Progress in PBC: Seladelpar in Trial as Second-Line Therapy

Dr Gideon Hirschfield from the University of Toronto Centre for Liver Disease discusses the potential of new drugs, including selective PPAR agents such as seladelpar, for the treatment of primary biliary cholangitis.

Gideon Hirschfield, MD, is the Lily and Terry Horner chair in autoimmune liver disease research at the University of Toronto Centre for Liver Disease in Toronto, Ontario, Canada. 

TRANSCRIPT:

Any views and opinions expressed are those of the authors and/or participants, and do not necessarily reflect the views, policy, or position of the Gastroenterology Learning Network or HMP Global, its employees, and affiliates.

Welcome to this podcast from the Gastroenterology Learning Network. I'm your moderator, Rebecca Mashaw. And I'm very pleased today to have with us Dr. Gideon Hirschfield, the Lily and Terry Horner chair in Autoimmune Liver Disease Research at the Toronto Centre for Liver Disease, which is part of the University of Toronto.

Thank you very much for joining us today, Dr. Hirschfield.

Dr. Gideon Hirschfield:

It's a great pleasure to be here. Thank you for asking me to chat to you today.

GLN:

So, let's start off with the basics about primary biliary cholangitis, which is our topic for today. How prevalent is this condition? Are there certain populations that are at a higher risk? And what's the prognosis for people with PBC? Let's just get a few basics.

Dr. Gideon Hirschfield:

I think that's a great question. So, I think of it as a common rare disease. Around about 3 per 100,000 people per year get diagnosed with PBC. An easier way to remember how many people are living with PBC is to think that 1 in 1000 women over the age of 40 live with PBC, and most of our patients are living with PBC for many decades. So, it's not as infrequent as people think. It's autoimmune. It's predominantly woman, but we see it all over the world and in all heritages. So, everyone will come across it. And in fact, most PBC is looked after by community gastroenterologists, not by hepatologists.

GLN:

And why is that?

Dr. Gideon Hirschfield:

Because that's where it's diagnosed, and making a diagnosis of PBC is relatively straightforward. Our patients present with or without symptoms, with elevated liver tests, in particular, alkaline phosphatase. You diagnose PBC largely without a liver biopsy by doing something known, the antimitochondrial antibody test. So, our diagnosis is relatively straightforward, and these patients are being referred to GI first before hepatology with abnormal liver tests. And it's part of the standard workup to make the diagnosis. And then, it's because for a large majority of patients with PBC, care remains ambulatory, remains in the clinic, so it's a really perfect disease for office-based practice.

GLN:

I see. What led you and your team to investigate the potential of this new medication, seladelpar?

Dr. Gideon Hirschfield:

We're very keen to make sure that everyone living with PBC gets the best treatment. For many decades, the only treatment was a drug called ursodeoxycholic acid, which you give in gram quantities, and which kind of soothes the liver. Then in 2016, there was a conditionally approved drug called obeticholic acid became relevant for the second-line management of PBC. And that was a step forward. And you give that drug to patients who don't do well enough on ursodeoxycholic acid or who are intolerant of it. And we define well enough based on your blood tests. So in essence, if your blood tests don't get beneath a certain level, the alk phosphatase's high, then you're eligible for second-line treatment. Obeticholic acid was a step forward, but it's not the most potent, and it does have a side effect burden, in particular pruritus.

The new drugs that are being developed are drugs that target, in particular, something called the PPAR pathway, which are nuclear receptors, which are important in controlling bile acid turnover and bile acid metabolism. And seladelpar is a particularly interesting molecule because it's a selective PPAR-delta. It's a delpar. So this drug is very particularly agonistic against the PPAR-delta nuclear receptor. These receptors are found in hepatocytes, and stellate cells, and biliary epithelium. So the question arises, does this drug, given in milligram quantities, really improve blood tests in patients with PBC? And by that, does it improve cholestasis? And by that, does it improve response to treatment when ursodeoxycholic acid is not enough?

And so the purpose of this study was to look further at the effect of seladelpar against placebo in patients with PBC, whose treatment is considered to be insufficient because their blood tests start off abnormal despite the first-line treatment. And then the question arose, how effective is it? To measure effectiveness, we're able to look at blood tests, symptoms and, of course, safety.

GLN:

So, what did you find out in the course of the study? What kind of results did you get?

Dr. Gideon Hirschfield:

So, it's exciting because it's nice to see for a common rare disease that there's hope for new drugs for patients because what we saw that 3 three months of treatment with seladelpar, selective PPAR-delta agonist, patients had significant improvement in their liver tests and in their serum biochemistry.

So, the first thing we can say is that placebo was not very good, and if you stayed on placebo, there's hardly any change. If you took 10 milligrams of seladelpar, by 3 months of treatment, there was a response, as defined by a drop in alkaline phosphatase beneath a certain threshold, of 80% of patients were responders. One in 3 patients nearly had a normal alkaline phosphatase. More to the point, on top of that, not only was there biochemical improvement in the disease control compared to placebo, so 1 in 3 normalized the alkaline phosphatase, 8 out of 10 met the primary endpoint, which is a composite biochemical response of alkaline phosphatase, but there was also an improvement in pruritus.

For anyone who looks after patients with PBC, they'll know that symptoms are very important. In PBC, itch is one of the symptoms that we really do think is very important and is really significant burden for our patients. And seladelpar not only improved liver biochemistry but also improved pruritus. This is also relevant because the current second-line therapy actually can make itch worse.

So, all in all, the participants and all my coinvestigators and the sponsor were very excited by the results to demonstrate biochemical efficacy and an efficacy signal on symptoms.

GLN:

You mentioned that women are more likely to present with this condition. What's the division in population? How many women to men develop this autoimmune illness?

Dr. Gideon Hirschfield:

It's a great question. So, on average, it's about 9 women for 1 man. There are some data with it that we aren't diagnosing more men, but it really is fascinating. You do not see this disease until a woman is post-pubertal, and you then see women over their entire life. Average age is closer to 40 to 50 to diagnose, and 90% of patients tend to be female. You also see that if a woman gets the disease younger, they get a more potent version of the disease. And indeed the younger patients are the ones were most keen to develop second-line therapies such as seladelpar.

GLN:

So the therapeutic armamentarium against this illness has been pretty shallow to this point. Does this represent a real step forward in treatment?

Dr. Gideon Hirschfield:

Well, we hope so. So, ursodeoxycholic acid is a good drug, but at least a third of patients don't respond sufficiently to it. And it's a drug that we're giving gram quantities because we don't really know how it works. Obeticholic acid was definitely a step forward because it showed people that we could develop second-line therapies for PBC, but the biochemical efficacy is not optimal, and there's a pruritus burden. So the new drugs in phase 3, and seladelpar is a good example of the new drugs in phase 3, are a step forward, do represent something to be excited about because we're moving into the era of treating this disease with drugs that are very potent, are small tablets taken once daily, which are highly efficacious, where the majority of people see a significant improvement in their blood test. And on top of that, there's an improvement in their quality of life. So we do predict that drugs such as seladelpar, such as will follow from this study, which will then have to be replicated in the ongoing sort of approval study, will be really a big step forward, and will represent a drug that community gastroenterologists feel at ease using not only because it's simple but because it's effective.

GLN:

Is this drug oral? Is it an infusion, an injection? How's it administered?

Dr. Gideon Hirschfield:

No, no, this is an oral therapy. This is easier. Our goal is to prevent end-stage liver disease and prevent cirrhosis. Drugs such as this, which will improve liver tests, which are taken orally every day, suppress potently and sustainably the liver injury. If we do that, our prediction and everything we know about PBC is that... our prediction is that we will stop this disease progressing. Patients will have better liver tests, some will normalize their tests, better quality of life and, most importantly, will never develop cirrhosis. That's our goal.

GLN:

So, that was going to be my next question. What's the prognosis for those with PBC both without treatment and with treatment?

Dr. Gideon Hirschfield:

Well, it's changed a lot. Before ursodeoxycholic acid, most of the patients were developing cirrhosis and getting liver failure. Ursodeoxycholic acid came along, and remains first-line treatment because everyone benefits, and there's a significant improvement and reduction in progression to cirrhosis. Second-line treatment such as this will have to prove that, but it takes a long time to do that. But it's our expectation that second-line therapies such as this that improve liver tests significantly will have a major impact on development of cirrhosis. Already with first and second-line treatments, that's urso and OCA, already rates of liver transplantation are going down for PBC.

But the other reason this is so exciting is that liver transplantation as an endpoint is somewhat arbitrary because there's usually an age cutoff, whereas our patients are now living into their 80s and 90s because that's normal life expectancy now. We really want to be offering them very simple oral therapies that are very potent and effective, so that their PBC's never an issue even if it's in their 80s.

GLN:

So let's talk about safety. Does seladelpar have any kind of risks that the community gastroenterologist needs to be aware of? And how does that balance with the benefits?

Dr. Gideon Hirschfield:

Well, at present, the answer is it looks very safe. These are early days. This was a 3-month study. There's been long-term safety for many years now in some of the other studies of seladelpar, and there's an ongoing phase 3 with a long-term safety extension as well, which is ongoing. To date, this drug appears to have no significant safety concerns that the community GI would need and, in addition, would be monitored for in the standard of care, which is to do blood tests routinely anyway in the evaluation of patients with PBC.

Now, clearly we are talking about patients who've not got liver failure. We don't have the data on the safety for patients with liver failure, but that wouldn't be where you'd be looking to derive any benefit from a drug like this. So, the whole point of drugs like this is to use it to prevent end-stage liver disease. There were patients with cirrhosis in this study, and there was nothing to suggest that there was any added adverse events. So, I'd say, as an investigator, we're comfortable and confident that this drug, as with other drugs in development, has an appropriate safety signal and will be a drug that the community can use without concern.

We're always very attentive to detail, as are the sponsors, for safety, and it's continually evaluated in an ongoing manner. But nothing worries us at present, and there's no specific safety monitoring being recommended to my knowledge.

GLN:

And as you mentioned earlier, not only does it not exacerbate the itching, but it appears to help relieve that symptom as well. Correct?

Dr. Gideon Hirschfield:

Yes, and symptoms are very important to our patients with PBC. We hope that this is the first of many new drugs that will improve symptoms. And those symptom complexes that are important to our patients are pruritus, which is itch, fatigue, abdominal discomfort, not sleeping so well. We hope to be able to see that there's an improvement in sleep if people are not itching at night, and that that then translates to less fatigue during the day. So, all in, this is good drug discovery and good natural history of how you get better as you try harder when you learn how to treat diseases effectively.

GLN:

It's interesting because, typically, you think about itching as not a major deal. You might itch with a mosquito bite. But we're talking about major pruritus that is a serious quality of life issue.

Dr. Gideon Hirschfield:

Cholestatic itch is miserable. You're itching your hands and feet. Feels like ants under your skin. You itch at night, so you don't sleep, so you're tired during the day. People don't understand it because they can't see any bites, so they wonder why you're itching. It's hard to explain. So, without doubt, pruritus is one of the more miserable symptoms in liver disease, in particular, PBC, which is a bile duct disease. We think that it's something to do with the cholestasis, the liver injury, and then something locally around nerve fibers and release of some cytokines.

And it's interesting. I just got back from the European Association for the Study of Liver Disease in Vienna, and there was a nice set of data from this trial, actually, where they showed that a cytokine called IL-31 went down when you gave patients seladelpar. It went down in association with the itch going down. So, it's nice to start to piece together the biology, albeit when we've already shown that it's an anti-itch effect in the study.

GLN:

But it may have clarified why these patients itch so badly. You may have the catalyst there.

Dr. Gideon Hirschfield:

I hope so. Unfortunately or fortunately, it just proved to be a really complex symptom to understand. So, I wouldn't like to say that we're at the end of the story.

GLN:

Exactly.

Dr. Gideon Hirschfield:

But I would like to say that the fact that the story is starting to have more chapters and more pages, and that there's evidence that there's an association between seladelpar efficacy biochemically and itch on IL-31, which is a cytokine that we recognize to be involved in the itch process, I think, is very interesting. I wouldn't like to know. We don't know yet whether it's specific to this drug or it's specific to the pathways. And that's something that there's going to be ongoing research for.

GLN:

Well, and that leads to my next question, that is do you have additional research planned on this subject and using this drug in additional studies?

Dr. Gideon Hirschfield:

For sure. This is a drug that's in phase 3, that's fully recruited, to my knowledge, where that's hoping to be the registration trial. Pleasingly, patients who are getting the drug in the trial are staying on the drug in the long-term safety extension, so that over many years, the idea is that you can show that this change in biochemistry and symptoms actually translates to living longer. So, it's not just your blood test getting better, but actually your life is longer. There's a lot going on in the PBC field at the moment, and this is one of the drugs that's in phase three where there's going to be new information.

GLN:

Is this trial multinational? Is it taking place in Canada, and the US, and perhaps even other nations as well?

Dr. Gideon Hirschfield:

Oh, for sure. Yeah, for sure. The study that I've talked about today and the other phase three programs, indeed all of the phase 2 and phase 3 projects that are ongoing in PBC and related diseases are international efforts. This is a rare disease. We work closely as a community of investigators and sponsors. And this is in the US. It's in Canada. It's in Europe, et cetera, et cetera.

GLN:

Well, we'll look forward to finding out more about how this progresses. And good luck with the remainder of the trial, but it sounds like this is very promising treatment for a patient population that hasn't had many options until now.

Dr. Gideon Hirschfield:

I agree. It's never been as good to have PBC. What a strange thing to say, but it's true. There's going to be newer and better drugs, and more and more options for our patients.