenter [study] in Europe. They enrolled patients who had inadequate biochemical response to ursodeoxycholic acid. They enrolled 100 patients, and they were randomized to either 400 mg daily of bezafibrate or placebo.

This slide shows you the results. They found normalization of alkaline phosphatase after 24 months in 67% of patients vs just 2% of those in the placebo arm. If you look at the graph on the right, this is the percentage of patients that had a complete response, which was defined as not only normal alkaline phosphatase but normal transaminases, normal bilirubin, normal albumin, and normal prothrombin time index. So, there's very strict criteria, but even then you can see that 30%, 31% of patients on bezafibrate met this endpoint after 2 years. This did not happen in the placebo group. It was well tolerated. The most common adverse events they had were myalgia, which was present in 20% of patients vs 10% of the placebo patients, and mild increases in serum creatinine, about 5% overall.

There are also non-fibrate PPAR agonists, and there are 3 that are currently in development for PBC: seladelpar, elafibranor, and saroglitazar. Each targets a slightly different set of PPAR receptors, but they all appear to be beneficial in the clinical trials of PBC. Seladelpar, as the name implies, is a selective PPAR-delta agonist. Elafibranor is a dual PPAR-alpha and -delta agonist. And saroglitazar binds to PPAR-alpha and PPAR-gamma agonist.

For seladelpar, they completed a phase 2 study but found that they had some grade 3 increases in transaminases with the 50 mg to 200 mg dosages, but they did have excellent improvement [in] alkaline phosphatase. Then, they proceeded to a phase 3 study using lower doses of 5 mg and 10 mg. And that phase 3 study met its biochemical endpoint. I'll show you that data in a few slides.

For elafibranor, they've also completed a phase 2 study and found significant reductions in alkaline phosphatase, bilirubin, and other disease markers. Their phase 3 trial is ongoing. Saroglitazar has completed their phase 2 clinical trial and found significant reductions in alkaline phosphatase and other disease markers. This was a 16-week trial, and they are currently recruiting for their phase 2b/3 randomized controlled trial.

For the seladelpar phase 3 trial, they enrolled patients with PBC who did not respond to first-line treatment and then they were randomized to seladelpar 10 mg or 5 mg -- with the option to uptitrate to 10 mg if they were tolerating well and needed additional response and were not cirrhotic -- vs placebo. Their primary endpoint was the same composite endpoint that the FDA used to give conditional approval to obeticholic acid, which was reduction of the alkaline phosphatase to within 1.6 times the upper limit of normal, with at least a 15% decrease from baseline and a bilirubin that was within the normal range.

This primary composite endpoint was achieved by 78% of patients in the 10 mg arm, 57% in the 5 mg arm, and only 12% in the placebo arm. And if we look at alk[aline] phos[phatase] normalization, this was achieved in 27% of the 10 mg arm, 5% in the 5 mg arm, and virtually none of the placebo patients.

Seladelpar was well tolerated. The adverse events were all mild to moderate. They were particularly interested in pruritus because that had been a significant adverse event in both obeticholic acid studies, and they found that the pruritus was no more common in the treated arms and the placebo arm. They were all in the range of 3% to 13%. In fact, there was a suggestion that perhaps pruritus was actually getting better with treatment.

With the PPAR agonist, you can see that most of the patients who had itching actually improved, particularly if they had moderate or severe, very severe pruritus. If they only had mild pruritus or no pruritus, they were more likely to not notice any kind of a change with the treatment.

Moving on to elafibranor's phase 2 study, they completed a 12-week, double-blind, phase 2 study. They enrolled 45 patients with PBC who had incomplete response to ursodeoxycholic acid, and they were randomized to either 80 mg, 120 mg elafibranor, or placebo.

I should have mentioned that in all these phase 2 studies, the ursodeoxycholic acid was continued throughout the study, and their primary endpoint was the change in alkaline phosphatase at the end of the 12-week period. In this graph, you can see the reduction in alkaline phosphatase, and there is, with both 80 mg and 120 mg, a nice rapid reduction in alkaline phosphatase compared to placebo that happens within the first few weeks, first 2 weeks, and continues throughout week 12, until they stop the medication, and then there is a pretty quick rebound.

The data can be looked at in a number of ways using different biochemical thresholds that have been associated with improved prognosis. In this graph, I'm going to start in the middle. If we look for just a clinically significant reduction of alkaline phosphatase of at least 20%, you can see that that was found in over 90% of the subjects. Moving to the right, if we increase the criteria to a 40% reduction, that was still evident in around 55% to 85% of patients. If we look for complete alkaline phosphatase normalization, that occurred in the minority of patients on elafibranor, around 15% to 20%, but it was even rarer in placebo. This difference didn't meet statistical significance, but remember this was a short, 12-week study.

On the left side of the graph, we see the composite biochemical endpoints, which were achieved in significantly more patients on elafibranor as compared to placebo. An important finding for this study was that overall, 80 mg seemed to be just as good as 120 mg, so that's the dose that they selected for future studies.

Elafibranor was generally well tolerated. Most of the adverse events were just mild to moderate gastrointestinal (GI) events, some fatigue, and headache. There were no significant changes in the laboratory parameters except for some mild and reversible increase in creatinine in the 120 mg group. Remember, this is a feature of a PPAR agonist that we also saw with bezafibrate.

In the graph, you can see what happened with pruritus in the elafibranor study, and really, it was stable to improved in the vast majority of patients in this trial. But again, this is a fairly short-term study to evaluate itch, and many of the patients did not have much itch to begin with.

Lastly, I want to talk about the saroglitazar studies. They've completed a double-blind, phase 2 proof-of-concept study. They enrolled 37 patients with PBC and randomized them to 4 mg or 2 mg of saroglitazar, or placebo. Their study lasted 16 weeks, and their primary endpoint was the reduction in alkaline phosphatase at the end of the treatment period.

In panel A here, you can see the change in alkaline phosphatase from baseline, and again, you see this nice rapid improvement in alkaline phosphatase that happens right away, and then a slower but continued improvement over the treatment period. They stopped the treatment at 16 weeks and didn't provide the rebound data. In panel B, this shows you the percent of people at each time point that reached the composite endpoint, that same one that was used to approve obeticholic acid, of alk[aline] phos[phatase] less than 1.67 times the upper limit of normal with at least a 15% reduction and normal bilirubin. You can see that really, at almost every time point, they had an excellent number of patients who met that biochemical response, around 70%, vs 10% or less of the placebo patients.

In panel C, you can also see that they had good improvements in gamma glutamyl transferase (GGT), which is another marker that has been linked to prognosis. The bilirubins in panel D fluctuated. There is a lot more variability in the bilirubin, but most of the bilirubins are in the normal range to begin with, so that makes it a difficult parameter to show any kind of improvement.

With saroglitazar, they measured pruritus on the itch domain of the PBC-40 questionnaire. What they found was really minimal change, 1- to 2-point drops across the board, including placebo, but there was no worsening. Again, in this study, low prevalence of baseline itch, which limits their ability to detect any kind of itch signal.

Most of the adverse events with saroglitazar were mild to moderate. They had 2 serious adverse events in the 2 mg group, which seemed to be unrelated, appendicitis and peripheral edema, and dyspnea. They had 4 patients that discontinued the study drug due to elevated liver enzymes. But those elevated enzymes are resolved within 3 months. They are currently recruiting now for their phase 2b/3 study.

In conclusion, the PPAR agonists are really showing promise for the treatment of PBC in patients who fail to achieve a complete response with first-line therapy using ursodeoxycholic acid. We are seeing really impressive reductions in alkaline phosphatase, including even normalization of alkaline phosphatase in many of the patients that are treated with PPAR agonists. This is a magnitude of response that we really have not seen before in this population.

Furthermore, we're not seeing any increase in itch, and the data that were collected in the phase 2 studies suggest that perhaps even these drugs may be improving itch. I think we're going to see in the phase 3 studies that they are going to focus on itch as an important endpoint, and hopefully we're going to get more data so that we can definitively say if these PPAR agonists improve itch in PBC patients. They are generally well-tolerated drugs. We do see some signal for increasing transaminases when the doses are very high, but these drugs appear to be potent enough that we can give small amounts, small milligram dosages, and avoid that potential adverse event. Currently, seladelpar, elafibranor, and saroglitazar are being evaluated in phase 3 clinical trials. Hopefully we'll be getting some of that data coming out in the next few years. Maybe we can do another webinar at that point and go over the end trial data.

Then lastly, I'll want to leave you with a concept that may be where the future is going with the treatment of PBC, and that is to use combination therapy. We currently use ursodeoxycholic acid as our first-line therapy, and then, in patients who don't get a good complete biochemical response, add an FXR agonist. That's the one therapy that's approved by the FDA in the United States, but not all patients can get complete normalization. In fact, the minority of patients get normalization of alkaline phosphatase even after adding FXR agonist. That raises the possibility ... what if you gave them ursodeoxycholic acid and then added an FR agonist, and then if they had itching or if their numbers hadn't normalized, then adding a PPAR agonist on top of that?

These drugs work by different mechanisms, so it's quite possible that they could work well in combination. We didn't show it today because the data are very sparse, but there are some very small case series using this approach that appear to be promising that their effects may be additive, but that needs to be evaluated in clinical trials.

Overall, this is a really exciting time for development of treatments in PBC. We have a lot of excellent options on the horizon, and I really look forward to seeing what's going to happen in the future with this.

In the last section, Dr Kris Kowdley will discuss a few other emerging therapeutic targets in PBC. Thank you for your attention.

Chapter 3: Other Emerging Targeted Therapies in PBC

Kris V. Kowdley, MD, FACP, FACG, AGAF, FAASLD: Hello, I'm Dr Kris Kowdley. I'm director at Liver Institute Northwest and a professor at the Elson S. Floyd College of Medicine at Washington State University. In the last chapter of this program, I'm going to review several other emerging therapy targets in PBC.

So, drugs approved or under evaluation for treatment of PBC are shown on this slide. You are already familiar with ursodeoxycholic acid, which has been approved as first-line therapy since 1999, and second-line therapy with obeticholic acid has been in place since approved in 2016. In the previous chapter, Dr Mayo reviewed the PPAR agonists, in particular elafibranor and seladelpar, which are currently in phase 3 trials. Fibric acid derivatives such as bezafibrate and fenofibrate are being used off-label in several countries.

What I'd like to focus on here are some new and emerging therapies such as the IBAT inhibitors, NOX inhibitors, and some non-bile acid FXR agonists, which are also being examined as treatment for PBC. So, tropifexor was studied in a phase 2 study for PBC. Tropifexor is a novel non-bile acid FXR agonist. And in this study, which was just published in Journal Hepatology Reports, or JHEP Reports, 61 patients with PBC who had an inadequate response to UDCA were randomized to receive 30, 60, 90, or 150 μg or placebo orally, once daily for 28 days. The endpoints evaluated included the effect of tropifexor on cholestatic markers and safety. And, in fact, tropifexor was effective in terms of both alkaline phosphatase reduction and reduction in gamma-GT when compared from baseline to day 84.

Most commonly reported adverse events were pruritus, which were noted to be grade 1 or grade 2, and these appeared to be dose related, highest in the 150 μg group. One patient in the placebo group and 3 patients in the tropifexor 150 μg group, had grade 3 pruritus. Interestingly, significant decreases in low-density lipoprotein (LDL), high-density lipoprotein (HDL), and total cholesterol were observed during the 28-day treatment period.

Now, linerixibat is part of a group of compounds called IBAT inhibitors, or ileal bile acid transport inhibitors, and these drugs block enterohepatic circulation of bile acids. Linerixibat is a minimally absorbed oral small molecule IBAT inhibitor. And current data suggest that linerixibat improves cholestatic pruritus, and as a consequence, improved sleep and fatigue in a phase 2a study.

A phase 2b study was conducted in 147 patients with PBC, with mild to moderate pruritus with a numerical rating scale (NRS) score of greater than or equal to 4. Patients were treated in a 4-week, single-blind placebo period, followed by a 4-to-1 randomization to placebo or linerixibat at doses ranging from 20 to 180 mg once a day, or 40 or 90 mg twice a day. And linerixibat was associated with a significant dose-dependent reduction in itch in the per-protocol population, but interestingly not in the primary ITT, or intent-to-treat, analysis. The most common adverse events with linerixibat were diarrhea and abdominal pain. [Fifteen] patients discontinued treatment due to diarrhea or abdominal pain; that is 10 patients and 5 patients, respectively. But you could see, there is a significant reduction in the highest dose group and in the intermediate dose groups, in terms of itch score, compared to baseline with linerixibat at the higher doses.

Now, there is a phase 3 linerixibat study called GLISTEN, currently ongoing. This is a 2-part, parallel design, placebo-controlled phase 3 study evaluating the safety and efficacy of linerixibat for treatment of cholestatic pruritus in PBC. Patients receive 40 mg BID (twice daily) or a placebo for 8 months, and the primary outcome is change from baseline in monthly itch scores over 24 weeks, using a numerical rating scale. Volixibat, another IBAT inhibitor is also being studied in patients with PBC and pruritus. This study is called VANTAGE. This is a randomized, placebo-controlled, phase 2 trial, and it is currently enrolling patients. Volixibat is being studied at a dose of 20 mg, 80 mg, or placebo twice a day, and the primary outcome is mean change in daily itch score using an adult-reported outcome.

Other novel therapies are being studied for PBC, for example NOX1/4 inhibitors. They are a class of compound that is currently in trials. NADPH oxidase is involved in the production of reactive oxygen species and is expressed in collagen-producing hepatic stellate cells, and NOX1/4 inhibitors reduce fibrosis in mice and block collagen production, resulting in a reduction in transforming growth factor-beta (TGF-β).

A 24-week, placebo-controlled, phase 2 trial was conducted in patients with PBC and inadequate response to UDCA with setanaxib, a NOX1/4 inhibitor. Setanaxib was studied at doses of 400 mg once a day, 400 mg twice a day, or a placebo, and an interim analysis conducted at 6 weeks showed a GGT reduction of 7% in the placebo group, 12% in the 400 mg once-a-day group, and 23% in the 400 mg twice-a-day group. And there was a 29% reduction in GGT in the 400 mg twice-a-day group in patients who had higher levels of baseline GGT, more than 2.5 times the upper limit of normal compared with only 8% in placebo. So NOX1/4 inhibition may be a promising therapy and warrants further study.

Several other agents have also been studied in PBC. Continuing to examine the FXR/FGF-19 axis, an FGF-19 analogue, aldafermin, was studied for PBC in a 28-day study and showed significant reduction in alkaline phosphatase compared to placebo in 45 patients. Other compounds that have been examined include immunomodulators. So far, the results have been disappointing, and in particular, there remains significant unmet need to address the vexing symptom of fatigue in PBC, which is often what our patients are most concerned about.

So, in conclusion, several novel PPAR agonists show promise for the treatment of PBC in patients who fail first-line therapy. These are generally well tolerated and have the potential to improve pruritus, unlike the FXR agonists, which may frequently worsen pruritus. And, for example, seladelpar and elafibranor are currently being studied in phase 3 clinical trials, and other agents with PPAR agonist activities, such as saroglitazar, are also under active investigation.

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This transcript has been edited for style and clarity.