Good morning, thank you for the invitation to be here. Initially, when Cynthia called, she asked me to talk about 20 years experience, and I had a reminder that it was actually 30 years. We started writing the initial study in 1987, started enrolling patients in 1988. So it has been a long time that we've been working on erythrodeoxycholic acid for PBC. I don't have any active disclosures at this point. This began sort of with some trepidation. Ketodeoxycholic acid is used to dissolve gallstones in the 70s, but those of you who are practicing then remember that about a third of patients ended up with abnormal liver tests during that time. They tended not to be progressive, would stop, would return to normal when the drug was stopped, but caused some concern. Erythrodeoxycholic acid, there's a typo, was introduced in the mid to early 1980s for gallstone dissolution, and with some hesitancy, a group of patients with, at that time it was called chronic active hepatitis, developed gallstones in Germany, and they were given erythrodeoxycholic acid, even with the concerns about worsening liver tests, and to their surprise, the gallstones improved, and five out of the six patients had improvement in their liver biochemistries. And so this was really, I think, one of the first times I could see where erythrodeoxycholic acid was used therapeutically for patients with underlying liver disease. This was followed by a study, an important study by the Poupons published in The Lancet in 1987 in 15 patients, and this shows changes in alkaline phosphatase over two years of treatment with erythrodeoxycholic acid. Up until then, penicillamine had not been effective. We didn't really have effective therapy for PBC, so this did catch people's attention. There was sort of reminiscent of what happened a couple years ago with abetacolic acid. A cautionary note to a letter to the editor about a patient with ascites and PBC receiving erythrodeoxycholic acid and deteriorating. And at that time, we were just in the midst of starting the study and really wondered what we should do in response to this, but ended up pushing ahead, and we were able to complete the successful study. When we've looked at other effects of erythrodeoxycholic acid, I'll show you soon effects on survival, it doesn't really seem to have anything to do to help paritis, fatigue, or bone disease. It did reduce the risk of varices, and of course it has effects on cholesterol levels. These are the data that came from three large placebo-controlled trials of erythrodeoxycholic acid versus placebo. One, they used a similar formulation and similar doses, which we'll turn to in a minute, and we were able to combine the data sets from these French, Canadian, and U.S. studies with 500-some patients. And these were the data that were used to convince the FDA to approve erythrodeoxycholic acid for PBC in 1998, so that was now 20 years ago. And this showed improve in survival free of transplantation with ERSO, compared to, or UDCA, compared to the group of patients that had received placebo in two of the studies. These are some modeling studies. This looked at using the Mayo survival model as a surrogate for the untreated patient. treated patients and found really very similar results as far as long-term survival if patients were treated. Another look at this showed the important difference of trying to select patients early. So the non-sorotic patients had a life expectancy in this modeling study comparable to the general population whereas sorotic patients tended to do poorly. Now in a different data set when we looked at did ursodioxicolic acid help sorotic patients, the answer was unequivocal, yes it did. But as far as patient selection, this shows the importance of early detection and initiation of therapy because really we want to have our patients have the type of outcome shown on the left. I mentioned the dose as being important. This looked at biochemical effects of three different doses, 150 patients, three in each doses. So the dose used initially was 13 to 15 milligrams per kilogram in the combined set. Question was would less be as effective but of course less expensive or would more be better? And so this study was done and it showed that less, five to seven milligrams was not as effective. This is just again looking at now different doses with duodenal enrichment and start to see that there is a difference, a low dose isn't. Here's an example of ursonil not having any effect. This is looking at the bone disease. might help improve the bone disease. But these data show, really over time, that there wasn't any change in the bone mass in the spine. Marina showed a slide looking at the end points. When the guidelines were written last year, we couldn't really come up with a consensus amongst the writing group as to which of these should be. just as the Lammers paper suggested, is good. But there's been a lot of interest in using values of 1.67. I mentioned that ursodioxicolic acid seemed to reduce the risk of varices. These are data from the initial Mayo study, 180 patients that were treated over four years. Varices developed in 16% of patients receiving ursodioxicolic acid, but in about 3 1⁄2 times more patients receiving placebo. And other studies from Montreal suggested similar findings. The use of ursodioxicolic acid is something that we try to do to avoid this happening. This shows the risk of developing major hepatic complications over the course of time in patients with PBC. And so these are not inconsequential risks. It rises to about 20% after 15 years. These risks are less likely to occur. This is another way of showing data that Marina just showed you, that in those patients who are non-responders, the risk of adverse hepatic events is substantially higher than those patients who have a biochemical response. However, you might end up defining that. So the goal for biochemical response is, I think is fairly clear. We're hoping to achieve this type of better outcome with this. Now, when we use ursodioxicolic acid, about 30% of patients after a year or two will have continued elevations of alkaline phosphatase over twice the upper limit of normal. So that would be a group of patients that could be defined as suboptimal responders. There's several drugs. More, of course, are on the list, but I wanted to highlight these few as drugs used in combination with ursodioxicolic acid. That has, I think, become more recently the direction that the field has moved. So I think we've learned a lot about the value and role of ursodioxicolic acid, but now we start to look at, are there other things that could be used in conjunction with it? Abetacolic acid is the only approved other therapy to be used with ursodioxicolic acid, and this shows data where the value of abetacolic acid at two different doses is clear as far as alkaline phosphatase at lowered alkaline phosphatase levels compared to placebo. The higher doses maybe had more itching. We've kind of moved towards a stepped therapy where patients who are eligible and qualified and can get the drug are placed on the lower dose, and if they don't respond, a higher dose can be used. We have to be careful, of course, with abetacolic acid in using it at the usual dose if patients have evidence of substantial or marginally compensated liver disease. These are data from another modeling. This is now part of the work that's trying to be substantiated in the COBOL, the clinical trial of long-term extension of obatacolic acid. But this was probably one of the earlier estimates of what the effect size might look like. Vesifibrate, not available in the U.S., has gained a lot of attention for treatment in PBC. These are looking at changes in L-CFOS in suboptimal responders to ursodioxicolic acid. I think one of the important findings about Vesifibrate was the effect on itching. Cynthia had written a nice editorial about that. I think this is in contrast what we see with ursodioxicolic. This, again, is not approved in the U.S. Phenofibrate. meta-analysis of phenofibrate available in the U.S. Phenofibrate still can a phenotype. The typo here is a PPR Delta. short-term study. So this is another mechanism that's being explored in conjunction with with our sodioxycolic acid. And then the last I wanted to show you was a acidinidase. One of the other roles that erythrodeoxycholic acid has assumed is in the attempt to try and prevent recurrent... a paper a couple years ago that showed that preventive So, that's kind of a short or quick visit through now 30 years of experience with this interesting and effective drug for patients with PBC. Thanks for the invitation. Thanks for the attention. And when you come to the mic, please introduce yourself. Li-Ping Lu from Hightide Therapeutics. I have a question for Dr. Hui-Ping Zhu because she mentioned about the study of the bile acid using the mice model, but because mice is so different from human. So whatever we learn from the mice and how do we translate that to human, where are we in terms of humanize the mice in terms of study the bile acid signal? Thank you. Yeah, I think this is a very good question. I think this is a very challenging area for the basic research in terms of all the mouse model we are going to use. So as I know, I don't think we have really good mouse model, humanized mouse model yet, but it's really what we need to do in the future. Yeah, because the bile acid pool and the composition, which is different with human and the mouse. Yeah. Akiya Sai from Cincinnati Children's. I have a question for Dr. Linder. What was the background on using the Urso instead of Tauro-Ursocholic acid, Urso-Turica for the treatment? I think it was because it was available. Came from Dr. Falk-Farmer. They had been the suppliers for the study that the Poupons had with 15 patients, and so we had their interest, willingness to use the Urso-Ursocholic acid. Um, thank you for the question. I'm looking at Dr. Keitel who can probably answer this better than me. It's there. I can't tell you who. I think the ones with biliary tract disease, the ones I think that are, at least in my mind, I mean, those are the ones that I would argue are quite good. I mean, many of us have had examples of patients who have come to us with chelation-unresponsive Wilson disease and it ends up being ABCB4 disease, you know. So these are things that are worthwhile looking at. I just want to congratulate you on a very interesting session. My question relates to pruritus. So I've never been able to truly understand... I'll take a stab. I mean, I think it's, I mean, I think the NTCP deficient patients are an excellent example of why bile acids themselves are not the peritogen, and I think that that's quite clear, but it appears that elevated bile acid levels are synergistically with something else, whether, are involved in, are important for developing pruritus. So, but it's not strictly the bile acid by itself. There's something else that the bile acids are signaling through in conjunction with something else that a cholestatic liver makes that's the pruritogen, and I believe that's the consensus, because even autotaxin by its, on its own, may be partially involved, but also partially a marker. So, there's something, and there's some very nice work showing that there is bile acid signaling through some other G-protein-coupled receptors in the central horn, the spinal cord, and others that trigger its receptors. So, it may be acting synergistically through those receptors, but there's something else coming from the liver as well. I mean, actually, I would actually be more interested in determining whether dwell time reduces, that, you know, we think about it, it's really not just concentration there. It's how much the bile acid... how often they're there, so how long the dwell time is. So I think one would, you know, this is certainly a unique N of one or maybe there's more than one place that can do this, but the information is quite valuable along those lines. If I may ask another question about the clinical trial design, I think from Dr. Marina Silvera, you know, for PBC and ALP has to be accepted as a surrogate biomarker for a clinical trial. And for the PSC, we have been very struggling, and I think that the panel here probably can give us a pointer. We are going to see the surrogate biomarker. If ALP is not enough, what else will be? And I would really like to hear what you think, and Dr. Kislino, thank you. I think the direction that... I think one of the things that Marina said in her talk I'd like to emphasize, I agree that I think it's likely to be a combination. I was sitting behind Cyril Ponson and we had worked hard trying to come up after an endpoints conference with the FDA on defining endpoints and it was normalization of ALCFAS and improvement in either elastography or liver biopsy. I think in further discussions with them and as time has gone on, it's become clear that there probably is no single one test or even combination that's going to happen. So I think Marina's point about meeting with the agencies and EMA had the same response in Europe to talk to those agencies about what the endpoints are because the endpoints that are eventually approved will, I think, be dependent upon the mechanism of action of the drug, the target that you're seeking to change. So I think that it's probably futile for us to be spending a lot more time on trying to come up with what are the endpoints that can be used for all trials. I think that, at least right now, they're much more in the mode of come talk to us about what you're thinking about and let us work together to define the endpoints. So I think that's been a welcome change, but it's been an evident change. Dr. Boyer? Congratulations. Really, this is an excellent session. Now, clearly, bile acids have to get into the liver to cause colostatic damage and the NTCP mutations illustrate that very beautifully. So, Paul, the question is, what about inhibitors of OST-alpha-beta because that reduces the bile acid pool size and, as Saul said, reducing the intrapanic levels of bile acids is the goal I think we all need to be working for. Is that a good idea or a bad idea? I think, in our experience, that the potential for blocking an efflux pump or an efflux transporter could lead to accumulation of bile acids and there's really limited information in human subjects we reported on an OST-beta mutant subject in hepatology last year, but there's also a very interesting abstract on Monday of an OST-alpha deficient patients and, interestingly, they present with evidence of colostatic liver disease suggesting that there's a very important role of OST-alpha in OST-alpha-beta in either miliary tract or hepatocytes. And so, in order to get to the basolateral membrane of the ileal enterocyte, it has to be absorbable, the compound, so it's going to get to those and potentially induce a colostatic phenotype. So, I don't think at this time that OST is, even though, in theory, there are some positive aspects of it, that that would actually be an attractive target. Yeah, so those cases that you just referred to probably are occurring because bile acids can't get out of the cholangiocyte, right, in the deficiency of OST-beta, so those cholangiocyte injury, thalic proliferation, and fibrosis. So, just, if I could make a brief comment about the need to focus on what bile acids are doing in the liver. The rest of the cholestatic disorders, bile acids are getting into the liver, building up concentrations, then exciting an inflammatory response and we need to focus much more on that process and how to therapeutically interfere with that. Yeah, but I guess Saul's point about trying to reduce the accretion of bile acid as an early event would block the events that you're talking about. And so it depends on where you do, but clearly we need to further understand how the accretion leads to the pathophysiology. I have a question about PSC specifically. We've heard a very messy situation described today about endpoints and we know it's become a real barrier for investment in clinical programs in PSC. We've also heard that we need a prospective structured database capturing lots of different laboratory and other markers. Now we've just heard from Keith that maybe we don't need that. Maybe we need to focus on MOA for the compound on the table. What's the answer here? Do we need a big prospective natural history study? And if so, what kinds of data are we going to capture with something like that? Just what we're capturing now or new things? If Marina hadn't just gotten married this Saturday, I would make her do it, but I'm trying to be nice. Again, I don't think there's a great answer for this. I think that the data sets are always useful. I look at what Mark Deneau did with the pediatric PSC patients. We finally have all of that, that large data set. I think we've gained a lot of insights from that, so I think that there's value in that. I think one of the other things that Marina mentioned in her talk was it's difficult to demonstrate that a surrogate works for a new drug. It's almost always after the fact. We can look at changes in ALKVAS, or really almost any changes in PBC, where there are sodioxycolic elements. I think that's a good point. So I think that's part of it. We've seen several mentions.

erythrodeoxycholic acid

PBC

liver disease

gallstones

FDA approval

clinical trials

bile acid signaling