This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes.

So welcome, everyone. I am Alan Bonder. I'm one of the hepatologists at Beth Israel Deaconess Medical Center in Boston. And I have the pleasure to have Dr. Stuart Gordon from Henry Ford in Detroit. Welcome, Dr. Gordon.

Today, we will talk about the gaps and unmet needs that we currently have in patients with PBC, now that we have the current second-line therapies available. So welcome, Dr. Gordon.

So let me start with a question. I think the first one that we actually how do we assess response. So how do we know if a patient who has PBC needs a second-line therapy?

Dr. Gordon: Well, it's an important question. It's kind of a loaded question, Alan, because it really sort of goes back to the beginning of PBC and - and our initial therapies. You know, we're talking a lot about urso therapy, and UDCA has been around now for close to 30 years for the treatment of PBC.

And the treatment was improvement in all cause outcomes. And we just knew that use of this agent was beneficial to improve our outcomes in our patients with PBC. We recognize that there was improvement in alkaline phosphatase, but we didn't really sort of correlate the value of alkaline phosphatase to the outcome. So we've learned a lot in recent years and especially now with the ability to use second-line agents for non-responders or incomplete responders.

The whole concept of response to urso I think has really come to the fore. So we looked at alkaline phosphatase values, but we really didn't look toward the magnitude of the response. And - and now with second-line therapies that are available, and especially with the realization that alkaline phosphatase values correlate with outcomes, we're recognizing the need to bring these values down to as low as we possibly can.

So some years ago, the value of 1.67 times upper limits of normal sort of became a cutting point. But in reality, we're looking at all values of alkaline phosphatase. We want improvement in the values on treatment. And if there's a lack of response on urso therapy, we're looking towards second-line therapy.

And so the number of 1.67 times upper limits of normal has - has generally been appreciated as - as a number below, which would - would define response as well as improvement in bilirubin as well. We've looked at composite endpoints, looking at both alkaline phosphatase and bilirubin, and a percent reduction of alkaline phosphatase. So we're really looking at a - at a variety of endpoints now to define response to urso.

And for people who are not really improving their - their - their alkaline phosphatase values on urso, I think this is a point where we need to consider second-line therapies. And unfortunately, we do have new second-line therapies and important to recognize how they work, why they work, when we should start utilizing second-line therapy.

So I think, you know, I've covered the biochemical, you know, aspects of it. What more can we add, Alan?

Dr. Bonder: So I think that kind of like answering your question, kind of the timeline is how long do you wait? You know, again, if we put a patient in front of us and you have someone who does not have an alk phos below the 1.67 of the threshold is, do you wait six months or you wait 12 months? Is there any other tools? I think you mentioned the bilirubin. Is there any other tools that you use in clinic to kind of risk stratify those patients that will need a second-line therapy sooner rather than later?

Dr. Gordon: Yeah. You know, currently our AASLD guidelines are telling us to wait 12 months after the onset of treatment to define what is really a response. But I think most of us who deal with this condition recognize that if there is to be a response, it's generally going to be within the first six to nine months of therapy. And so I think it's reasonable to consider a second-line therapy as early as six months after initiating urso therapy if there's not a meaningful response, because we really want to bring these numbers down sooner rather than later.

Dr. Bonder: So is - Dr. Gordon, do you use a lot of liver stiffness as a kind of surrogate marker of response, or as a tool to try to get patients into a second-line therapy sooner rather than later? Is that something that you would recommend using?

Dr. Gordon: We - we use the FibroScan, the liver stiffness, the elastography scores at the outset in lieu of liver biopsies to try to assess their histologic severity. And - and probably those patients who have more severe fibrosis or stiffness would be at a higher priority for treatment and for second-line therapy. Yes, we recognize that this isn't available all around the country, but assessing degree of fibrosis, not just at the outset but during therapy is really key because ultimately this is going to be our goal is to improve fibrosis histology.

So yes, we do look at it. How about you? Are you looking at it in your institution as well?

Dr. Bonder: Yeah. I mean, this is like a vital sign in any liver clinics, right? So any patient who comes in with PBC or even elevated liver tests, we do elastographies and liver stiffness to really kind of, in a way, risk stratify those patients to see if they need kind of a sooner therapy. Again, if you look at the data that we've looked at before, is elastography, around 9.6 puts you at higher risk of having kind of poor liver-related outcomes.

So again, you mentioned the six months. I think you're right. In a patient with an elevation of alk phos or even a mild elevation alk phos, but that elastography showing a result of close to 9.6 or higher, I wouldn't wait the 12 months, I wouldn't wait 24 months. We would try to get those patients really sooner into therapy, because we know that they already have progressed and they have fibrosis, and we don't want those patients who have any really poor liver-related outcomes, meaning death or complications or needing a liver transplant.

So when we look at gaps, Dr. Gordon, we looked at, for example, symptoms. You know, I - I think it's a well-known fact that physicians don't do a really good job about asking about symptoms. In your practice, how do you assess for symptoms? Is - is there any tools that you use to make you aware, or you or your staff about treating or managing symptoms and quality of life in patients with PBC?

Dr. Gordon: Well, it's an important question. And of course, the cardinal symptom that's been associated with this disease right from the outset has been itching. And I've always been impressed by how often patients have not been asked those three words, do you itch? And when it comes up in the clinic setting, you'll often see their eyes light up. Why do you ask? No one has ever really asked them about their itching.

And - and when you probe deeper, you find out that it's often apparent even when they don't think that it's apparent. We'll ask, do you use a back scratcher? Do you itch more than your partner, etc.? And indeed, I think a lot of people have sort of masked or covered up their symptoms. It can be any part of their body at any time of the day, often worse at night.

But we've recently implemented an itch survey type of a question for our PBC patients, so that they're asked at the outset before the visit how much they itch, sort of 5-D itch survey to try to glean, you know, how much do they itch, you know, has this been brought up at the - at the appointment? Because frequently in a - in a brief appointment there's so much to review. You know, there's the - there's the labs, there's the quality of life issues. How are you doing?

But, you know, there's so many extrahepatic manifestations of hepatitis C that we're trying to think. Dry eyes, dry mouth, you know. How's your energy, etc. and looking for thyroid type issues. So there's so many different type questions that I think frequently the main question about itching often gets overlooked. And what we found is - is indeed a lot of these patients have more pruritus than they really care to admit. And when you probe a little bit deeper, it's there.

So I think, you know, among the many symptoms to bring up in the clinic setting, it would be the degree of pruritus. And so we're trying to make it a little bit more formal, especially as we'll talk about now that there's potential treatments available to address the itch issue.

Dr. Bonder: And I think you bring up a good like point, right. For example, the tools that we have in clinics to try to take this information out of patients, because sometimes, you know, the itching or the pruritus comes with stigma. I mean, personally, that's what I've seen. And again, with the stigma, you know, patients don't want to talk about symptoms. One, because they are afraid about, you know, maybe they have some kind of infectious process, some contagious process. But two is we never really talked in detail that we have really good therapies available.

And then again, it's kind of the thought that if you don't talk about it, you know it - you know - or you don't - if you can't talk about it, you won't be treated it. So I think, you know, as healthcare providers and physicians, we really need to do a better job about asking. And I think the tools like the 5-D itch. So I think making this subjective symptoms more objective in clinic makes a huge difference to trying to - trying to get that information out of our patients.

Again, if you looked at data that we actually published, is up to 60%, 70% of patients really tell, you know, in their surveys that, you know, we don't even ask about those symptoms and quality of life. So I think right now is I think those tools are available. We have a bunch of questionnaires, we have a bunch of tools that we can use. But even just reminding ourselves that we have to ask about this kind of symptoms is so important in patients with PBC.

The other thing that comes up a lot, and I just don't know if that really comes up in your clinic is, well, I have itching, I have PBC and my hepatologist, gastroenterologist said, “Well, UDCA or urso will actually take care of the problem.” I mean, we know that UDCA does not treat itching. So I don't know if in your experience, you've seen a lot of those responses.

So, is - again, a gap about how to manage symptoms, right? So now we - we have the - you know, the question is do we have symptoms? And the answer is yes. So well that second part of that question is how do you manage those symptoms? Do you have an idea? Do you have an algorithm? Do you have some type of medications that you prefer to use? Or now with the second-line therapies, is there any patient profile that you would like to use one versus the other one? So I…

Dr. Gordon: Yeah. Yeah. No, these are all issues that I think about on a daily basis with my patients. And you brought up the stigma issue. And that's really true because I've had patients who cover their arms because they don't want people to be seeing the scratch marks on their arms. A lot of people don't even consider it an itch. It's really more of a bugs crawling or a neuropathic type of a symptom where they really can't get to the itch because the more they rub it or scratch it, the more - the worse it gets.

So it's really, I think, a little different than an itch. It's worse. I had a patient who thought that her dogs had fleas because she felt crawling up and down her legs at night. So it's been described as - as ants crawling, and it's sort of difficult to sort out all the different constellation of symptoms. So there is the itch, which affects the quality of life, which affects the sleep. But actually, as they've looked in some of the more recent studies about quality of life issues, some of these are independent.

So the fatigue is sometimes overwhelming with liver disease in general, but in particular with PBC, I don't specifically use medications to treat the - the fatigue itself. I'll talk about caffeinated coffee, etc. But getting back to the urso, it was never really designed to treat the pruritus, which is of course been an enigma for - for half a century now. So we don't really expect the urso to treat the itch. It's not designed to do so.

Some people respond, but there's actually, I believe, some literature where some people get a little worse on the urso. So it's not sort of designed for the - for the itching. And it really gets to the whole issue of what do we use, you know, I mean, is it antihistaminic agents? But it's really not an allergic or histamine related itch. So it just sort of makes them a little bit sleepy.

And then you get to the whole gamut of - of agents that have been used, you know, from sertraline to rifampin. And I've used a few of them, some with success, but always with a little bit of trepidation because it's - it’s always somewhat off label, and we don't want to get in trouble with some of these different agents, you know, in terms of toxicity.

So we try to incorporate the itch into the questionnaire, also talk about their quality of life and their fatigue level, and try to make it on a more systematic basis. I think I've sort of covered a lot of the issues. Maybe you have a couple of pointers to add there?

Dr. Bonder: Yeah. I mean, I think the other thing is when we talk about second-line therapy and biochemical response is, you know, is there any ballpark of percentage of patients, do you know, they don't respond to what the first-line therapy was UB, UDCA? What - what's your personal experience in that?

Dr. Gordon: You know, I don't find that people are responding to UDCA. I've - I’ve used rifampin. I think now that we have additional second-line therapies that are out there, both of which have shown improvement in the pruritus score, it’s time for us to sort of move into the next arena here of offering some of these.

Now people are agonists that have shown to improve itch as well as improve biochemical response. So I think we're sort of entering into a new era here, which is very exciting.

There's of course, other agents now that are in development for the treatment of - of strictly the cholestatic itch. But I think that - that the traditional second-line agents that we've been using for many years are now pretty much out the door now that we have agents that are going to be specifically addressing the unique cholestatic itch.

Dr. Bonder: So if I can really kind of put it all together, a patient with PBC who has, for example, pretty normal liver function tests, including an alk phos, but their itching is pretty bad. Have you seen the PPAR is basically as or any other new approved second-line therapies work for itch regardless of - of their liver enzymes?

Dr. Gordon: I have, and it's really very gratifying to suddenly have people say, you know, the itch is actually getting better. And we see that in the literature but when you actually see it in the clinic setting and see improvement in their itch scores, it's really very gratifying. You know, it's one thing to watch their alkaline phosphatase values come down, and that's important as well. But to see people have improvement in quality of life and in particular in their pruritus is - is - is very real and it's very gratifying. How about you?

Dr. Bonder: I would say the same thing. Again, I think right now as this is kind of like a one year later when those medications got approved. So I think we are basically between the payers and us trying to see if, you know, even with normal function tests, we know that the biochemical response does not correlate with symptoms. So I mean, that's really an important kind of message to send to providers that sometimes we do have patients with normal liver tests and their itching is up to the roof.

And then we also have the other way when the alk phos is really high and they actually don't itch and don't have fatigue. So kind of the message is symptoms and quality of life don't get along with the biochemical response. So I think it's so important again just assessing those problems even if your normal liver function - if you have normal liver function tests. But I think…

Dr. Gordon: I couldn't agree with you more. That's so important. We - I just saw one just like that a couple of weeks ago. Her alkaline phosphatase had returned down, but she was still miserable with her itching. And so this presents some unique challenges here in the clinic setting.

Dr. Bonder: Yeah. I mean - and again, one of the big kind of things right now is how do we get everyone to understand about kind of the second-line therapies? I think there's another gap that we have out there, which is basically understanding what the new approved second-line therapies. We only on to one year since they got approved in the US and they're getting approved through the world. But you know, I think one of the other really kind of problems that I see in the community, really, physicians, GI - even some kind of, I would say, general hepatologists don't feel comfortable prescribing this new medication.

So I don't know if you've actually seen this. But again, I think basically in an academic centers, we are more aware about the studies, but we should basically communicate to the people in the community that this medications are very safe. Both PPARs are safe. They don't have a lot of drug-drug interactions. They really kind of like don't really cause them a lot of side effects. And they are very, very effective treating both symptoms and actually the disease activity.

So again, personally, I just want to express that to everyone who's listening to this podcast because it's so important to actually just spread the message around there. So I don't know if you want to just send any other messages about.

Dr. Gordon: No, I really - I would agree with you entirely. This sort of hearkens back to the hepatitis C era, where we - we had new agents that were out there, but a lot of the primary cares and, you know, GPs and APPs were - were sort of reluctant to take this on their own, whereas now it's sort of, you know, common knowledge that anybody can treat hepatitis C. These agents are - are so safe and effective.

And I think it's true with anything new. But we've been so fortunate with these new agents, the PPARs, both biochemically in terms of rapidly dropping the alkaline phosphatase and witnessing improvement biochemically, but also improvement in - in - in pruritus, which is really remarkable in our careers to finally have a drug that was shown in a double blinded fashion to improve pruritus.

So this is a remarkable advance. Physicians are fortunate to have such a safe and effective, and usually once a day type of a pill that I would agree this is - we need to have more uptake, improvement for quality of life. And hopefully we will witness improvement that will translate to all cause outcomes as well.

Dr. Bonder: One of the key questions, another kind of gap that I see is do we - do you understand what responds in symptoms or in quality of life means? Because again, we have a pretty kind of like map about what we need to do with an elevated alk phos and elevated bilirubin and elevated liver stiffness. What do we do with those symptoms were so subjective? Do you have any kind of like expert opinion on how to manage that and how to consider the response based on your symptoms, or how do we actually address them once we start a second-line therapy in patients with having really poor quality of life?

Dr. Gordon: You know, I think a lot of us rely on the clinical trials wherein these patients completed, you know, very extensive quality of life type measures. Realistically, it's difficult in the usual clinic setting for people to be completing extensive quality of life type questionnaires apart from clinical trials, assessing itch is - is doable and I think should be done.

I think a lot of us are relying on - on gestalt of talking to the patient. How do you feel? You know, because sometimes it's - it's somewhat subjective. But what I've been witnessing on patients on these newer therapies is that they are, you know, improving their itch and to an extent, quality of life as well. They've been very pleased to be put on this second-line therapy and are pleased to see their numbers coming down as well.

So I don't think we are using formal quality of life type measures, but I think you know it when you see it. And so, you know, that's been my experience. Tell me about yours.

Dr. Bonder: Again, I think, you know, I - I mirror what you just said. I think in clinic I've had substantial amount of people getting into second-line therapies for poor biochemical response. And I see the biochemical response really mimicking what the clinical trials did. So you see that drop in the alk phos four, five weeks into treatment and they do pretty well.

And as far as symptoms again, I actually again mirror what the trials did. So I see improvement in their mild to moderate itching. Again, I see a lot of people now maybe getting better with the fatigue, specifically in one of those second-line therapies. So I know two second-line therapies. One is maybe better for one and one is the other one for the other types of symptoms. But again, what I've seen personally is both - you know, both symptoms really do respond to this type of therapy.

So again sending the message that we need to ask about the symptoms and we need to really take care of them. Because even if the biochemical response is there, we need to basically improve quality of life, which should be. And one of those our goals in the next couple foreseeing near future in patients with PBC.

Dr. Gordon: Right. I would also sort of mentioned the normalization of alkaline phosphatase. I don't think we specifically addressed that, but we're actually witnessing these numbers coming down, down, down. And as we look at long-term outcomes in some of these clinical trials, normalization should be our ultimate goal. It's not always possible when people start off with very high values. But the improvement of symptoms, yes. But also, you know, the ultimate goal of normalization of alkaline phosphatase.

Dr. Bonder: Yeah. So I think one of the also the kind of gaps is in our guidance is we don't - we don't aim for normal. So I think instead of the 1.67 should - our monitor should be normalized, should be completely normal in the future, Dr. Gordon?

Dr. Gordon: Yeah. No, I think this 1.67 in my opinion is - is always been somewhat arbitrary. It even again goes back to the hepatitis C days where normalization of enzymes was the goal. But we're really sort of aiming to improve the overall disease. So I mean, I think that normalization of alkaline phosphatase should clearly be our goal. And hopefully with longer term therapy that can be achieved in more patients. But yes, I think the lower the better.

Dr. Bonder: So kind of like kind of the last question. If you want to summarize what the second-line therapies have done to your PBC practice in the last couple of months, what would you say to people who are treating PBC now they have this new two medications available?

Dr. Gordon: I think this is really very exciting times for gastroenterologists, for hepatologists, for the internists, for the APPs who are managing these patients. First of all, I would sort of back up and say, make the diagnosis. You know, I mean, make the diagnosis. Any abnormal alkaline phosphatase needs to be pursued. We see this in women, but we're increasingly seeing it in men. We see it in all races. And I think that there's a gap in terms of understanding, making the diagnosis in the first place, ordering the mitochondrial antibody, just simple type stuff. It varies making the diagnosis.

But then once we have these patients to follow their alkaline phosphatase, this has sort of become a key parameter here. There was a lot of interest in ALT value some years ago. Know your ALT. This is knowing your alkaline phosphatase value, looking at the value. There may be a little variation in race and ethnicity in terms of what's upper limits of normal.

Interestingly, we saw that Asians have generally lower values than - than other races. So I think there may be some racial ethnic variations. But know the alkaline phosphatase. And - and really, when you have these PBC patients who are not responding with improvement in their alkaline phosphatase, be aware of these second-line therapies, which are fortunately very safe and effective. And - and now, as you say, FDA approved and easily available.

So I would take advantage of these newer drugs and - and offer them to our patients who are in need.

Dr. Bonder: So my, I would say, summary or conclusion is I think I'm looking forward using more of the second-line therapies. What I'm actually looking for is I would call it personalization of PBC therapy. So I think you and me talk about symptoms and elevated alk phos. But we need to find the right patient that fits for treating, you know, with the right drug. So again right now with the current available therapies, we can try to basically fit this kind of therapy to meet this specific patient criteria.

So I think for the future, if we can personalize medicine, personalization of PBC therapy for symptoms, quality of life and as well as disease activity should be our goal. And again, the next goal should be is we should be aiming normal. So our new normal should be normal for the future. And hopefully our guidelines will actually state that in the near future. So we can basically convince payers and convince every different providers that even if you have an elevated alk phos, you know, you will have better outcomes if you have normal liver tests and a good quality of life.

So I just want to end up our conversation saying, thank you so much, Dr. Gordon, for, you know, being with us and discussing about kind of the new second-line therapies and gaps in PBC therapy and hope we can just meet again to have another chat.

Dr. Gordon: Thank you, Dr. Bonder. This has been a lot of fun and I've enjoyed it as well. Thank you.