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A New Paradigm in Pediatric Cholestatic Liver Disease

  • Authors: Emmanuel Gonzalès, MD, PhD; Valérie McLin, MD; Richard Thompson, BM BCh
  • CME / ABIM MOC Released: 5/31/2023
  • Valid for credit through: 5/31/2024, 11:59 PM EST
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Target Audience and Goal Statement

This educational activity is intended for an international audience of non-US hepatologists, gastroenterologists, pediatricians, and other physicians involved in the diagnosis and management of cholestatic liver diseases.

The goal of this activity is for learners to be better able to differentially diagnose Alagille syndrome and implement appropriate management strategies.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Treatment options for Alagille syndrome
    • Clinical data evaluating new and emerging treatments for Alagille syndrome
  • Have greater competence related to
    • Differentially diagnosing Alagille syndrome


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  • Emmanuel Gonzalès, MD, PhD

    AP-HP. University of Paris-Saclay
    Antoine-Béclère Hospital, Clamart
    Maritime de Berck, Berck
    Hôpital Bicêtre AP-HP
    Bicêtre, France


    Emmanuel Gonzalès, MD, PhD, has the following relevant financial relationships: 
    Consultant or advisor for: Albireo; Laboratoires CTRS; Mirum Pharmaceuticals; Vivet Therapeutics
    Speaker or member of speakers bureau for: Albireo; Laboratoires CTRS; Mirum Pharmaceuticals

  • Valérie McLin, MD

    Associate Professor
    Swiss Pediatric Liver Center
    Division of Pediatric Specialties 
    Department of Pediatrics, Gynecology and 
    University of Geneva
    Geneva, Switzerland


    Valérie McLin, MD, has the following relevant financial relationships: 
    Consultant or advisor for: Albireo; AstraZeneca; Mirum Pharmaceuticals

  • Richard Thompson, BM BCh

    Professor of Molecular Hepatology
    King’s College London
    Institute of Liver Studies
    King’s College Hospital
    London, United Kingdom


    Richard Thompson, BM BCh, has the following relevant financial relationships: 
    Consultant or advisor for: Albireo; Generation Bio; Mirum Pharmaceuticals; Rectify
    Speaker or member of speakers bureau for: Albireo; Mirum Pharmaceuticals
    Research funding from: Albireo; Mirum Pharmaceuticals
    Stock options from: Generation Bio
    Owns stock (privately owned) in: Rectify


  • Gillian Griffith, BA (Mod), MA

    Medical Education Director, Medscape, LLC


    Gillian Griffith, BA (Mod), MA, has no relevant financial relationships.

Compliance Reviewer

  • Amanda Jett, PharmD, BCACP

    Associate Director, Accreditation and Compliance, Medscape, LLC


    Amanda Jett, PharmD, BCACP, has no relevant financial relationships.

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This activity has been peer reviewed and the reviewer has no relevant financial relationships.

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A New Paradigm in Pediatric Cholestatic Liver Disease

Authors: Emmanuel Gonzalès, MD, PhD; Valérie McLin, MD; Richard Thompson, BM BChFaculty and Disclosures

CME / ABIM MOC Released: 5/31/2023

Valid for credit through: 5/31/2024, 11:59 PM EST


This activity includes discussion of therapeutic products that have not been approved by the US Food and Drug Administration, off-label uses of approved products, or data that were presented in abstract form. These data should be considered preliminary until published in a peer-reviewed journal. Readers should verify all information and data before treating patients or employing any therapies described in this or any educational activity. A qualified healthcare professional should be consulted before using any therapeutic product discussed herein.



Emmanuel Gonzal...: Good afternoon, everybody. We'll start the symposium, but before we move ahead, for those of you who haven't had a chance to download the barcode, please do it now. It will help us for the Q&A and for some polling questions. So, I'm very happy [00:00:30] to welcome you to this symposium, a new paradigm in pediatric cholestatic liver disease. As you will see, we will mainly focus on Alagille syndrome, and we will talk a lot about this new medication that you have heard about with IBAT inhibitors. So, I'm Emmanuel Gonzalez. I'm a pediatric pathologist from a Bicêtre Hôpital in the unit that was created by Daniella Anghelina in France, 50 years ago. [00:01:00] And our faculty professor, Valerie McLin from Geneva, she's in working the Swiss Pediatric Liver Center and Professor Richard Thompson from Kings College London in the United Kingdom. So, here is the agenda with the first session we will try to... Valerie, will walk us through the differential [00:01:30] diagnosis of cholestatic liver disease with anthesis on Alagille syndrome. Then Professor Thompson would provide us with the data obtained from clinical trials, especially in IBAT inhibitory Alagille syndrome. And we will discuss altogether how is this clinical trial data can be used in our current clinical practice in these patients. [00:02:00] So just as an introduction, here is a repetition of the causes of cholestatic liver disease we observe in infants in tertiary care center like the one we have in Bicêtre. And as you can see pretty much one third of the causes are related to hepatocellular diseases that include PFIC, those also those genetic [00:02:30] canalicular transporter disease and other associated disease. But two third of the causes are due to biliary diseases and as you probably all know, the most frequent biliary disease is biliary atresia accounting pretty much for half of the patient we have in charge in pediatric pathology unit. But the second most frequent cause is Alagille syndrome, which would be the main focus [00:03:00] of this symposium. Neonatal cholestatis is prevalence is estimated to be around one in 2,500 births which make all the causes rare diseases. As you know, the cutoff for rare disease in Europe is 1 in 2000 births. So obviously all the [00:03:30] disease we're talking about are rare diseases and the most frequent, which is biliary atresia is has a prevalence estimated between 1 in 10,000 to 1 in 20,000 births. While PFIC collectively probably account to about one in 550,000 births and Alagille syndrome prevalence is estimated somewhere between 1 in 30,000 and 1 in 50,000 [00:04:00] births. So what are the possible manifestation for chronic and cholestatic liver disease in infants? Obviously, jaundice is a main manifestation, but also stool discoloration, which clearly is a red light that should made us suspect biliary atresia, liver or spleen enlargement obviously are [00:04:30] indicative of chronic liver disease. And the manifestation can include also all the consequences of cholestasis, which is fat-soluble vitamin deficiency, failure to thrive as it is in decompensated child and on the long-term pruritus may arise, which is probably and unusually not observed during the first three months of life because you need the neurological development [00:05:00] to be completely ready for the child to be able to itch. So, neuro-neonatal child below three months usually do not manifest itch which is which, but we don't know if they experience itch. Xanthoma which is due to accumulation of cholesterol is obviously a late manifestation probably after six months to one year and it's very frequent in Alagille [00:05:30] syndrome and probably very much less so in other diseases. So, before we start the symposium and we go through the presentation, there is this first polling question to see where exactly are we starting from. So, if you can answer this question, how confident are you right now in your ability [00:06:00] to differentially diagnosed Alagille syndrome? Are you not confident, slightly confident, moderately confident, mostly confident or very confident? Oops. We'll move to the next question. How confident are you right now in your knowledge of new treatments for [00:06:30] Alagille syndrome? So again, are you not confident, slightly [00:07:00] confident, moderately confident, mostly confident or very confident for these new treatments? And the last question is, how confident are you right now in your ability to manage Alagille syndrome overall? Are you not confident, slightly confident, moderately confident, mostly confident, or very confident? Okay. So, I think now we can move forward and I'm inviting Professor McLin to present the differential diagnosis of cholestatic liver disease in infants. So please, Valerie. Valerie McLin: [00:07:30] Good afternoon, everyone. So, the purpose of this first section of the symposium is to go over differential diagnosis of cholestatic liver disease in infants with a special focus of course on Alagille syndrome. So, we saw the audience survey of confidence relative to the diagnosis. The next step is to try to give tools on which to rely to diagnose Alagille syndrome. So, at this point in the symposium, [00:08:00] which of the following one of the common manifestations of Alagille syndrome in infants can you identify? You have the option between aortic stenosis, erythroderma, posterior embryo toxin and spinal kyphosis. [00:08:30] I think there might be a technical glitch. So, we'll move on. To focus on, we thought we'd use an illustrative case of an infant presenting with a neonatal cholestasis to illustrate the approach to diagnosing a child with Alagille syndrome. So, this is a male infant referred four days of life. He was full term but small for gestational age and the [00:09:00] pregnancy was remarkable for maternal methadone use. On his newborn pediatric check, he presented with acholic stools, and the physician diagnosed a heart murmur and his bilirubin was elevated. There's a typo, it was 140 micromolar. So he was really referred as is appropriate in these cases to rule out biliary atresia. On clinical exam, the acholic [00:09:30] stools were definitely confirmed, the heart murmur was present and there was a clerical unusual feces which also he helped orient our management. So, he underwent abdominal ultrasound which revealed the smooth liver, normal appearing gallbladder, normal flow in the hepatic artery and portal veins. Lean size was normal for age, but it did show some hyperechoic kidneys. So that's a relevant feature. And [00:10:00] of course given the presentation he underwent cardiac echo which confirmed bilateral pulmonary artery narrowing. On chest X-ray, no specific findings were identified, it was classified as normal. And his optho exam revealed bilateral posterior embryo toxin. Naturally he underwent some lab tests, so the abnormal values are in orange and the normal values [00:10:30] in blue gray. So, you see that there were a lot of abnormal values. So, he had elevated aminotransferases, elevated gamma GT at 452. So that's multiple, multiple times the upper limit of normal in excess of 10. His total bilirubin had risen By the time he reached us it was at 180 for 160 conjugated and he had hypercholesterolemia. So, we were faced with [00:11:00] an infant with elevated gamma-GT cholestasis which opens this differential diagnosis on the left side of the screen. It includes biliary atresia of course, for which he was referred Alagille syndrome, other biliary tract disease, gallstones, alpha-1 antitrypsin deficiency, neonatal sclerosing cholangitis, MDR3 deficiency and of course cystic fibrosis. And this is by opposition with [00:11:30] the low gamma-GT cholestasis which orients clinicians more towards the bio acid transporter defects and the bio acid synthesis defects. So, we were in the situation where we had elevated gamma-GT cholestasis and also some clear clinical features. And so, these clinical features really are the ones that should raise suspicion for Alagille syndrome. So, first of all, so in orange are the key diagnostic criteria for Alagille [00:12:00] and in blue are those that can also be present but aren't considered key features. So, the patient I presented did have the posterior embryo toxin. You see that this is a key feature we queried whether he had these facial features. Sometimes it can be difficult to identify in newborns. He had a PPS stands for peripheral pulmonary stenosis that was clearly identified on cardiac echo. Of course, other cardiac malformations can exist [00:12:30] as well. And although we didn't have a liver biopsy to show bile duct paucity, he did have jaundice and hyperbilirubinemia that fit those criteria as well. He did not have the butterfly vertebrae, but he did have dysplastic kidneys which can be a feature and therefore definitely tipped us off to this possibility. He was too young to have frank pruritus. He was IUGR, which sometimes can be a feature and at this point we didn't have any evidence [00:13:00] of vascular anomalies, but he didn't have CNS imaging. So, the key message here is that actually Alagille... We always say neonatal cholestasis this is an emergency because we have to rule out biliary atresia, but Alagille can mimic biliary atresia. And what helps orient clinical decision-making diagnosis and management are these key features shown in orange on the previous side. So, it's really largely a clinical [00:13:30] diagnosis in the setting of neonatal cholestasis. So again, to summarize the steps in diagnosing Alagille syndrome, it's an infant referred. So if we take the typical infantile presentation, it's an infant referred for high gamma-GT cholestasis with more than two phenotypic features. So characteristic features that were highlighted in orange on the previous slide, such as the posterior embryo toxin, the butterfly vertebrae, the heart murmur. Who may present with [00:14:00] pigmented or non-pigmented stools if you have sufficient clinical features. Liver biopsy is not necessarily mandatory to confirm bile duct paucity, especially in this age group that can be challenging. And of course, genetic testing is confirmatory and we're looking for a JAG1 or a NOTCH2 variant with the majority of the patients upwards of 90% having JAG1 variant. So genetic analysis is concerned confirmatory [00:14:30] except very occasionally a few patients cannot be confirmed on genetics. So, in summary, to summarize this classical presentation, patients are often referred very early on for biliary atresia rule out, but it's quite easy and practically doable to work up the patient for Alagille syndrome. At the same time, it's easy to obtain a cardiac echo in most of our hospitals, an optho consult, a chest X-ray. So, in other words, always consider Alagille syndrome [00:15:00] even with a acholic stools because this will hopefully avoid an unnecessary Kasai procedure. Of course, when in doubt we all remain clinicians and a intraoperative cholangiogram may help tease out the final diagnosis. So that was the approach to diagnosing the infant with high gamma-GT cholestasis. But the purpose of the session is also to improve confidence in diagnosing [00:15:30] Alagille syndrome in other clinical scenarios. So, this is another case somewhat in between different presentations referred at three months old for persistent cholestasis was sent to the referring hospital with an alleged normal ultrasound and satisfactory growth. On workup patient had a relatively normal ultrasound except for some hepatomegaly and no [00:16:00] other findings of significance notably no evidence of kidney disease. But on chest X-ray did have butterfly vertebrae and was indeed found to have peripheral pulmonary stenosis on cardiac echo. Ultimately, the patient underwent genetic testing by confirmed a JAG1 mutation. And as is often the case in these infants who present with features of Alagille syndrome, the clinicians took a good look at [00:16:30] the father and thought, "Oh there's a uncanny resemblance." The father had these triangular feces highly suggestive of Alagille syndrome. And so, it was recommended that the father have a workup of his own and tell his GP about this. And indeed, the father was found to have a decreased GFR to have dyslipidemia, hypertension. He unlike his daughter, did not have any liver involvement and did also harbor the JAG1 mutation. So [00:17:00] clearly, illustrating in this family the phenotypic variability of this syndrome as has also been widely shown in the literature and these are some of the most telling examples of monozygotic twins with this wide phenotypic discordance of one child having mostly the cardiac manifestations in the other, having mostly the liver manifestations. So, with that I hope that you're more confident about diagnosing Alagille syndrome. And before [00:17:30] we go through the poll again, we wanted to share this video with you of a patient and their parents' experience of living with Alagille syndrome. Speaker 4: Hello, I'm Kitty and I am 25 and I have Alagille syndrome. I was diagnosed as a BFA, so my mom here is going to explain how the diagnosis came about on kind of the early childhood of [inaudible 00:17:58] syndrome. Speaker 8: [00:18:00] Kitty was born in August 1997. And we took her home at 36 hours old, so she hadn't yet had a pediatric check. I noticed the jaundice developing that afternoon after I took her home and as the week progressed, she got increased me yellow. And by day five I had asked the community midwife just to check her serum bilirubin levels for me. That evening I got the phone call that devastated myself and my husband in our world [00:18:30] crashed around us. We were told that she was at exchange transfusion level and to get her to hospital quick and within a few hours we knew that Kitty had liver disease and significant cardiac disease as well. That process then led us to be transferred over liver specialist unit in Birmingham when Kitty was two and a half weeks old where the diagnosis of Alagille and was confirmed, tick box to [00:19:00] facial features, tick box to butterfly, vertebra, tick box to embryo toxins in her eyes, tick box to cholestatic liver disease, tick box to pulmonary stenosis and peripheral pulmonary stenosis. And that began our complicated journey with Alagille syndrome and the first year was spent in and out of clinics and hospitals. We finally got down to a bilirubin level. It was normal when the expectation and diagnosis [00:19:30] had been that she wouldn't get through her first year without a liver transplant. By 19 months of age, then we discovered that Kitty had benign intracranial hypertension, a feature of Alagille syndrome which was only there described in the literature. And by three, they then were looking at elective transplantation from a liver point of view. Kitty was assessed, investigated, and thankfully at the end of that week of investigation [00:20:00] they decided to leave well alone and see how she would progress. At seven and a half years of age, then the cardiac difficulties became challenging and there was palliative surgery carried out in which Kitty had a pulmonary angioplasty and they closed her VSD. Unfortunately, the closure of the VSD led to life-threatening problems and they had to remove the patch that placed over [00:20:30] to her moderate VSD became a large VSD. She had a problematic recovery from surgery and developed lots of pleural effusions. And then for the next year, Kitty had multiple problems and we thought we were sliding towards heart lung transplant. And the chronic features of liver disease were its head and the pruritus, and the malabsorption became huge features again. And then we trembled along until Kitty was about 13. She went for [00:21:00] a scan, and they discovered she had regenerating nodules in her liver, which threw another curveball for us as a family because with the Alagille they were often concomitant with hepatocellular cancer. And the next major event I guess was when they were querying vascular disease a few years later because they discovered then that basically all the arteries in Kitty's body are half of the amount should be. But in spite of that, she [00:21:30] has achieved lots and been highly motivated, miss independent, and is here to tell her own story today. Speaker 4: So, I think for me personally, the biggest challenges with Alagille syndrome is the pruritus is the constant. When it comes, it comes, and it can be quite prevalent at nighttime [00:22:00] and in the heat. So going away the hot countries and stuff just wasn't really a thing because my itch would just get so bad. And the other thing would be the tiredness. And I think in my teenage years I kind of realize that I wasn't always able to keep up with my peers because I didn't have that energy that everyone else had. I was constantly tired in school, [00:22:30] it would've been the concentration and not be able to stay on a task for too long, constantly switching from one thing to another. There was a lot of support there that I was able to avail of that helped me through it all. And I know I qualified youth worker and working with young people with learning disabilities. And so, despite all the diagnosis I think [00:23:00] I've come along with, I try my best and I know my limits. So, although I have Alagille syndrome, I do not let it stop me do anything that I want to do. Valerie McLin: So, an illustration of a complex multi-system disease and its impact on quality [00:23:30] of life. So now back to the knowledge question, which of the following is one of the common manifestation, sorry, of Alagille syndrome in infants? Aortic stenosis, erythroderma, posterior embryo toxin, and spinal kyphosis. So, I think mission accomplished. I'll hand over to the next speaker. Thank you for your attention. Speaker 2: [00:24:00] Thank you, Valerie. Emmanuel Gonzal...: Yeah. Thank you, Valerie. And we'll move to the next speaker. Professor Richard Thompson who is going to detail the new approaches to manage Alagille syndrome, new treatments and clinical trials. Richard Thompso...: Thank you, Emmanuel. If anyone's looking for a seat, there are seats over this side, feel free to come down and cross [00:24:30] over because I don't... You don't have to stand. So, thank you. So, we've heard about there are difficulties in making a diagnosis. I think we're all still learning, but most of the time we can come to a reasonable conclusion about the diagnosis. We've now heard something about the clinical features and the problems associated with Alagille syndrome and as I hope you now realize that there's a potential through clinical trial data to actually move the treatments [00:25:00] forward, which is really great news for our patients. So, first question before we go into any trial data is which of these treatments which are all being used widely in Alagille syndrome are actually based on clinical trial evidence? Feel free to choose any or all of those four answers. And [00:25:30] over 50% thinks I bet quite correctly have been subject to clinical trials. A significant portion, I think bio acids such as also have been subject to clinical trials. Certainly not randomized placebo controlled clinical trials, that's for sure. And despite their widespread use, obviously, vitamins and cholestyramine, et cetera have been used. But like many of the drugs that we use in pediatric cholestasis, they've not been subject to clinical trials [00:26:00] so far. So, most of the treatment until very recently has been supportive. It's been dietary, it's been fat-soluble vitamin supplementation, relief of symptoms, but not actually addressing the underlying disease. And we've concentrated on the pruritus obviously and the nutritional support. And these are the drugs we've used specifically apart from [inaudible 00:26:22] and vitamins, cholestyramine, rifampicin, which many of us have used widely and some many of us and certainly the families [00:26:30] believe have had some benefits. But again, there's no randomized trial data. And the frustration with the above listed as meant, we've gone on to use drugs like Ondansetron and Naltrexone and sertraline. Well outside their original indications in desperation, try and prime prove the symptoms of our patients. Small numbers have undergone biliary diversion surgery, which of course has been used much more widely in PFIC than Alagille and again with variable results. [00:27:00] So as with PFIC, many of us have thought that despite the limited data on surgical interruption of the enteropathic circulation that there would be merit even in this complex syndrome that is Alagille syndrome of reducing the bile acid pool size and improving the liver function and hopefully the symptoms consequently, and I mean this in context of Alagille and in other phenotypes, this has been done in many [00:27:30] different ways. Most commonly by partial external biliary diversion, surgical diversion from the gallbladder. But as you know in episodic disease, nasopharyngeal drainage have been done more in adults, internal diversions have been done and as you're now very well aware pharmacological intervention by IBAT inhibitors. And so, as you know, they are the large area of interest at the moment. And mimicking we think largely the surgical [00:28:00] diversion concept. And we'll go through the clinical trial data that's available. And as you know, in Europe and North America, maralixibat is licensed for the treatment of cholestatic pruritus in Alagille syndrome. And the second IBAT inhibitor, which you'd have heard some about this morning [inaudible 00:28:21] we will show you what the current data are on that molecule. But IBAT for those that have escaped the previous session [00:28:30] is the ileal bile acid transporter. It is essential for the reclamation of bile acids that haven't been used in the absorption of dietary fats and to try and prevent the spill over into the colon and the loss from the body and to maintain the enterohepatic circulation of bile acids, which in health is obviously desirable, but in illness it's possibly is actually contributing to the cholestasis by recirculating the bile acids to the liver. And the key study in maralixibat was actually my co [00:29:00] speaker Emmanuel, was the clinical lead for this was a quite a novel treatment design which was using maralixibat with a lead-in period of 18 weeks which all patients received and then a randomized four-week withdrawal to equal numbers of placebo and drug and then all patients went back on drug after that. So, the carers, their physicians and the patients were blinded as to which arm [00:29:30] the patients went into, although everyone knew that it would happen after 18 weeks and last for four weeks. The eligibility criteria are down there, and these are all clearly patients with persistent cholestasis with a diagnosis of Alagille syndrome, either on clinical or genetic criteria who hadn't undergone other interruptions of enteropathic recirculation in the past. And these are the data, and this is the [00:30:00] bile acid reduction data. As you can see the placebo group is in red and followed obviously the drug treatment group for the first 18 weeks because they were both on drug. But then when the drug was withdrawn there was a return to baseline of the mean bilateral level in that treatment group. And by the next assessment of 48 weeks, they had rejoined the treatment arm. So, there's absolutely very [00:30:30] clear evidence that there was on the basis of serum bile acids, there was a response in the majority of patients and there was a complete loss of response after four weeks of treatment. And if you look across the right-hand side, at least for the first 96 weeks, there's a good numbers there and persistence of the effect. In the longitudinal fall out there was the option to go to twice day dosing. And as you can see there's now patients write out to [00:31:00] four years with persistence of the bile acid response. And this is exactly the same study, but this is the change in pruritus scores on the four point [inaudible 00:31:13] score and again they returned to baseline of the mean [inaudible 00:31:18] sorry, pruritus scores after the four weeks drug withdrawal. And within six weeks of drug reinstitution, we have the pruritus scores, which again they had rejoined [00:31:30] the patients who stayed on maralixibat about throughout the whole study. And again, there's a continuation of the effect over the 98 weeks there and then in the extension up to four years with this persistent reduction of pruritus. So, as you've also heard from previous presentations, these drugs do have side effects largely because we are sorry, adverse [00:32:00] effects which may or may not be related to drug. The ones that are undoubtedly related to drug are the changes in stool pattern and the abdominal discomfort which is largely short-lived but is related to the effect that we're hoping to achieve, which is to move some bile acids into the colon. Most of these adverse events were short-lived and improved after a few weeks and certainly there was no serious adverse events related to study drug in this study. Importantly, as [00:32:30] you've heard from the video and from what Valerie was saying, the quality of life is impacted by this disease considerably. And here we can see on the left in the baseline and end of treatment at 48 weeks the improvement in quality of life going from green to blue on the left-hand side in the responders and in the right-hand side, the ones that didn't achieve a response that really the lack of change in the quality of life which remains poor. On the [00:33:00] right-hand seat you can see the individual scores just to give you an idea of what they are raw data look like with the responders and the non-responder separated, but that's what they actually looked like and that was not significant over that period. But clearly, the trend was in the direction which we would like to see. So at this meeting there are some more data on maralixibat in use and the most importantly of course we're now moving into the era of [00:33:30] real world data, which we all know is not the same as clinical trials. And we do need to see what these things look like in the real world and in the longer term and both effects on hypercholesterolemia and xanthoma but in different geographical regions locations related to safety and efficacy. So, I would encourage you to go to see those four abstracts that are all tomorrow. Then the second drug, which has been subject to clinical trials in Alagille syndrome [00:34:00] is odevixibat, and this is not yet licensed, but it is approved for the treatment of PFIC but not Alagille syndrome and it is being assessed by both agencies. But the phase three study, which was a straightforward randomized placebo control trial and I think most of you hopefully have just heard Nadia Ovchinsky present those data in the other session. But prior to an hour ago, the only publicly available data were these which are on the SLD website [00:34:30] after the presentation in the last autumn, which showed on this six-month randomized placebo control trial, significant improvements in both pruritus, bile acids, and sleep parameters that the data are presented here for out of expat in Alagille syndrome as well. And in this meeting you've heard Nadia's talk just now, but there's another talk tomorrow and I thought there was some more slides anyway, another presentation tomorrow [00:35:00] lunchtime on the use of this drug in Alagille syndrome as well. So, the clinical trial data are encouraging. Clearly, they obviously would, we are not allowed to do randomized placebo control trials over years of duration, which we'd all love to have those data but know what is going to subject children to that. So, we're going to have to be restricted to following these patients in the long term, comparing them to historical feature follicle data [00:35:30] as which luckily now have been collected through particularly through the GALA Study. And what we really want to know is not only have we improved the biochemistry, have we improved the serum bile acids in particular, have we improved the clinical features? What we really want to know is whether we've actually made a difference to the need for liver transplantation and the long-term outcome from the liver and other points of view. But in the short term the data are suggestive that that's what we're [00:36:00] achieving. But clearly that remains to be proven. So far, we do think that we have got within our hands class of drugs which are potentially very useful in the management and add to our largely symptomatic and supportive evaluation that we've used in the past. So I hope this question is now clear. I think the majority of people had answer for last time, [00:36:30] but that has changed a little bit in the right direction so maybe you're not just all asleep so that's good. Okay. So now as I've just hinted at and we've got some abstracts tomorrow, which I think are critical, clinical trial data is fantastic. It proves things are effective, it allows these drugs to be licensed, which is a major hurdle to be overcome and this is fantastic that we've been able to do randomized [00:37:00] studies which are allow the licensing of the drugs but then we have to learn how to use these in real life. And so, I would like to hand back to Emmanuel at this point to come and tell us something about that and what we've learned so far. Thank you. Emmanuel Gonzal...: Well, thank you [00:37:30] very much Richard. And so, we'll see that I would not give you recipe, but I would rather raise questions that we will have to discuss altogether. So, before we start, just a polling question. How confident are you right now about the role of IBAT inhibitors in managing Alagille syndrome? Not confident, [00:38:00] slightly confident, moderately, mostly, or very confident. Since the most of you are already quite confident, even maybe even more confident than I am. So, hopefully we'll see if the talk improve your confidence here or not. [00:38:30] So, I think it's clear from Richard to that now these IBAT inhibitors clearly improve pruritus, serum bile acid levels, xanthoma, cholesterol levels and quality of life in an important subset of patient with Alagille syndrome and that this improvement can be sustained. It's clear [00:39:00] as well that those non-absorbed drug are rather safe and well tolerated beside those transient, usually transient digestive symptoms that were already mentioned. Oops. And this data led to the license obtained from [inaudible 00:39:23] in Alagille syndrome, starting two months of age in Europe, three months of age [00:39:30] in the US. But the drug is not available everywhere and there may be some constraints in healthcare resources that can prevent the use of this drug. And so, to address a little about this issue, we will consider scenarios for using these IBAT inhibitors later on. But just before going to this scenario, would like to wrap up a little bit the pro and the cons of [00:40:00] the main two antipyretic drug that we can use today, the rifampicin. Most of we've been using rifampicin for decades. Clearly, there is a wide clinical experience worldwide. Clearly, it improves itch and not so many side effect observed and it's inexpensive. But on the other hand, there is no real data, [00:40:30] hard data that demonstrates its efficacy. Its not licensed. It does not decrease serum bile acid, it does not decrease cholesterol level, it will not improve. And even if it's rather safe in our experience it still has theorical liver toxicity. And as you know it's also modified direct metabolism. On the other hand, we have these IBAT inhibitors which are licensed. [00:41:00] The efficacy have been demonstrated in clinical trials and in addition they decrease serum bile acid, they decrease cholesterol level, and they can decrease xanthoma. On the other hand, this drug we don't have much experience with. And so far, the cost is important and again there are these slight [inaudible 00:41:28] residents. So, with this [00:41:30] in mind, rather than saying what to do, I decide to raise a few question about how to use this IBAT inhibitors in the real world in current practice. Because if you give a treatment to a patient, then you want an answer to the treatment, then you have to evaluate the consequence of your treatment. And in clinical trial we define clinical responder [00:42:00] with a decrease in itch. We define biological responder with a decrease in serum bile acid, and this are endpoint that can be used to make statistics and to assess trials. But when you're with a child with Alagille are you satisfied with a one-point decrease in itch? Or would you like the child to be completely itch free? Are you satisfied by a decrease of 30% of serum bile acid or would you expect [00:42:30] more? So, we need to have goals and without the full potential of the drug. And it seems that the potential of the drug is not the same in every children. So, this is difficult to translate those endpoints to our clinical practice. And obviously to assess itch response we need to use some kind of scale of scurrying [00:43:00] because all of that's also very subjective. So, this is something we have to work on, in the clinical practice, are we happy with the response? Are we completely convinced that there is a response? So this is something we'll have to discuss. Also, the family wants to know how quick is the child going to respond to the drug. And what I can tell from my experience and from the data is that usually serum bile acid and itch [00:43:30] moves in terms of weeks, and this has been observed in the trial, but for xanthoma and cholesterol level it's much more lagging behind in terms of months to have this kind of improvement. And also, we have been observing a few late responder in terms of itch.And also, we have been observing a few late responder in terms of itch. Another question is when the child has both a clinical response [00:44:00] and a biological response, you are very much convinced that things are improving. But in some patients there is a reduction in itch with no movement in serum bile acid this is also a situation that is not very easy to deal with in terms of current practice. So, also have you been seeing the dosage of the maralixibat has been increased to BID during the trial. [00:44:30] And so, even if it's not completely in the license, you might ask yourself the question, should I increase the dosage? If I consider that the improvement of the child might not be... it's not full responder, it still have a little bit of itch, serum bile acid decreased amount that much would you consider pushing the dose? Or on the other hand, if you have a full relief, would you consider lowering the dose? So these are question, we don't really have the answer and we'll discuss [00:45:00] together what we think we should do. And the last but very important question is does do disease IBAT inhibitors really change the course of the disease in terms of fibrosis with an impact of native liver survival. So we don't have this answer, but for sure the response to this question will probably change the way we use the drug in [00:45:30] the future. So, rather than give you recipes, I suggest that we move to a few clinical scenario and ask ourself some question and discuss together and with our faculty what to do in two kind of child. So, the first child is a three years old age Alagille patient. And in the first scenario he will have significant pruritus [00:46:00] despite maximum [inaudible 00:46:02] and rifampicin dosage. So, this is a typical patient that was included in the clinical trial and of course this is the main indication today for IBAT inhibitor is to address the refractory pruritus. So, you treat the patient with an IBAT inhibitor. And how in your clinical practice would you assess the efficacy of this treatment? And this is [00:46:30] something that maybe Valerie or Richard could share its thought about, Richard. Richard Thompso...: Emmanuel, thank you very much. So, I think Valerie reflected earlier that she was told by a very eminent hepatologist when she was training that transplantation doesn't have a role in Alagille syndrome. But I think it is a key sort of pivot point that we should think about because obviously we do have used liver transplantation. [00:47:00] And liver transplantation is a irreversible procedure. It's not something we can try and see if it's necessary or we can reverse. So, I think that's one of the key decision-making process we have to have in our thought processes because we've now got more options for treatment. Obviously, in the long term what we're all seeking is quality of life and health and really, we have to think about these tools. Can we avoid transplantation [00:47:30] for symptoms? Can we avoid transplantation for a chronic liver disease? Are we going to actually have... I know a much higher proportion of these patients reaching adulthood. Untransplanted as you know from the longitudinal data, the GALA data, actually the majority of Alagille patients are going into adulthood with liver transplantation, which actually seemed quite surprising to us but is actually true. So, I think we need to [00:48:00] use the drugs. I've just been turned off. Yeah. So, I mean think it's fantastic. We've got another tool now we have to use it in a systematic fashion. But most importantly we have to really decide when it's failed, and that's actually much more difficult to know when we have to admit defeats and it's going to be obviously not a single decision we're going to make, it's going to be make a decision or make with the families. But clearly, I think it's all around when if we're going to resort to transplantation, [00:48:30] are we going to avoid transplantation? Have we got evidence so far that this gives us another tool to avoid transplantation? Emmanuel Gonzal...: So, to assess the efficacy of the drug, it means that you need to score the itch somehow. And so, this is something that we probably should do in our current practice, which is not so easy that we need scale, and we need... and so this is something that [00:49:00] we might implement in our practice. Richard Thompso...: That's a good question. Let's have a quick show of hands actually because I'd be really interested to see we've got a fantastic audience. And in clinical trials we use objective measures of pruritus. We use either visual analog scales, we use the percussion instruments, we use the [inaudible 00:49:18] tool which are on a try and score itch. I'll be honest, in clinic I don't use that. I look to see [00:49:30] what impact it's having on the family. But just quick show of hands, who routinely uses a quantitative tool to try and assess pruritus? Not a single hand has gone up. Is one apparently. So who asks about quality of life and uses that as a decision making factor? Emmanuel Gonzal...: More. Richard Thompso...: More. Emmanuel Gonzal...: Yeah. Richard Thompso...: What's everyone else doing [00:50:00] who really uses serum bile acids as their decision-making point for escalation of treatments? A few spattering. Very few. Emmanuel Gonzal...: So, this is a main tool. What's everyone else doing? Richard Thompso...: Can you work it out? What's everyone else doing If they're not using bile acids, they're not using a quantitative score, they're not using quality of life factors like sleep and et cetera. What are you using to decide whether to escalate treatments or [00:50:30] not? Do jump to a microphone and tell me because I'm slightly puzzled, am I missing something? Valerie McLin: You can either go to the microphone, introduce yourselves and ask the question or write the question in the app. Richard Thompso...: Yeah. That's true. Emmanuel Gonzal...: Now maybe you should use a- Valerie McLin: Yeah. The idea here is to discuss that there's... we're not going to have a perfect recipe [00:51:00] at the end of the session. Sorry. Speaker 6: Hi Richard, Chris [inaudible 00:51:04] from Bristol? I don't work in a liver unit but I look after liver patients, so I don't have that many who are in this situation. I was going to ask you, can you use bile acids as a marker of compliance of this condition of taking the medication? Emmanuel Gonzal...: I think it's complicated to answer this question because not all the patient would respond to treatment in terms of decreasing serum bile acid. So, [00:51:30] it would be difficult to make the difference between lack of compliance or lack of biological efficacy of the drug. Richard Thompso...: So, another difference in obviously real-life data and clinical trial data is for good reasons in the clinical trials, the serum bile acid will blinded to the investigators and the patients. In real life of course, we will do serum bile acids on normal clinical testing and those information will be available to us and [00:52:00] the patients. And it is quite possible that knowing that the serum bile acids have come down is at least psychologically encouraging to everyone and may influence how people feel about the whole situation. But I mean, as everyone knows, there's a poor correlation between serum bile acids and pruritus. It's not a fantastic way of judging pruritus. But of course, it is an important biochemical change that reflects that we've done something biologically different in the patient. We've achieved a [00:52:30] change which may or may not translate into pruritus, may or may not translate into long-term native liver survival. But yes, Chris, it's a tangible change that we've done something that's for sure. Emmanuel Gonzal...: I think an important question considering the current cost of the product is would you consider stopping the treatment after months or so? If you do not observe [00:53:00] any kind of response though it's not quite clear or you're going to assess your response. Will some of you rather consider starting the drug and keep the drug on whatever happens? Or would some of you consider at some point see how it works and decide maybe to stop it? Would some people consider stopping it? Valerie McLin: So, by show of hands, who would stop it in non-responders? Richard Thompso...: [00:53:30] Okay. And we've got less than 10% actually. Although people are clearly shy today about putting their hands up I think. But- Emmanuel Gonzal...: Right. Right. So, let's move on to maybe a different scenario. So, we have this three-year-old Alagille child, but this time is completely itch free provided let's say maximum treatment with rifampicin. The situation is [00:54:00] acceptable, I mean, in terms of quality of life. But then would you consider switching to IBAT inhibitor? Would you consider adding IBAT inhibitor despite the child is not itching anymore, which would not be clearly in the recommendation of the product yet? Or would you just let the child busy of rifampicin? So, who would consider [00:54:30] just the situation is acceptable and you don't change anything? Okay. And who would like to introduce an IBAT inhibitor on top of rifampicin? Richard Thompso...: With good control. Emmanuel Gonzal...: With good control, which is not completely well, so that's a... and who would try to switch? Richard Thompso...: Nobody. Emmanuel Gonzal...: Nobody. Richard Thompso...: Okay. I mean, I don't know how many patients who've got absolute [00:55:00] perfect control on rifampicin and conventional treatment is the truth. Emmanuel Gonzal...: So, maybe we're still a little shy with [inaudible 00:55:10]. Speaker 7: Depends on what your [inaudible 00:55:13] of treatment. Richard Thompso...: Well, it does depend and that's why- Emmanuel Gonzal...: Yeah. It depends on [inaudible 00:55:16]. Richard Thompso...: What we're aiming for of course is long-term nature liver survival with good quality of life, which is a tall order in Alagille syndrome. It has to be said but that of course should be our aim. There's no question at all. I think the fact that we don't know the answer. Emmanuel Gonzal...: We don't have the answer. Richard Thompso...: We're not going to tell you [00:55:30] the answer because we need the data, and the long-term follow-up data are going to establish this. But I think you need to be thinking about these things and I'm sure most of you already are is exactly how these fit into our armamentarium. Exactly the sequence we're going to introduce these drugs and potentially the sequence we withdraw drugs if we actually get the good response that we're all looking for. Yeah. Emmanuel Gonzal...: Okay. So, let's maybe move on to another scenario. [00:56:00] So, now we have a two months old child just recently diagnosed with Alagille syndrome, moderate journeys and it is only two months so it doesn't manifest itch yet. But we know that serum bile acid are elevated because he has jaundice and we are quite confident that he might develop itch shortly, but there is no itch. I mean, if [00:56:30] possible, how many of you would be willing to introduce an IBAT inhibitor before itch manifest? I mean, it's- Richard Thompso...: Just assuming it was available, licensed- Emmanuel Gonzal...: Assuming we can do- Richard Thompso...: ... et cetera for that purpose, in that scenario. How many at this moment think there's enough data to initiate treatment in an asymptomatic patient with Alagille has got abnormal biochemistry, raise serum bile acids? Again, very small number of people so far [00:57:00] feel confident enough to do that. Okay. Emmanuel Gonzal...: Okay. So, most of you would wait for itch to appear before taking a decision. Speaker 9: Why not [inaudible 00:57:13]. Richard Thompso...: So, you are putting your hand up in retrospect now, is that what you're saying? Yes. Yeah. You'd believe you would use it? Speaker 9: Yes. Richard Thompso...: You think it is? There's enough evidence. Speaker 9: [inaudible 00:57:23] I came from Lebanon from a very poor country. And it's a very frustrating [inaudible 00:57:29] and we don't have any [inaudible 00:57:33]. So, I bet [00:57:30] that question would you accept to include the patients [inaudible 00:57:40] country [inaudible 00:57:41]. I will try to be so [inaudible 00:57:46]. Emmanuel Gonzal...: So, you would like to treat the patient preemptively but you cannot afford it or it's not clear that in your country- Richard Thompso...: It's not funded at the moment anyway. Certainly, that's for sure. Emmanuel Gonzal...: But I think this is things that we might have to consider in the... And on [00:58:00] my part, if I can do it, I think I'll discuss with the family for the interest of decreasing serum bile acid in this patient and probably I would like to do it, but- Richard Thompso...: It answers your very question. There's no clinical trials that are recruiting at the moment in Alagille syndrome unfortunately. So that is not a possibility. But clearly also lots of treatments of a liver disease, whether it's these drugs transplantation, there [00:58:30] isn't equity of access in all countries throughout the world and that obviously should be one of our missions is to try and achieve that, to answer your question. Valerie McLin: So, Emmanuel, let me ask you this, would you do it because you want to prevent the child from developing itch or because you believe it will change the natural history of the disease? Emmanuel Gonzal...: Well, hopefully both. But more importantly is what you would do with a child coming back two months later and then manifesting with itch, then you would definitely need to start [00:59:00] something. And would you start first with rifampicin? Raise your hand. Richard Thompso...: So, in this new world, symptomatic patient straight in with rifampicin or go straight to IBAT inhibitor. Who would try rifampicin first? Valerie McLin: High in the sky scenario where every country has access. Emmanuel Gonzal...: Yeah. You can do whatever you want. Richard Thompso...: You got access, there's not a problem. Valerie McLin: Got access. That's the premise. Emmanuel Gonzal...: Who would start with rifampicin? Richard Thompso...: Who would start with rifampicin today? This is a symptomatic patient not on treatment so far. Emmanuel Gonzal...: And we would start with- Richard Thompso...: Who would go straight to an [00:59:30] IBAT inhibitor and bypass rifampicin? Emmanuel Gonzal...: Yeah. Richard Thompso...: More people for sure. Emmanuel Gonzal...: Yeah. Okay. So, we don't have all the answer but I think we have at least the clue for what we need to think about. Richard Thompso...: How many years do we need to come back do you think? And ask the same question again and gets a clear answer. Emmanuel Gonzal...: Yeah. I think we need to move forward because... So, hopefully with [01:00:00] this polling question you might be more confident right now that you used to be. So, if you just been helpful or did we raise more questions that we provide you with answer? We'll have to do the comparison, but... Richard Thompso...: We maybe achieved something, it's still worse- Emmanuel Gonzal...: We'll analyze that. Valerie McLin: I think we can conclude there's a change. Richard Thompso...: I'm not sure we've got a P value- Emmanuel Gonzal...: We need a statistician there. Richard Thompso...: Yeah. [01:00:30] Go on Chris, quickly. Emmanuel Gonzal...: I'm sure- Richard Thompso...: Time is up, but- Speaker 6: So, are you going to be recording those number of patients will be starting on IBATs according to their wish as opposed to the evidence that's out there at the moment. How's that going to be done? Richard Thompso...: So, I believe that there are requirements for post marketing surveillance and follow up data that the regulatory authorities are asking for. I can't tell you the exact details of those yet, but [01:01:00] we as an academic community definitely want to collect those information and I think there's actually some requirements on the companies to do that as well. So, between us, I hope that will become possible. Quick summary up and then we've got a... we need to get the last QR code, so you can fill in the evaluation. Emmanuel Gonzal...: Right. So, well before we close, I think it's clear now that we have those IBAT inhibitors as a new class of treatment for patients with a Alagille syndrome that fairly they have some positive clinical effects in a subset of [01:01:30] patients that the safety profile is good and the good thing also is that they clearly provide an opportunity for a collaboration between pharma, between clinician, we have all this international registry. And this collaboration clearly can further improve the care of patient with chronic liver disease, cholestatic liver disease, and in particular also with Alagille syndrome. So, I think I'll move to the last [01:02:00] slide, so you can scan the QR code to get your CME. And I want to thank all faculty and I will thank you very much for- Richard Thompso...: Thank you for your time. Emmanuel Gonzal...: ... your retention and for coming here. Valerie McLin: Thank you for your participation.

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