Philip Rosenthal, MD

 Our listeners include gastroenterologists, hepatologists, and other health care personnel. What advice would you give them? Obviously, recognize the disease, screen for the disease, and then treat the disease. Let’s start with Phil. Any words of advice for our listeners?

 IBAT inhibitors are approved, and we should consider utilizing them earlier in the therapy of individuals who have significant cholestasis and itching in particular. That’s what they’re approved for. As we get more familiar with the use of these drugs and we get more data, we’ll have a better understanding of who the appropriate candidates are. I’m hopeful that there will be much more data looking at the genetic differences of these individuals and whether we might be able to tweak who the ideal candidate would be to receive these drugs.

 We’ll get some guidelines from the pediatric GI [gastrointestinal] society [North American Society for Pediatric Gastroenterology, Hepatology and Nutrition; NASPGHAN], AASLD [American Association for the Study of Liver Diseases], and so on. Jennifer, any parting comments or words of advice for our listeners?

 Before we talk about some of the management, which we have reviewed, the first thing I’d bring up and encourage people to look for is the symptoms themselves. Sometimes, if you’re sitting in the office, you have to be not only direct but sometimes creative in the way you ask these questions. If you simply ask, “Is your child itchy?” you may miss something. Sometimes, rather than asking whether they’re itchy, I focus on something like how they’re sleeping, whether they’re waking up at night, what’s causing that. In some of the more severe cases, parents will tell you that when they wake up in the morning, they notice that their child has been scratching so much that there’s blood on the sheets or the pillow case and things like that.

We’ve alluded how itchiness is subjective. Are there more objective ways that we could be measuring this? There are some tools out there. But you need the wherewithal to know that pruritus is a known complication of Alagille syndrome and to make sure you’re asking the appropriate screening questions in a way that encourages response. That’s the first step. Then management-wise, we’re going to have a lot of more interesting conversations in the months to come. Don’t be afraid to utilize a lot of your colleagues who may be seeing these patients. As hepatologists, we sometimes forget that we often see several of these patients. Depending on where you’re practicing, that may or may not be the case, but the resources are out there.

 Thank you, Jennifer. Ryan, do you have any words of wisdom?

 These are great. I’m probably the least wise person in any of these conferences, but that gives me a great opportunity to listen and learn. That’s the big thing that I apply to this Alagille population. These children are so rewarding. We love the ones we get to take care of. They’re some of the sweetest ones. It can break your heart with the type of itching they go through and when you see excoriations on them. They can crack you up when they come in for a clinic visit. They’re wonderfully complex. I recommend that when you think about Alagille, you embrace the entirety of it. Trying to be a medical home for them is key, but with that comes great responsibility. You have to manage a lot of spinning plates and be aware of a lot of things that could happen. But at the same time, it’s so worth it. That’s my big takeaway.

 Amen. Embrace the challenge. Maintain that holy curiosity. It can be extraordinarily rewarding when we have success. Reggie, final words?

 I’d summarize it in 3 bullet points, the famous NASPGHAN message point. First, Alagille is a chronic multisystem disease that may be difficult to treat and is associated with complications. Second, families need to understand that we’re here to advocate for them, and as the captains of the ship, we should be most able to help them navigate the journey. Third, the future is bright with the development of these new IBAT inhibitors to treat the very disturbing symptom of pruritus and perhaps avoid the progression of liver disease.

 Well stated, Reggie. Thank you. This has been a terrific discussion. The 1 conclusion I’d also draw is that we need to get together again in 6 or 8 months to see how this field is evolving. It’s moving that rapidly. I sincerely want to thank all of you for this very informative discussion and thank all of you who are watching this 

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Experts in pediatric hepatology share advice for the optimal management of Alagille syndrome.

Clinical Pearls for the Management of ALGS

 Ryan, what do you tell your families in the clinic? They’re going to come in and say, “I heard about this new drug on the Alagille Syndrome Alliance website.”

 Absolutely, and we have to encourage it. We have to get our families to ask questions and invest in the care of their kids. If it’s something that’s a little off, we have to tell them, “It doesn’t make sense for you.” But when it’s something that has good data and real-world experience behind it, we have to be supportive and do our due diligence to make sure we’re ready to go with whatever that might be. We always want to chat with our patients about those new opportunities.

We’re a center that has prescribed maralixibat for children with Alagille syndrome, and odevixibat for children with PFIC [progressive familial intrahepatic cholestasis]. We’re starting to go from the research and the data collected to saying how this is going to work for me, for the patient, and for the families we prescribe it for. Real-world experience and getting to know the unexpected downsides or how much better things have gotten are going to be important. We want to hear and see those stories.

We’re going to want to talk a lot about the availability of these medications. What does it take? It’s one thing to know, “I have a symptom, and I have my treatment.” How do we get from first to second base? How can we make sure we’re able to offer these drugs to all the children who need them? We’ve already had to jump through a few hoops with insurance companies as it is. I don’t think that’s going to get any easier, especially for a medication like this that’s dedicated to such a small population and is going to have a price tag associated with it, which we’ll need to talk about.

Secondly, are we going to try to expand the use of these medications beyond the pruritus that it has the clinical indication for? We’re starting to see data trickle out at different meetings that growth has improved with children who are on these medications, and some other factors that may benefit from using IBAT inhibitors. When we talk to our families, we say, “We’re your partners. We’re staying close to you guys. You know us by our first names. Let’s make sure we keep working hard to uncover good data and do everything we can to make your child comfortable.” On our end, we have to stay active and involved. I’m looking forward to getting back to meetings, being able to chat in person with other people, and discussing the ups and downs of what we’re all seeing. That’s also going to be a big factor.

 Thank you, Ryan. That’s very well said. We talked about short- and long-term issues. There’s no question that the short-term issue is itching. Patients think about it every night when they go home. The long-term issue, which you can talk about in a second, is down the line. I can put that off. We talk about what’s right in front of them. My mantra has always been that our patients deserve the absolute best treatment available for their pruritus because it has such an impact on their quality of life. As we sort through these questions that you and Jennifer raised, we should keep that in mind.

Reggie, we talked about short-term issues, but what about the longer-term problem we’re trying to solve? Does this medication hold any hope for not just solving the problem of pruritus but perhaps allowing the progression of end-stage liver disease to be blunted to some degree? Do you have any thoughts or data that you could share with us?

 I alluded to that when I talked about the ICONIC trial. I’m gradually becoming a believer that modifying serum bile acids will lead to modification of progression of liver disease. There are ongoing trials using IBAT inhibitors in patients with biliary atresia with the primary aim to prevent or at least slow down the progression of liver disease. If the short-term goal of achieving reductions in serum bile acids in the vast majority of these patients who were treated in the trial remained in the long term, these drugs might be used in that manner. But the jury is still out. We may be talking in another 5 years, maybe even a little longer, about using IBAT inhibitors not for itching but for anyone who has cholestatic liver disease, not limited to Alagille or PFIC. IBAT inhibitors may become the next ursodeoxycholic acid for all we know.

 Right. Theoretically, the concept works. As Ryan said, you’re reducing bile acid pool size, so theoretically you’re unloading bile acids from the liver. We know that if bile acids sit around long enough, certain bile acids can exert a hepatotoxic effect. Let’s cross our fingers and hope that dream will play out, but it’s a little too early.

Drs Ryan T. Fischer and Regino Gonzalez-Peralta provide insight on educating patients and their caregivers on emerging treatment options for Alagille syndrome and the potential impact of evolving therapies on the progression of liver disease.

Patient Education and Future Directions for ALGS Management

 This will allow us to transition into looking ahead at how we’re going to use these tools. They still present some challenges to all of us. Jennifer, we’ve all used this drug in clinical practice. What are the remaining challenges? How does this fit into that nice treatment outline that you discussed with first tier, second tier, lots of tiers?

 It’s funny. Reggie and I were engaged in a conversation talking about this earlier in the week. That seems to be the million-dollar question.

 That’s true. One thing that I’m interested in, that the studies didn’t look at, is pill burden. If patients are on additional medications, such as antipruritics, it’s not clear how many of our patients will be able to decrease the number of antipruritic agents that they’re taking. In other words, I’d love to be able to sit down and market this as monotherapy: that this is all we need, and this is the answer we’ve been waiting for. Some of that remains to be seen. That’s the hope within our community.

The second thing is: Where does everyone’s comfortable level lie? Are we comfortable using this up front? Are we going to shy away from using ursodiol at this point? Will it be combination therapy and then, if things go well, we’ll feel a little comfortable peeling things off? I’ve been asking myself those questions. Since this has been commercially available for only the last couple of months, I’m interested to see what the coming year shows. As you point out, that’s one of the big questions.

The other remaining challenge is recognition, making sure we get these patients to the appropriate specialist, such as ourselves, who will have more familiarity with this medication and can help guide patients in a way that they need to be guided. Disease awareness, marketing, and education to a lot of the players we talk about are important.

I’d be a little remiss if I didn’t talk about what happens as they get older and become young adults, and we’re looking to transfer them to our adult partners who may not be as familiar with taking care of patients with Alagille syndrome or as aware of lot of the intricacies or different organ involvement outside the liver. Perhaps they have some familiarity with some of these new therapies for other indications, so maybe we can take advantage of some of their experience there.

 Exactly. Very well said. Obviously, we’re going to need more real-world data and clinical development profiles as these drugs continue to be utilized and marketed. Phil, is there anything else on the horizon in terms of follow-up of the ICONIC study, such as other drugs?

 Maralixibat is approved for use in patients over 1 year of age.

 Right, for Alagille. Many of these patients have itching and cholestasis long before they’re 1 year old. There’s an ongoing trial for younger-age patients to be enrolled in a maralixibat trial. In the ICONIC trial, I believe there were only about 30 patients.

 We aren’t talking about large numbers. Perhaps when they get up to 60 patients on the drug, we might see benefits or disadvantages that we haven’t observed based on only 30 patients. There’s a lot of information that we’d still like to garner. For example, genetically, not everyone who has a JAG1 or NOTCH defect has the identical defect. Some data suggest that in PFIC [progressive familial intrahepatic cholestasis], PFIC2, and BSEP deficiency, there are differences in the genetic makeup as far as response to IBAT inhibitors. Perhaps the same occurs in Alagille syndrome, because not every patient has an excellent response to the IBAT inhibitor.

 Well said, Philip. There’s also another IBAT inhibitor in development, odevixibat, which is approved for PFIC. We don’t have head-to-head comparisons—we may never—and we don’t know the relative binding affinity to the ileal receptor and so on. As Jennifer alluded to, we’ll gather a lot more data as we learn about this, and hopefully we can continue to share our experiences.

Jennifer M. Vittorio, MD, and Philip Rosenthal, MD, comment on remaining challenges for the management of patients with Alagille syndrome and discuss novel therapeutic agents under investigation for disease management.

Unmet Needs and Novel Agents for the Management of ALGS

 You mentioned clinical data. Reggie, are you familiar with the published data, especially from the ICONIC trial, which allowed the FDA approval of these drugs for children with Alagille syndrome?

 I have some knowledge. I love the name of the trial. ICONIC sounds iconic. Interestingly, it’s one of what I call backward placebo-controlled trials. It’s a medication withdrawal trial—that’s the fancy name—where everybody up front received the drug openly, indifferent to the usual trial where half the patients get the drug up front and half don’t. In this one, everybody got it up front. Supposedly, this improves or diminishes the subjective bias of itching.

Patients received maralixibat 380 µg/kg once a day for 18 weeks. Half the patients were continued on therapy, and in the other half, the medicine was removed. No one knew who was in which group. That was done for 4 weeks. Then everybody got back on open label for an extended period of time, up to 48 weeks. That’s where the ICONIC trial stopped. There’s an ongoing long-term arm of this trial, but ICONIC stopped at 48 weeks.

The take-home message was that in the first 18 weeks of open label, their ItchRO [Itch Reported Outcome] score dropped by almost 2 points. One point is considered clinically important in validation of the ItchRO, so a drop in 2 points is quite significant. As you might have imagined, during the 2 to 4 weeks where the drug was withdrawn, the effect remained in those who continued on drug. But in those where the drug was withdrawn, their itch scores rose back to baseline, clearly suggesting that this medicine was helping the itch.

Furthermore, after everybody gets on open label again, even the patients on placebo get back on the drug, and their ItchRO scores improve. The differences in improvement during the open labels and placebo are pretty dramatic. If you look at these patients at a year out, about 80% of the patients experienced a greater than or equal to 20% reduction in serum bile acids. Serum bile acid reduction was correlated to improved pruritus.

The medicine showed not only improvement in itch but also improvement in the serum bile acids, which may be getting a little off topic or to the next topic. There’s a conversation about serum bile acids being a biomarker of liver outcome. If you lower your serum bile acids, you might get more bang for your buck. You might get rid of the pruritus, but you might also be able to improve or prevent progression of the liver disease, although that might be a question for another one of these conversations. That’s a summary of the efficacy data of ICONIC.

Of course, you have to talk about adverse events, which did happen. As you might imagine, the most common were GI [gastrointestinal] related. Vomiting, abdominal pain, and diarrhea occurred in 50%-plus of the patients on treatment. Fortunately, these adverse events rarely led to drug discontinuation. They were quite tolerable, so the vast majority of patients were able to complete the trial. In the ongoing long-term arm, that seems to be the norm.

 Reggie, thank you for very nicely summarizing it. The drug, of course, was maralixibat.

Regino Gonzalez-Peralta, MD, reviews clinical implications from the phase 2 ICONIC trial evaluating the use of maralixibat for the management of Alagille syndrome in pediatric patients.

Using Maralixibat for the Management of Pediatric ALGS

 Let’s make the move toward the problem that we’re hoping to be able to solve: persistent pruritus. We could divide it into the old approach, the standard approach, or the initial approach—perhaps that’s the best way to look at it—and some of the pros and cons, then we can maybe see what’s new on the horizon. Jennifer, you can lead off. Tell us what we traditionally do for these patients. You already mentioned [biliary] diversions. Let’s go into all of that.

 Sure. Pruritus is probably [one of] the more frustrating symptoms or complications of Alagille syndrome that we encounter. Historically, there were 3 different options in terms of treatments. One would be pharmacologic therapies. Another would be surgical intervention, such as partial external biliary diversions. The third, of course, is liver transplantation. In terms of medical therapy, most of us are probably familiar with the choleretic agents and aren’t hesitant to use something like ursodeoxycholic acid. That’s one of the staples in the hepatology world and something that we’re all quite comfortable with. In some instances, this may provide some relief, but for some of the more challenging or refractory cases that we’re talking about, this is just the tip of the iceberg.

Other pharmacologic agents include things like antihistamines. Those are challenging. Certainly, they’re an advantage at night when symptoms of pruritus tend to be a lot worse. These children are often distracted during the day, but when you go to lie down at night, it becomes rather overwhelming. It isn’t ideal to have a school-aged child receiving medications that are potentially going to make them sleepy throughout the day. Rifampicin is something that we all use without hesitation in a lot of these patients as well. That has shown to have some good effects.

When these combination therapies aren’t working, we’re looking at things like opioid antagonists, such as naltrexone, potentially SSRIs [selective serotonin reuptake inhibitors], or many of the bile acid sequestrants, and the list can get a little overwhelming. Depending on the age of the patient, you’re going to encounter obstacles like palatability. Many folks absolutely refuse Questran [cholestyramine], and ultimately it isn’t worth the fight with that toddler. Not to mention that the pill burden is quite significant for many of these patients, not only with a lot of these antipruritic therapies but often we forget—our families even forget—that a lot of those vitamin supplements we’ve been focusing on are also vitally important. When you’re looking to space out medications or find a way to give these, it becomes quite overwhelming.

We’re getting into [thinking about] how we’re helping to improve the quality-of-life aspect. Historically, we were finding that a lot of our therapies were often not enough. Despite all of this, patients were still coming in miserable, with scratching and alopecia from pulling out their hair, and things like that. There are some new drugs on the horizon, which we’ll talk about in a bit, that might change the game plan. But when you’ve exhausted a lot of the medical options, it can become a bit overwhelming to talk about surgical interventions.

For patients who maybe don’t have significant fibrosis or portal hypertension, perhaps a diversion surgery is an option. We can all probably weigh in and give our own experiences or thoughts on that. But from my observations, they tend to work for some time but don’t seem to be long-lasting, or we’re met with other complications, like fat-soluble vitamin deficiencies that we can’t overcome. Being a trainee, the idea of performing a liver transplant for something like itchiness always seemed crazy to me. But then you meet a lot of these patients, and when you’re sitting in the office with them and you find yourself wanting to scratch, you understand it a little better, and suddenly it doesn’t seem like such a crazy idea. But with a liver transplant, it’s almost like trading one disease for another. We’re all advocates of liver transplantation here, but it’s met with its own challenges and complications and medications with adverse effects.

 Thank you, Jennifer. Obviously, you brought up the issue, these may have some success, but at what price? Certainly with the diversion, an ostomy, which isn’t well received by many families, and with transplant, you’ve traded one disease for another, as you said. Phil, before we get into the treatment, maybe you could define or capture what itching is all about, how we score it, how we grade it, and how the families can help us in that regard.

 Itching is on a spectrum from mild to moderate to severe. In the past, we generally used the clinician scratch score, which made it possible to distinguish between a patient who has mild itching and severe itching. I’d caution that itching is a rather subjective evaluation and dependent on the family and the clinician. Because it’s on a continuum, it’s hard to distinguish between a patient who has severe-mild itching and a patient who has mild-moderate itching. Where do you draw the line? What’s to say that this is moderate and this is just mild?

There have been validated itching scoring systems. There’s the ItchRO [Itch Reported Outcome] that was developed to help with the IBAT [ileal bile acid transporter] inhibitors, which we’re going to talk about in a little while. I won’t go into the details, but that helps to assess the degree of itching that the family or patient is observing. There’s also an app available based on the ItchRO that’s called the ItchCheck that patients can utilize on their own. You can download it to your iPhone. There might also be an Android app available at this point. I’m not sure, but I have it on my own iPhone.

The nice thing is that it’s confidential and secure. You can make a PDF to show your physician your scoring over time. The best indicator isn’t how much itching you had 1 day, but over time, is your itching getting worse? Is your itching getting better? Is your itching staying about the same? When it comes to the different therapies we’ve been talking about—either the classic drugs we’ve used or some of the newer drugs—it’s useful to look at weeks to months to years rather than 1 day in a week as to the progression of what’s going on.

 Phil, that certainly is key. You mentioned that it’s variable, not only from patient to patient, but variable from day to day and in fact from minute to minute. These children itch worse at night and when they’re tired or angry or frustrated, so it’s very difficult to quantify. The scoring you mentioned, ItchRO—RO means reported outcomes—has helped us, and we’ll hear more about those scoring systems.

Let’s talk about the new drugs that are available and first give a quick overview of what these new drugs are all about. Then we can get into the details of the studies. Ryan, maybe you can tell us what these new drugs are and what they do.

 The new class of medication that we’ve been trialing at our centers and have been approved to use are the IBAT inhibitors, the intestinal bile acid transporter inhibitors. These medications work by getting into the ileum and interrupting the reabsorption or enterohepatic circulation of our serum and basically hepatic bile acids that have been put into the intestine. They are there to help us digest food and absorb the nutrients that we need, and our body recycles them.

You can imagine that when you have cholestatic liver disease and you have trouble getting bile out of the liver to begin with, that recycling and bringing it back in may contribute to some of that increased serum bile acid and hepatic bile acid load. Therefore, the logic of blocking that reuptake, blocking those bile acids from coming back into the system, and perhaps blocking some of those detergent or proinflammatory effects that those bile acids may have inside our liver, could make sense. Not only that, but we’re affecting those serum bile acid levels again. They’re elevated in children with cholestatic disease. When we inhibit that reuptake from the intestines and can lower those levels, we’re seeing data that show that these patients can itch less. That goes to that still unknown—to me—mechanism of that association between having those elevated serum bile acid levels and the increased itch that goes with it.

It stinks because we certainly see patients who have elevated levels without much reported itching, and those with itching but with without the high levels. Obviously, there are other factors going into it. But for the most part, the more elevated those bile acids can get, the more we tend to see those children itch. By interrupting that with these newer medications, we seem to have what is close to a game-changing option to make the lives of these children so much better and prevent one of those major indications from transplantation—that severe itch—from taking over.

 Thank you, Ryan. Well said. I simplistically think about this as a medical biliary diversion. What Jennifer talked about was an external biliary diversion. This is a medical diversion. You’re blocking bile acid uptake, dumping bile acids into the colon, reducing bile acid pool size. Granted, you said bile acids may not be the pruritogen, but it certainly runs in the same neighborhood. We now know that lysophosphatidic acid, lysophosphatidylcholine, and autaxinall may play a role. But the biomarker may well be serum bile acids.

Jennifer M. Vittorio, MD, leads a discussion on initial treatment approaches and new drugs on the horizon for the management of persistent pruritus in patients with Alagille syndrome.

Treating Persistent Pruritus for ALGS

 Ryan, we talked about the issues in tailoring treatment, but I’ve been impressed by the parents’ groups networking and the alliances that have been formed. Many times, the parents come in and say, “I heard about this on the Alagille Syndrome Alliance. I heard about this, and I went to a meeting.” That can be very helpful in individualizing therapy. Tell us a little about your perspective as you tailor your treatment to the patient.

 On those lines, I tend to walk into that one because I often recommend that our parents get online and Google, and do what you need to do. That creates more work for the physician, especially when there’s bad information that you have to address or talk someone back from the ledge on. But at the same time, those parents’ groups can be wonderful. Not simply for the treatment options that may or may not be discussed on there, but simply for the support that they get.

That ties into what we need to offer for these kids long term and how we need to think. Because we’re the primary managers of Alagille syndrome for these patients, we want to focus on those quality-of-life issues that may be coming up. You can put those blinders on and be like, “I’ve got this liver. I have to take care of it. I have to do what’s right.” But we’ll see these kids come in at various time points with multiple other things that we need to be aware of, like a cross country runner who has a lot of foot pain. Maybe there’s something going on that isn’t related to running a little too far. Maybe it’s truly a fracture or malformation in the bones of the foot and we need to make sure that we get them to the right people sooner rather than later to help assess that. Those things can be important.

As we mentioned at the outset, this disease is fascinating. It makes you go back to your resources over and over again because you learn something new or see something different that you didn’t expect from this patient coming into your office. Then you find out that there’s a way that we can put the strings together between these 2 points that says, “This makes sense. This is something that can happen for these patients, and we need to be ready for that.”

I still want to learn more about how we predict and best screen for the possibility of stroke or cerebral vascular anomalies in these children. Do we wait until they can hold still for an MRI? Or do we need to do something sooner? Do we need to do better with managing cholesterol in these children? A lot of them are going to have hypercholesterolemia associated with cholestasis and the disease itself. I’ve seen statins get mentioned as being used for children. I haven’t used them personally, hoping to do other things to limit cholestasis and help them out. But beyond the itching, which we’re going to talk about later, there are all these little other areas that come up, notwithstanding the good cardiac care and renal care that they’re going to need.

 Thank you, Ryan. That clearly is a perspective. You reminded me of a statement I make to our fellows all the time: If you’ve seen 1 patient with Alagille syndrome, you’ve seen 1 patient with Alagille syndrome.” Because the next one is going to be very different. We talked about all the other common [issues], but we didn’t mention the autoimmunities, which are becoming more prevalent. We’ve certainly seen patients with Alagille with juvenile arthropathies and other autoimmunities. We need to also keep those in mind.

One last comment about the fractures. Reggie mentioned a 4-year-old coming into the emergency department with neurological symptoms. Yes, they could have a stroke, but I’d almost guarantee that everyone on this panel has had patients who had a minor injury bumping into the coffee table that was dismissed, and it turned out to be a pathologic fracture. That education component is key. Reggie, before we get into specific treatments, do you have any comments about any issues that we didn’t talk about in terms of treatment success, patient-related factors, or things that we need to be aware of and have our families and trainees aware of?

 It was all pretty well covered, particularly with Ryan’s comprehensive assessment. I’d throw in that it’s happened more than once where you talk about fractures being missed after perceived minor trauma, for example, but the other way is also important. I’ve had families become [engulfed] in the division of family and children’s services for the other way around, where it’s a minor trauma and there’s a fracture, and they say, “This must be neglect or abuse,” and a molehill becomes a mountain. These families get put through the wringer, even as you’re saying, “This person has a reason and a risk for having a fracture.” It takes a while before that translates to, “It’s OK. It wasn’t child abuse.” That also needs to be thrown in the mix.

 I see our panel all shaking their heads. We’ve all had patients exactly like that. Not just with Alagille but with PFIC [progressive familial intrahepatic cholestasis] and so on.

Drs Ryan T. Fischer and Regino Gonzalez-Peralta highlight the importance of tailoring treatment to a patient’s symptoms and define treatment success for Alagille syndrome. 