Mirum Pharmaceuticals, Inc. (MIRM) Earnings Call Transcript & Summary

Ladies and gentlemen, thank you for standing by, and welcome to the Mirum Pharmaceuticals Inaugural IR Day Virtual Program. [Operator Instructions] As a reminder, today's program may be recorded. And now I'd like to introduce your host for today's program, Ian Clements, Chief Financial Officer. Please go ahead, sir.

Thanks very much, indeed, and good morning, everybody. Welcome to Mirum's Inaugural Investor Relations Day. For those of you who don't know me, I'm Ian Clements, CFO at Mirum. I'm super excited to be here today and glad that you could all join us to be part of what I believe promises to be a great event. Before starting, I would like to remind everybody that we will be making forward-looking statements today. So investors should read the risk factors set forth in Mirum's Form 10-K for the year ended December 31, 2019, and any subsequent reports filed with the Securities and Exchange Commission. So I do encourage you to visit the SEC website to see our latest filings. Before turning to today's agenda, it would be remiss of me not to mention today's news. Earlier this morning, we announced that we'd entered into a financing arrangement with Oberland Capital. I'm very excited about the flexibility that this strategic financing partnership gives us, as we potentially head towards both a U.S. and a European launch. Just recapping a few of the highlights of the deal here. This gives us access of up to $210 million. The structure is that it is a capped tiered revenue-based funding agreement based on net revenues of maralixibat. In terms of the funding itself, there are tranched payments consisting of -- by the end of the year, $60 million, including $10 million in an equity investment; $65 million upon acceptance of our rolling NDA filing for maralixibat in Alagille; a further $35 million upon approval of maralixibat in Alagille; and finally, $50 million for potential new product acquisitions. So with that summary of this morning's news, let's get to the agenda. We'll be covering a number of topics today, focusing on our 2 ASBT inhibitors for rare cholestatic liver disease in children and in adults, namely maralixibat and volixibat. Additionally, we'll also be covering in some detail our launch planning activities. From a core logistics perspective, we will take questions at the end of the meeting via telephone. With that, it's my pleasure to introduce today's guest speakers. Dr. Phil Rosenthal is the Director of Pediatric Hepatology, Medical Director of the Pediatric Liver Transplant Program and a Professor of Pediatrics and Surgery at the University of California, San Francisco. He joined the UCSF facility in 1995 after serving as Professor of Pediatrics at UCLA. Our second speaker today is Professor Catherine Williamson. She is a professor of Women's Health at King's College London and an Honorary Consultant in Obstetric Medicine at Guy's and St. Thomas' NHS Trust. She's also a Fellow of the Academy of Medical Sciences. Her focus is on the endocrine signals that influence alterations in bile acid, lipid and gluco-homeostasis in normal and pathological gestation. She also studies the maternal and fetal etiology and outcomes of ICP, which will be the focus of her discussion today. In addition to our guest speakers, I'm delighted to be joined by some colleagues of mine from Mirum. Rather than spend time going through their bios here, I won't say much to say, the team has come together with the breadth and depth of experience across not only liver disease but rare diseases. And importantly, as we approach launch, commercial expertise that spans over 50 medications. So today, we'll be joined by Chris Peetz, our CEO and Founder; Pam Vig, our Chief Scientific Officer and Co-Founder; Ed Tucker, our Chief Medical Officer; Peter Radovich, our Chief Operating Officer. And during the Q&A session, Lara Longpre will also be joining us for Q&A, our Chief Development Officer and also a Co-Founder. So without further ado, I'll hand the microphone over to Chris. Chris?

Thanks, Ian, and thanks, everyone, for making time to learn more about Mirum and our programs today. At Mirum, we're very excited about what we've built and the future ahead and leading the way in rare liver disease with a focus on bringing life-changing medicines to patients in need. That's built on a foundation of what's upon us in the year ahead with the launch of maralixibat and advancing maralixibat in 2 important near-term indications of Alagille syndrome and PFIC. We'll spend some time today digging into the science and data behind that program. Quite excited about having our guest speaker, Dr. Rosenthal, talk through those programs. And we've established a growth profile behind that with a pipeline of indications directly targeting cholestasis and the bile acids that create such burdensome diseases and poor outcomes, with programs launching in biliary atresia, primary sclerosing cholangitis and intrahepatic cholestasis of pregnancy. Very excited about unveiling some of the details of those programs as we get into the programming here today. All of this, the team with a track record of success and tremendous market potential, I'm excited about what the future holds for Mirum. Looking at the pipeline and some of the topics that we'll touch on today starting with maralixibat in the pediatric cholestasis settings. When Alagille's -- in Alagille syndrome, we're in the midst of our rolling NDA with all of the clinical and nonclinical modules now completed and submitted, waiting on the expected completion of the CMC module to be submitted in the first quarter. As part of our commitment to addressing the unmet need in patients within this setting, we also have an open expanded access program available across many countries in North America and Europe. Behind this, we are advancing maralixibat in primary -- progressive familial intrahepatic cholestasis, or PFIC, with exciting news last week about the validation of our MAA for PFIC type 2. In parallel to that filing, we also have ongoing Phase III study, the MARCH-PFIC study, allowing for label expansion potential with higher doses of maralixibat and additional PFIC subtypes that's on track for completing enrollment in the second quarter next year. And then in the expansion areas with biliary atresia, a new Phase IIb study that we'll talk a bit in detail about here today. In the adult cholestatic settings, volixibat is initiating Phase IIb studies in primary sclerosing cholangitis and intrahepatic cholestasis of pregnancy, both of which on track for randomizing the first patient in the first quarter of this year. That backdrop and what we have ahead of us in 2021 is really just the beginning of the potential for Mirum, with a vision of creating a leading company in rare liver disease, addressing unmet needs and advancing standard of care across a number of different settings, looking to the future of multiple commercial products and an expanded portfolio of agents that can target rare disease. At Mirum, as we approach development and advancing some of these important medicines, we always start with the need and the patients. And so we'd like to do the same here today and share some of the patient journeys of families with Alagille syndrome and PFIC. And so with that, let's hear it from some of the words of the parents of children with these conditions. [Presentation]

And as you can tell, this is hard to put into words on a page what the clinical burden is for these settings. And I thank the families for contributing their stories as we've put these materials together. Really highlights the need and humbles us to be able to work in these settings. And moving into the next section of our programming here, I'd like to highlight what we've seen from the Alagille syndrome data and our PFIC studies. Within Alagille syndrome now with multiple randomized studies and 5-year follow-up, we've seen significant durable reductions in that cholestatic pruritus that you heard described in the video, which is one of the highest clinical needs in this setting as well as improvement across other markers of cholestasis: serum bile acids, xanthomas and growth. And then in our PFIC study, we've seen now an improvement in 5-year transplant-free survival in those that have a serum bile acid response to maralixibat as well as an event-free survival analysis showing an advantage for maralixibat against a matched natural history control group that was submitted as part of our MAA filing. And quite excited about what the ongoing MARCH study means to show more beyond what we have already demonstrated in our clinical program. So with that, now I'm quite excited to turn it over to Dr. Phil Rosenthal to get into a bit more of the science and data behind maralixibat in pediatric cholestasis. Dr. Rosenthal?

Thanks very much, Chris. It's a great pleasure to be here and to be able to share my enthusiasm for what is going on in these rare diseases in the pediatric population. So let's begin with an understanding of what indeed is cholestasis. And by definition, cholestasis is a direct disruption of bile flow leading to clinical symptoms and serum laboratory abnormalities. And there are 3 different areas of cholestasis that we're going to focus on today. The first is Alagille syndrome, which you can see here reflects problems with the intrahepatic bile ducts. There's actually a paucity or decreased numbers of these ducts in the liver. Biliary atresia, the leading indication for liver transplants in children, affects both the extrahepatic bile ducts and the intrahepatic bile ducts. And PFIC, or progressive familial intrahepatic cholestasis, refers to bile acid movement and transport from the hepatocyte into the canaliculi. Now cholestasis is actually observed in numerous pediatric diseases. And certainly, we don't have time to go through all of these different disorders. But again, we're going to focus on Alagille's, biliary atresia and progressive familial intrahepatic cholestasis. Cholestatic liver diseases can significantly impact patient quality of life. And I'm sure you noted that in the families' descriptions of the problems that their children had with their cholestatic liver disease. They can have long-term deficits in cognitive skills and obviously, decreased quality of life, even following a liver transplant. These can be reflected in impaired school performance, sleep disturbances and fatigue, pain, decreased physical functioning and general health, mental health problems and depression, a negative impact on a child's social activities and behavioral issues. Now let's dig in a little deeper about differences between Alagille's, PFIC and biliary atresia. As I mentioned, Alagille's occurs because of intrahepatic bile duct paucity but it's also multi-system. And there are other organs such as vertebral abnormalities, butterfly or hemivertebrae, ophthalmologic findings, problems with the heart, such as peripheral pulmonic stenosis that are all associated with Alagille syndrome. Alagille is an autosomal-dominant mutation in the Jagged 1 or Notch 2 genes. Patients present with cholestasis in the first 3 months of life, and it's negatively impacted by the surgery that's utilized in biliary atresia, known as the Kasai procedure. PFIC occurs intrahepatically, and the 3 biggest PFIC disorders are PFICs 1, 2 and 3. And these are autosomal recessive mutations in ATP8B1, ABCB11 or ABCB4. And this results in disruption of bile flow and transport from the liver cells, the hepatocytes, into the canaliculi, the bile ducts. This also typically presents with cholestasis, that's jaundice and itching, in the first 3 months of life. This can improve with some surgical management, as was mentioned in the film of biliary diversion. But most patients require a liver transplant as the disease progresses. Biliary atresia occurs both intra and extrahepatically affecting the bile ducts. Greater than 80% of biliary atresias are not genetic. Most recently, the biliary atresia splenic malformation syndrome has been noted to be due to the gene, PKD1L1. This is an inflammatory or necroinflammatory bile duct obliteration that occurs. Patients present with jaundice and pale-colored stools, also known as acholic stools, between 2 to 6 weeks of life. This can improve with surgical management. This is the Kasai portoenterostomy, and approximately 50% of patients will need a liver transplant in the first 2 years of life if they're diagnosed with biliary atresia. Now the outcomes to surgical intervention. Liver transplant is frequently required, and you'll note here that transplant-free liver survival is poor across Alagille's, PFIC and biliary atresia. If you look at the far left slide in Alagille syndrome, you'll see that transplant-free survival in Alagille's is only 24% at 18.5 years of age. In PFIC2 or BSEP, survival with native liver in patients with a non-truncating PFIC2 BSEP problem undergoing surgical biliary diversion, with a surgical biliary diversion, they have better outcomes than with no surgical diversion. But you'll see here that only 32% have transplant-free survival at 18 years of age. And this is partly the result of the fact that the disease progresses even in spite of surgical diversion. In the right-hand panel, biliary atresia is only 15% to 20% transplant-free survival by adulthood. And if you look at this curve, you'll see that overall survival is in the 90% range. That's due to the fact that these patients undergo liver transplantation, which in children, nowadays, has over a 90% success rate. But transplant-free survival without a liver transplant, you can see, is much, much lower. Maralixibat has significant potential to impact these children's lives. So let's talk a little bit more about that. Maralixibat reduces toxic accumulation of bile acids. And by reducing bile acids, maralixibat may reduce the toxic effects of some of these bile acids, potentially improving both the pruritus and other quality of life measures. The way this works is that maralixibat is what's known as an IBAT inhibitor or intestinal bile acid transport inhibitor. Normally, bile acids are reabsorbed in the terminal ileum, the last part of the small intestine, and through an enterohepatic circulation, they recirculate back up to the liver. By blocking the absorption of these bile acids in the terminal ileum, maralixibat increases fecal bile acid excretion. And ASBTi or these inhibitors, clinical studies show that there's reductions in pruritus, reductions in serum bile acids and impacts on bile acid pharmacodynamic markers, such as cholesterol, which is the nucleus of bile acids, 7-alpha-C4 and FGF19. So let's get into a little bit more detail into the studies on Alagille syndrome. As I mentioned, Alagille's is a rare debilitating autosomal-dominant disorder. About 90% to 98% of the mutations are in the Jagged 1 gene and about 2.5% are in Notch 2. And nowadays, genotype testing is the preferred method to confirm the diagnosis. In the days before genetic testing were available, one actually needed to go by clinical acumen to make that diagnosis, looking at the characteristic facies, whether or not there were vertebral abnormalities, whether or not there were ophthalmologic abnormalities, if there were cardiac lesions. Notch signaling regulates the development of the intrahepatic bile ducts, the craniofacial structures, the heart, kidney, spine and vasculature. And that is the reason why many of those organs are affected in Alagille's. The interesting thing is that not all patients have problems in all of these different organs. Now Alagille's at a glance. This is a complicated and burdensome disease as I'm sure you've already heard. Diagnosis includes genetic testing, the heart and blood vessel test, an eye exam, spinal X-rays, abdominal ultrasound, kidney function tests and even a liver biopsy. Signs of Alagille's related to the cholestasis include the yellow skin or eyes or jaundice and icterus, severe itching, stunted growth and xanthomas. Organs affected by Alagille's, as we've mentioned, include the liver, heart, kidneys or central nervous system. Children with Alagille's experience severe, unrelenting itch, as was demonstrated in the film that you just recently saw. And there's disruptions in sleep and impaired quality of life. Alagille's indications for transplant are predominantly due to these terrible symptoms and poor quality of life. There are, however, some patients that do go on to end-stage liver disease with cirrhosis and portal hypertension. There's only 24% transplant-free survival at 18.5 years in cholestatic Alagille syndrome. And currently, there is no approved medications that exist to treat Alagille syndrome. We use off-label drugs like rifampin and antihistamines to try to control the itch. We use off-label ursodeoxycholic acid to try to improve the cholestasis. And then eventually, we use liver transplants to get rid of the problem altogether. The disease most commonly manifests as pruritus and xanthomas, and here is just further examples of the severe itching that can be seen. Here, you can see the crib with blood from the severe itching occurring day and night in this child. And the middle panel has the characteristic facies of an Alagille's patient with a pointed chin, broad forehead and wide-spaced thighs. And then on the right panel are the xanthomas due to these cholesterol deposits in the skin. Just an anecdote, I had a patient who had severe xanthomas from his Alagille's syndrome. He could not hold a pen or a pencil. Luckily, he was able to use a computer to do some of his work. To roll ahead from about 20 years, this patient that I followed his whole life, eventually, did receive a liver transplant. And after going to school, [Audio Gap] the phlebotomist, I'm sure that, that was secondary to his multiple blood draws over the years and his experience in dealing with the medical profession. So let's look at maralixibat in the Alagille's patients. So there were significant reductions in serum bile acid levels that were maintained long term. If we look here on the graph, we'll see at the baseline over on the left-hand side that mean serum bile acid levels were elevated. The patients in -- on all parts of this study received maralixibat, and you can see that there was a significant decline in serum bile acid levels by 12 weeks. Patients were then randomized to either continue on the maralixibat or to receive placebo for the next few weeks. And you'll note, in red, the patients that went from the maralixibat to the placebo had an increase in their serum bile acid levels, again, back up to their baseline levels, whereas the patients who maintained on maralixibat continued to have a decline in their serum bile acid levels. Then if we go to week 22, where all patients were again put back on maralixibat, you can see that even in the patients who had been on placebo, there was, again, a decline by 48 weeks to lower levels of serum bile acid. And then in the extension phase of the study from weeks 48 on, you can see that there continued to be, on maralixibat, declines in serum bile acid levels. Now what about itching in these patients? There was, again, observed significant reductions in pruritus levels long term. Same group of individuals is in the other slide, and you can see that they start over on the left at baseline with just considerable itching. They go on the maralixibat, their ItchRO score, their observed itching parameters, decrease. The patients who are in red with the placebo go back up to their baseline when they are off the maralixibat. And then when they're placed back on maralixibat, they decline in their itching and this continues to progress over the course of the extension trial with improved itching in all of these patients. Next slide. If we look also at long-term xanthomas and growth in these patients, you'll see that clinical xanthoma scale scoring decreases. And in the long-term extension over on the right -- left-hand panel, this decreases further. This is really great for many of these patients. And further, which is really nice to see, is that their height percentiles increase from baseline to week 191 up to 16%, which again, children's most important thing is to be able to grow. And this is clear proof that the maralixibat is helping these patients to better absorb fat, fat-soluble vitamins necessary for their growth. Also, we need to be concerned about safety when we're using these new drugs. And the safety summary of the ICONIC and placebo-controlled summary of the ITCH and IMAGO studies shows that maralixibat is well tolerated and has comparable GI events to placebo. And not to go through all of these but to just focus on diarrhea, which is known to be a side effect of malabsorption of bile acids in the intestine, which is what IBAT inhibitors do by blocking the reuptake of bile acids in the terminal ileum. And you'll note here in the shaded green that in both studies, maralixibat, compared to placebo, had identical percentages or numbers of patients with diarrhea as was the placebo. Now let's switch gears and look at progressive familial intrahepatic cholestasis, which for the sake of our discussions, I'm going to only refer to as PFIC. PFIC is a heterogeneous group of rare diseases that disrupt bile formation. And the 3 major PFIC groups that we're going to focus on is FIC1 or PFIC1; BSEP, which is the bile salt excretory pump defect, which is PFIC2, which happens to also be the most common form of PFIC; and MDR3, or multidrug resistance 3, or PFIC3. In FIC1, the gene is ATP8B1. The protein is known as FIC1 and its functional defect is bile salt secretion. I should also mention that FIC1 is not only expressed in the liver but is also expressed in the intestines and is also expressed with hearing. And many of these patients, besides having the problems with the biliary problems, also can have hearing loss and can have diarrhea from FIC1. BSEP is ABCB11, and this is a bile salt secretion from hepatocytes into the bile canaliculi. In BSEP, this disease seems to be more progressive, much more rapid and much worse than the other PFICs and has even been associated with hepatocellular carcinoma as young as 2 years of age in the literature. MDR3 is the ABCB4 and is related to phospholipid excretion into the bile. And this causes increased biliary lithogenicity, which gives rise to potential for gallstone formation. And genetic testing is the only reliable way to distinguish between PFIC subtypes. Again, before we had the ability to do genetic testing, we had to rely on clinical symptoms, and this would involve either familial diagnoses or the fact that in both FIC1 and BSEP, these patients have low or normal GGT or gamma-glutamyl transpeptidase levels, while most patients with cholestatic liver disease actually have elevated GGT levels, which is also seen, for example, in MDR3, PFIC3. So in PFIC2 or the BSEP, the most common and most aggressive of the PFIC subtypes, as I mentioned, and that we are learning now that the clinical severity of BSEP deficiency is linked to the type of ABCB11 mutation, and it predicts the survival of the native liver. So if we look here on the left, if you have a mutation in one copy of D482G or E297G, this is a non-truncated mutation, this is referred nowadays as BSEP1 and its predicted severity is mild. And in fact, median native liver survival is about 20.4 years, as illustrated on the right-hand curve. Now if you are -- have at least one missense mutation other than those 2 already mentioned, this is again a non-truncated mutation. This predicted severity is moderate and if you look on the right-hand curve, you'll see that the median native liver survival is 7 years, so much decreased. But if you go then down to BSEP3, which is nonfunctional protein, nonsense or frameshifts or splice site mutations, these are truncated mutations. The predicted severity is severe and, in fact, median native liver survival is only 3.5 years. So PFIC2 accounts for almost half of all the PFIC cases. And this journey begins in infancy and it impacts the whole family. We've already heard a bit about these. I'm not going to go through all the details here, just to point out that they have debilitating itch, stunted growth, vitamin deficiencies, progressive liver damage and ultimately, liver failure and need for transplant. There's less than 1,000 children with PFIC2 in the U.S. and Europe. PFIC impacts the entire family, as we saw in the films, and there's no approved medications to treat PFIC at the current time. So what about maralixibat's use in PFIC? So here's the INDIGO study, which was a Phase II open-label study in children with PFIC looking at ItchRO reported pruritus scores over time in PFICs 1 and 2. And PFIC1 is in the red, and PFIC2 is in the blue on this slide, and you'll see that ItchRO scores decreased significantly over time in these patients. There were 8 with PFIC1, 25 with PFIC2. And 19 of the PFIC2 patients had non-truncated mutations, as we showed earlier in the other slide. They received maralixibat for 266 micrograms per kilo every day for years 1 and 2 and then 266 micrograms per kilo, once a day or twice a day in years 3 to 6. There were 10 sites in 4 different countries, and you can see here improvements considerably, especially in the PFIC2 patients. In fact, serum bile acids decreased to normal levels and many of these patients' mean ItchRO scores decreased significantly and height percentiles increased significantly. Serum bile acid control is associated with transplant-free survival. Patients who achieved the serum bile acid threshold of less than 102 micromoles per liter or a 75% reduction experienced native liver survival to 15 years, post-surgical biliary diversion data from the NAPPED consortium, which is a worldwide consortium groups that are studying patients with PFIC. And you'll see here on the panel A on the left, if the serum bile acids were less than 102 micromoles per liter after the diversion, that close to 100% of those patients survived with their native liver. Whereas if the serum bile acids after the diversion were greater than 102, you can see that survival of native liver was not as good. The same on panel B. If they were greater than 75% decrease in serum bile acids, they did very well, but not so well if there was less than 75% decrease in serum bile acids. INDIGO serum bile acid response associated with transplant-free survival. 100% of maralixibat serum bile acid responders remained transplant-free over greater than 5 years of treatment. This is quite amazing. Improvement or normalization of liver parameters, growth and quality of life, as I've shown you in some of those other slides, also occurred in these patients. And again, you can see here that close to 100% survival without the need for a liver transplant is just remarkable. So the drug is really doing what we hoped that it would do. In over 5 years of treatment experience for patients with PFIC, again, the safety summary looks very good. There were really no differences between the patients on maralixibat and the control group. Again, most frequent related AEs are diarrhea, as expected, but these in the majority of the patients were transient and not requiring them to have to stop the medication. So now let's switch gears to the last disease, biliary atresia. Biliary atresia is an inflammatory cholangiopathy of infancy. We don't know the cause in the majority of cases of biliary atresia. It's a necroinflammatory destruction of the bile ducts involving the intra and extrahepatic bile ducts. In the old days, we used to refer to the disease as extrahepatic biliary atresia because of the destruction of those bile ducts. But we now know that biliary atresia affects both intra and extrahepatic bile ducts, and that's why we just call it biliary atresia. This leads to bile accumulation in the liver and results in progressive cholestasis and liver damage. You get scarring and fibrosis, which goes on to cirrhosis. It presents after the first 2 weeks of life, though there's much data now to suggest that this might even be occurring in utero. The Kasai procedure or the Roux-en-Y portoenterostomy is performed within the first weeks of life. It's the current standard of care. It occurs in about 0.5 to 0.80 per 10,000 live births, so it's rare. Patients post-Kasai have been attempted to use steroids or antibiotics or immunoglobulins, but these have not been shown to have any efficacy. And as I've mentioned earlier, it's the #1 cause of pediatric liver transplants. These patients have damage to both the intra and extrahepatic bile ducts. There's a patient in need of a liver transplant. They have jaundice, acholic stools, dark urine. They can have non-hepatic malformations. Also, they can have heart lesions, for example. They can get bleeding, failure to thrive, a big distended abdomen full of ascites fluid. They get liver fibrosis and cirrhosis, with portal hypertension and gastrointestinal bleeding from varices. And they certainly need a liver transplant. We know that biliary atresia is the leading cause worldwide of pediatric liver transplants. And there's increasing evidence that biomarkers might be predictive of the need for a liver transplant from our Childhood Liver Disease Research Network, which I actually am a part of. Bilirubin post-hepatoportoenterostomy may predict future transplant. If your bilirubin is less than 2 on the left-hand panel, you can see that patient's need for a liver transplant is much less than if your bilirubin is between 2 and 6 milligrams per deciliter or greater than 6 milligrams per deciliter. And over in the right panel, similar to bilirubin, if your serum bile acids post-hepatoportoenterostomy are in the normal range, the likelihood of transplant is exceedingly low. But if your bile acids are elevated over 40 micromoles per liter, the likelihood of liver transplant as time goes on increases significantly. So in closing my part of the talk here, I just want to point out a few things. Maralixibat may provide an alternative to liver transplant for patients with pediatric cholestatic diseases who are in desperate need of treatment. There is certainly a tremendous unmet need in pediatric cholestasis with a high burden and with transplant rates that are higher than we would like. In Alagille's, maralixibat shows durable reductions in itching and long-term improvements in xanthomas and growth. In PFIC, maralixibat shows 5-year transplant-free survival, which is just amazing. And maralixibat has promise to impact biliary atresia. I would now have the honor and privilege to turn over my part of the program to Dr. Ed Tucker, who is going to fill you in on the current maralixibat studies.

Thank you, Dr. Rosenthal. I really appreciate that very detailed description of 3 pediatric cholestatic diseases that are within the maralixibat clinical development program. You gave a clear description for the 3 diseases, the data that we've generated so far in the development program, and then also the data which is enabling our registration pathways in the United States, the Alagille NDA, and also for the PFIC submission in Europe, which was recently validated. But now I want to turn to some trials, which are ongoing or soon to be started. And the first is the Phase III study, which was mentioned earlier, that's our MARCH-PFIC study, which involves 30 patients with non-truncating PFIC2 and an additional 60 patients in the supplementary cohort to explore other PFIC types. And in this study, we're extremely excited to explore maralixibat at the higher dose to see whether or not we can drive deeper responses for our patients with PFIC and also a broader responder rate. The patients have been enrolled into the study, randomized in a 1:1 fashion with maralixibat at 570 BID. At 6 months, we'll measure the primary endpoint of ItchRO, which is a measure of pruritus in the PFIC2 patients. We will also look at the secondary endpoints of pruritus, serum bile acids and, of course, safety, and additional endpoints will explore the supplementary cohorts to see the effects of maralixibat in those other PFIC types and also examine quality of life and growth. All the patients from this 6-month study will have the opportunity to then further their maralixibat treatment in an open-label extension, where we'll capture efficacy and safety, which will enable us to potentially compare with a natural history comparison in the future. Our enrollment is planned to complete in quarter 2 of 2021 for the study. And this potentially is label-enabling for us in the future in regulatory discussions. Now turning to biliary atresia. We have designed a study, which is a biomarker-driven study to explore the use of maralixibat in biliary atresia. This is the EMBARK study, where we'll enroll 72 patients into the primary cohort. Those patients are less than 3 months old, but they've had a Kasai surgery already. We're also enrolling a supplementary cohort of children who are older up to the age of 18 years old. These patients will be enrolled into the maralixibat versus placebo for a 6-month study. And at that point, we will measure the change in the total serum bilirubin, as was shown earlier by Dr. Rosenthal, as a potential marker for improvement of outcomes in this disease area. We'll also measure serum bile acids, bilirubin normalization and other markers of liver injury, including transplant-free survival. All patients after 6 months of treatment will then be able to continue in an extension study where all patients will be treated with maralixibat, and that will enable us to gather further efficacy and safety and that potentially can offer, again, another comparison with a natural history cohort. We're excited to be able to bring our first patient in. We anticipate it's going to happen in quarter 1 of next year. So I'm sure you'll agree that maralixibat, based upon Dr. Rosenthal's presentation and some of the anticipated results that we could hope for in our clinical program, offers the potential for a transformative new treatment in pediatric cholestasis. For Alagille, we're launching maralixibat in the United States as an alternative to liver transplant in the future. In PFIC, as Dr. Rosenthal showed earlier, we have the 5-year transplant-free survival, which enabled our registration pathway with the European Agency. And as I mentioned, our MAA was validated recently. For biliary atresia, we are very excited to see how the EMBARK study can influence the outcomes of patients with biliary atresia with the potential for maralixibat to be disease-modifying in that space. Overall, we believe that the maralixibat clinical development program in rare pediatric liver diseases has the potential to deliver 3 global indications in high unmet medical need for these children. Now I'm going to turn my attention to volixibat, which is our second ASBT inhibitor in Mirum. I'll quickly go over the mode of action that we'll expect. It's very similar to maralixibat, which was provided by Dr. Rosenthal in his presentation. It's an ASBT inhibitor that inhibits the enterohepatic circulation of fecal bile acids and thus increases the excretion of fecal bile -- the excretion of bile acids via the fecal routes. As you heard earlier, this confers clinical benefit and reductions in pruritus in cholestatic liver disease, reductions in serum bile acids and improvements in pharmacodynamic markers, including cholesterol, 7-alpha-C4 and FGF19. Volixibat is highly active in increasing the excretion of bile acids. The right-hand panel here that I'm showing is demonstrating a recent healthy volunteer study, which enrolled 60 patients into 5 dose cohorts. And as you can see here, there is a linear dose response from 5 milligrams BID to 80 milligrams BID when measuring the biomarker of 7-alpha-C4. And this is informing for the future registrational studies, which we plan for volixibat and the doses that we will provide in those studies. We also have the support of earlier studies of a 48-week safety data, which was provided to us and provides information on safety with this medicine. So the focus of our clinical development program for volixibat is intrahepatic cholestasis of pregnancy and primary sclerosing cholangitis. Both of these diseases have very high unmet medical needs. In the United States, there are 29,000 patients who have PSC and 50,000 patients in Europe. With ICP, approximately 1% of pregnancies worldwide are affected by ICP. But also in some populations, over 5% can be afflicted by this disease. And as you'll hear from Professor Williamson shortly, there are no approved therapies neither for intrahepatic cholestasis of pregnancy nor PSC, which Dr. Vig will present later. So it's my pleasure to introduce Catherine Williamson, who is a world-renowned expert in ICP, who will describe both the disease and also the design of our study with volixibat. Thank you so much.

Thank you very much, Ed. Intrahepatic cholestasis of pregnancy is the commonest gestational liver disease. As Ed mentioned, it affects approximately 1% of pregnant women. It affects more women of South Asian or South American origin. Pregnant women with intrahepatic cholestasis typically present with pruritus and following a blood test, are identified as having abnormal liver function, characterized by elevated serum bile acids and liver transaminases. The extent of the elevation of serum bile acids is variable. They are always over the normal rate for pregnancy, which is about 10 micromoles per liter, but 25% are over 40 micromoles per liter and about 10% over 100. And I've managed women with considerably higher serum bile acid concentrations as well. The elevation of AST and ALT liver transaminases is variable and may relate to the underlying etiology. Of relevance to this, about 20% women have mutations in the ABCB11 and ABCB4 genes that you've heard about, and a small proportion have other genetic variations in known biliary transporters and genes of relevance to cholestasis. The condition typically presents in the second or third trimester of pregnancy. This is likely related to elevated reproductive hormones, which can also influence bile acid homeostasis. And in most women, it resolves relatively rapidly after delivery, again likely due to the reduction in the reproductive hormones concentration after delivery of the baby. The condition causes maternal features, in particular, pruritus and liver impairment. But also, obstetricians and obstetric physicians such as myself are concerned because there is an increased rate of a number of adverse pregnancy outcomes, including stillbirth and preterm birth. As a consequence, we are very keen to identify effective therapies for both maternal and pregnancy outcome concerns, and there is a high unmet need for therapies for both. To understand effective therapies for cholestasis in pregnancy, it's important to understand bile acid transport from the baby to the mother in normal pregnancy and then in ICP. Whilst I'm sure most of you will know about bile acid synthesis in the liver, that bile acids are transported within the bile to the gallbladder, released into the gut where they aid fat absorption, and about 5% are lost in feces every day. You may not know that the fetus synthesizes bile acids from early in gestation. And by the end of the first trimester, there is known to be a gradient of bile acids that flow from the fetus to the mother because the fetus is not able to eliminate bile acids, obviously, by passing them in the feces. So transplacental transfer enables the mother to be capable of eliminating the bile acids from the fetus, but the fetal bile acid concentrations are relatively low. In intrahepatic cholestasis of pregnancy, in contrast, the maternal serum bile acids are considerably higher than the fetal bile acids. And as a consequence, the gradient shifts such that the mother's bile acids are transferred to the fetal circulation and fetal compartment. And it's thought that this is the reason that there is an increased risk of the adverse pregnancy outcomes, including preterm birth and stillbirth. So firstly, just to focus on the maternal features of the condition. Aside from impaired hepatic function and the elevated bile acids, most women have pruritus. It's typically generalized and usually more marked on the palms and soles of the feet. As with the children with rare liver diseases, although there's not a rash associated with the pruritus, excoriations are common. And the pruritus can be very severe, such that many women cannot sleep, and then this in turn is associated with impairment of quality of life, fatigue and anxiety. To put this in context, I was one of the principal investigators of a recent large trial in -- of ursodeoxycholic acid as a potential treatment for women with cholestasis in pregnancy. We studied just over 600 women who were randomized either to ursodeoxycholic acid or placebo. And through the study, we evaluated the extent of their pruritus. And the typical score on a visual analogue score up to 100 millimeters was somewhere between 50 and 60. But there is a subgroup that had much worse pruritus, which causes considerable distress, and this was a feature that wasn't considered in terms of decisions about initiation of delivery. Thinking about the adverse pregnancy outcomes, as I've mentioned earlier, there is quite a marked increase in women with raised bile acids in cholestasis of preterm birth, also asphyxial events and features of fetal distress, such as meconium passage, which is where the baby passes feces into the amniotic fluid. There is also an increased risk of stillbirth and increased perinatal mortality. In terms of the morbidity, particularly spontaneous preterm birth and mortality associated with elevated maternal serum bile acid concentrations, this is the only biochemical measurement in the blood that has shown to be convincingly associated with the adverse outcomes. 40 micromoles per liter seems to be a threshold in the blood. Above which, adverse outcomes occur. And then as the maternal bile acids continue to rise, the risk of the adverse outcomes also rises. So one of the studies, for example, showed that with a doubling of maternal serum bile acid concentrations, there is a doubling of the risk of stillbirth. So you can see at the bottom, the high rate of preterm birth that occurs in cholestasis in pregnancy. And many of you will know that preterm birth, aside from being very distressing and difficult for families, has a major economic implication as well related not only to the problems at the time of birth but also subsequent needs of the child. We'll come on to the next slide, please. So the treatment that has most commonly been used for cholestasis in pregnancy is ursodeoxycholic acid. This is the drug that we also studied in the large trial that we published last year in the journal, The Lancet. Unfortunately, most of the data emerging about ursodeoxycholic acid do not show that this is a very effective therapy for the cholestasis in pregnancy. Some studies have shown improvement in itch and in liver biochemistry. But in the study that we performed and published last year, where we studied just over 600 women, we showed that ursodeoxycholic acid treatment compared to placebo did not cause a reduction in maternal serum bile acid concentrations. It did have a slight impact on itch, but it wasn't a major impact. And the difference in itch on the itch analogue scores, on average, was about 7 millimeters. So it can be questioned whether this is sufficient to be clinically meaningful. Ursodeoxycholic acid also did not improve the rate of a composite of adverse pregnancy outcomes that included preterm birth, stillbirth and perinatal mortality and admission to a neonatal unit for 4 hours or more. So we very much need new therapies for cholestasis in pregnancy. Our current options for maternal pruritus and maternal disease are off-label use of ursodeoxycholic acid. And it's possible that a subgroup of women do respond, and the small improvement in pruritus may be sufficient for some women to be worth using it. But it's not a convincing therapy for the majority of cases. Similarly, rifampicin or cholestyramine can be used for pruritus, but again, the data don't show a major impact. And I personally would say, although dexamethasone has been used in the past for pruritus, it should really only be used for fetal lung maturity, as there are data to show that prolonged use of the drug can be detrimental to brain growth and subsequent function of the child. There are also over-the-counter treatments that can be used for pruritus. But again, there's limited effectiveness of these therapies. And for the adverse pregnancy outcomes, the intervention that is most commonly used by most obstetricians is elective preterm delivery. And this is because of concerns about the stillbirth, which does seem to occur increasingly with advancing gestation. So typically, most clinicians that decide to deliver early because of concerns about cholestasis would deliver at about 36 or 37 weeks of gestation. And from a paper that we published last year in the journal, The Lancet, I think that the 10% of women with bile acids over 100, many clinicians would now deliver at about 35 weeks. This is very reasonable in terms of concerns about stillbirth. But as most people will know, elective preterm delivery is not without risks itself. And in particular, there is evidence for increased hospitalization up to age 18 and poor cognitive performance and more school-related problems in later life. So on the background of the paucity of effective treatments for intrahepatic cholestasis of pregnancy, I'm delighted that the OHANA study is being developed and should be ready very, very soon for recruitment of patients. The study will recruit women with intrahepatic cholestasis of pregnancy, 260 women. And in the first instance, women will be randomized 3 ways to one of 2 doses of volixibat or placebo. And after the first 60 women have been recruited, there will be an interim analysis, firstly, to establish efficacy and safety, but also to select the dose that will be used for the subsequent 200 women that will be randomized on a one-to-one basis to the chosen dose of volixibat or placebo. And the primary endpoint for the trial will firstly be a change in serum bile acids from baseline compared to the placebo group, such an important endpoint because it's associated with the adverse pregnancy outcomes. And additional secondary endpoints will be safety, tolerability, pruritus and also other adverse pregnancy outcomes. So I will stop there, and I'm delighted to pass on to Dr. Pam Vig, who's going to talk about primary sclerosing cholangitis.

Thank you, Professor Williamson. It's a pleasure to be here talking to you today. I'll be speaking about primary sclerosing cholangitis or PSC. PSC is a chronic and debilitating cholestatic liver disease. It's characterized by bile duct strictures, which is a result of inflammation and fibrosis of the bile ducts. This leads to a backup or an accumulation of bile salts in the hepatocytes and also an elevated systemic serum bile acid level, which is resulting in a chronic cholestasis. And this disruption in the bile acid homeostasis really drives further inflammation, stellate cell activation, fibrosis as well as cirrhosis. And most patients will require a liver transplantation due to the progressive nature of the disease driven by this chronic cholestasis. Cholestatic itch can significantly impair quality of life in these patients. The prevalence is reported to be between 70% to 80% at any time during the course of the disease. And refractory pruritus, in and of itself, even in the absence of disease progression, is an indication for liver transplantation. The etiology is still under investigation of this disease, but it's thought to be related to a combination of genetic predisposition factors as well as environmental risk factors. The pruritus experienced by patients can be quite severe, leading to excoriation due to the constant scratching of the skin. And this itching doesn't stop at night and patients often complain of significant fatigue because of this. In a survey that was conducted by PSC Partners, if you look at the graph on the right, this survey was conducted in 819 PSC patients. Fatigue was the number one symptom likely driven by the daytime and nocturnal burden of pruritus. And 75% reported that pruritus had an impact on their lives, with just under 50% stating that pruritus had a major impact. And so this shows that pruritus in this setting is very likely to be underreported, possibly due to having no approved therapies to treat it. In instances of very severe pruritus, it can be quite disruptive to normal daily life and patients can be unable to work, unable to socialize. They become quite isolated and depressed. And this type of pruritus has been described as a suicidal itch. Elevated serum bile acids as well as primary conjugated bile acids have recently been linked to disease progression and clinical events, including liver transplantation and death as well as the severity of fibrosis. Also, altered genetic expression has recently been correlated with disease progression and research on this is still underway to further elucidate. With that, I want to talk about ASBT inhibitors in PSC. ASBT inhibitors are quite well poised to target the underlying cholestasis and pruritus in PSC by reducing the level of toxic bile acids and the accumulation and improving normal bile acid homeostasis. CAMEO was a Phase II open-label study, conducted in 27 patients using maralixibat. On the left, we show pruritus results and on the right, we show serum bile acid. On the left, pruritus was significantly reduced in the overall population of 27 as well as in those with any itch, which is the graph in the middle. And importantly, in those with the most significant pruritus or what we refer to as a clinically meaningful pruritus, we observed a 70% reduction. On the right, serum bile acids were also very significantly reduced in the overall cohort. And in those with the clinically meaningful itch, there was a 45% reduction in serum bile acids. And you can see that those with higher pruritus at baseline had higher serum bile acids. This data really positions volixibat as a drug that may reduce underlying cholestasis and the effects on pruritus and quality of life and can potentially have an impact on disease progression by reducing the accumulation of the toxic bile acids that drive liver injury. So I'm delighted to be presenting our Phase IIb PSC study with volixibat. This is quite exciting. The study is a placebo-controlled randomized study that will evaluate cholestatic pruritus in patients with PSC. The primary endpoint is the change in pruritus after 28 weeks of treatment. The study will enroll 120 patients and a minimum threshold of pruritus score will be required. Patients will be randomized in a 1:1:1 ratio to receive one of 2 doses of volixibat or placebo, and an interim analysis will be conducted so that we can evaluate the safety and efficacy of volixibat in order to take one dose forward into the pivotal phase of this adaptive study. Other endpoints will include serum bile acid, quality of life as well as markers of fibrosis. And after the completion of the 28-week study, importantly, patients will be allowed to transition to an open-label phase, where the durability of response, pruritus and serum bile acids can be assessed as well as other markers of disease progression related to the underlying cholestasis. To summarize what we've just heard in totality for volixibat, there are no approved therapies for both ICP or for PSC. And patients cycle through unapproved treatments without getting a durable relief of their symptoms or an appropriate reduction in serum bile acid. So we're very pleased to announce that both the PSC and the ICP studies are kicking off with first patient and planned for the first quarter of 2021, and we look forward to addressing the unmet need in these important indications with volixibat. And with that, I would like to hand it over to Peter Radovich.

Thank you, Dr. Vig. I'm very excited to have the opportunity today to review with you some of the activities that are going on here at Mirum to prepare to launch maralixibat next year in 2 pediatric cholestatic liver diseases, Alagille syndrome and PFIC, and to facilitate the transition back to talking about the pediatric setting, again, as well as to set context for these activities. I'd just like to take a moment to bring back into focus the patient and caregiver experiences that you heard about earlier in the video. You never forget the smell of blood in the morning when you first walk into the room. He wore nothing but footed pajamas until his fifth birthday. They protected his skin from the open cuts that developed from his constant itching. We have seen our 6-year old have surgeries, be rushed to hospitals, confound doctors and medical teams, scream in agony, wake up covered in everything from blood to scratches to leaking tubes. I think there's no way, as Chris said at the outset, that we can fully characterize the awful and horrific burden that these families and children have to bear, which really, for many of these patients, truly rob them of their childhood. In terms of what is available to take care of Alagille and PFIC patients today, really, as was reviewed earlier, there are a handful of off-label treatments that are used in this very unsatisfied market setting that really have a very limited impact on the natural history as well as the symptoms. Urso is given very frequently, but quite often or so substantially, always urso is not enough. And things like antihistamines, rifampicin and SSRIs even are tried to try to control that horrible pruritus that you've heard about today. And I think in the words of the KOLs here, it's -- rifampin is an old antibiotic. It's used to treat the pruritus but really has quite a variable effect and a fleeting effect for these patients. And the perspective of caregivers being that rifampin and other such treatments are really just a mask and don't really fix the underlying problem. So that sets up really what we at Mirum hope to do with maralixibat and exploit its potential to transform the paradigm of treatment in Alagille and PFIC from the current paradigm that's shown here, which is symptoms, various off-label pharmaceutical interventions, unfortunately, increasing severity of symptoms that lead to surgical intervention and ultimately, transplant in a large majority of the patients. And then the hope and ambition that we have for the future is that really upon diagnosis, there's an opportunity with maralixibat to address the cholestasis itself and all the things that you'd hope that flow down from an effect on cholestasis, including symptoms, pruritus, xanthomas, in the case of Alagille, quality of life improvement and extension of event-free survival and really, the promise that maralixibat can delay or avoid liver transplantation. So we spent a fair bit of time at Mirum talking to a lot of experts, but not just the sort of top experts in the disease but also GI hepatologists who spend most of their time doing clinical care, neonatologists, nurse practitioners, physician assistants as well as payers from around the world, particularly United States and European countries and families. And reviewed the product profile we have with them to get their feedback as we prepare to commercialize the product. And at Mirum, we're very encouraged by what we've heard, which really centers around a lot of receptivity to the long-term efficacy and safety data that we've been able to generate in the clinical development program. On the efficacy side, we -- our stakeholders are really very impressed with the dramatic and durable anti-cholestatic effect and all the clinical benefits that go along with that. On the safety side, I think there's a couple of points to make here. In the context of this very severe and sometimes life-threatening disease or these diseases, the safety profile itself is seen as very acceptable and favorable. Mild-to-moderate GI effects really being seen as acceptable in the benefit-risk profile here and even creating a lot of interest amongst clinicians to trial the product in a broad variety of patients, given that profile. But I think just as important as the profile is really how well described the profile is and that we have over 120 pediatric patients who have been exposed to this and several with greater than 5 years of exposure. It's not a common safety database to have for an ultra-rare product at the time of approval. And that, I think, certainly in the minds of several stakeholders, physicians, payers, families, is an important attribute of the profile that we're bringing to market. We've also had a lot of positive feedback on the administration for maralixibat. The flexibility to provide it once or twice daily. Obviously, in Alagille, we'll be going forward with once daily. But the safety and efficacy data to back up the scenario where a clinician could escalate to twice daily for this very severe disease and attempt to capture more responses, that is really viewed very favorably. The grape-flavored oral solution, much like Children's Tylenol or Children's Advil, medicines that people are very familiar with, is well received. And the medicine as really in solution is quite important and not a suspension or a powder as that can create challenges with taste. And even if there's not a taste issue, a palatability issue, particularly for a chronically administered medicine, it's pretty -- it's an important point. And with the liquid format, the ability to deliver a precise dose and not have to worry about, did the child eat all their food that particular day and the flexibility to give it with or without food. So we feel that based on the feedback we've heard that the efficacy profile as well as the safety profile and the convenience really provide the promise that maralixibat can be an alternative to surgery with the robust long-term event-free survival, transplant-free survival data we've generated. So I'm going to transition to talk a little bit about the addressable population. And here, we've summarized the literature rates of newborn incidence in the 3 pediatric cholestatic diseases we're talking about. I'll focus most of my comments on Alagille, where we see approximately 1 in 30,000 newborn incidence; in PFIC, where admittedly, the literature is a little bit more thin, but somewhere between 1 in 50,000 and 1 in 100,000 incidence across all subtypes of PFIC. So as we think about the commercial rollout that Mirum is planning, we are very focused on getting maralixibat to as many patients as we can worldwide. Our immediate efforts are really focused on directly commercializing maralixibat really through Mirum staff both in the United States as well as in core European countries, where we intend to directly commercialize maralixibat but also in several discussions with partners, local/regional partners, to ensure that we can bring maralixibat to patients around the world. As you see here, there are over 20,000 addressable patients, pediatric patients with Alagille and PFIC worldwide. And zooming in on the United States, where I'll comment a little bit more on the subsequent slide, we have approximately 25,000 (sic) [ 2,500 ] addressable Alagille pediatric patients and about 1,600 PFIC. And it should be noted, that's all PFIC, really about 40% to 50% of that is PFIC too. So here, I'm going to go into a little bit more detail on the United States, an addressable population where we've done probably the most work in terms of geographies around the world. This is the result of a quantitative survey that we conducted with 10 experts as well as 79 pediatric GI/hepatologists. And we surveyed physicians from a variety of care delivery settings, the pediatric liver transplant centers that many of you know very well, but also children's hospitals and academic medical centers that don't have a liver transplant program as we do see patients being managed in those settings and then even private practice, pediatric GI clinics. And we got a robust -- we really wanted to get a robust geographic sample, particularly for a homozygous recessive disease like PFIC, there can be a lot of clustering, so I think it's an important -- in families and regions as well. So it's important to get a broad coverage. And the results of that exercise led us to estimate a diagnosed prevalent pediatric pre-transplant population, if you will, these are not patients that have been transplanted already, of approximately 2,500 Alagille pediatric patients and 1,600 PFIC. Now I think the point on the bottom of the slide here should be emphasized, and it's a little bit of an editorial comment for me that I think this methodology could be conservative, and it might actually underestimate disease burden in both diseases. And the reason for that, and this is kind of reflecting on what we've seen in other rare genetic diseases, like hereditary angioedema, porphyria, is that there's often low disease awareness in the broader medical community. And then when new sponsors come into the field and sponsor education and awareness, one often sees an increase in the diagnosis rate over time. And here, just to expand a little bit on that point, is focused in on Alagille. And this is data from several hundred patients where we have electronic health record data de-identified as well as claims data. And what we -- the key point here is that the journey to diagnosis of Alagille syndrome can actually be quite protracted. On the left panel, we see that approximately 44% of patients in this EHR, multi -- several hundred patient data set, did not receive their Alagille diagnosis until they were over 6 years old. This is certainly not what's written in the medical textbooks about the neonatal cholestasis presentation. In fact, when you zoom in on several of these 44% of patients, you see a heartbreaking journey, quite frankly, where several patients saw hundreds of health care professionals over the course of years before they found their way to a diagnosis. So this is where we think, with industry and supporting education, that there might be an opportunity, as has been seen in other rare genetic diseases, to increase awareness of these diseases and hopefully, get patients into care earlier so that they can be appropriately managed. And then the other point here is that -- and we've heard this point from our collaborators and the patient advocacy community in Alagille that there are, in fact, many adult patients with Alagille syndrome who are -- who still do suffer from liver-specific symptomatic manifestations. This shows that we actually saw a 43% of patients over the age of 24. And to be fair, several of these patients will have been transplanted already and many might not have liver manifestations. But we do think it highlights that there probably are patients out there, a subset of that 43%, that could be interested in a therapy directed towards their liver manifestations of Alagille syndrome. So I'm going to transition to talk a little bit about our go-to-market strategy in the United States. And I think the key message here is that care delivery for pediatric cholestatic diseases that we're talking about is, in fact, very concentrated in the United States. This slide is about the United States. I think it's also true in Europe. Probably true in most severe life-threatening pediatric diseases that there's really a handful of centers that take care of those kids. And certainly, in this field with the role -- large role of liver transplantation, we probably see an even greater phenomenon to that effect. So we think that there'll be approximately 125 accounts that will really represent the vast majority of the opportunity at the time of launch. We are hiring a field team of approximately 10 that will focus on those accounts at the time of launch; a small payer team that will focus on the national accounts that are roughly shown here, which we think the majority will be commercial, but a significant minority of Medicaid payers -- already a medical affairs team in place that's really focused on the academic medical centers and conducting scientific exchange there. And then really, a team of patient case managers to make sure we can do everything we can to support the patients through this journey. And here, I just want to talk a little bit more about what we're doing on the patient case manager side of things. We have really a commitment to -- primarily to the patients and families, but also to the health care community to do -- when a patient and a physician decide that maralixibat might be an option they want to pursue that we do everything we can to remove all the barriers, financial and otherwise, to make sure that, that can be done. So you might have heard a few months ago, we announced an agreement, a services agreement with EVERSANA, and we're very excited about working with them, and they'll be providing several of the services noted here on this slide that could range from financial and co-pay support for the patients where there is an out-of-pocket co-pay that if we can support that, we'll be able to provide support there. Support to both the payers as well as the physician offices around reimbursement assistance, prior authorizations, paperwork along that line of thing. Product and services education. We think there's a chance not just to make sure patients know everything they need to know and caregivers know everything they need to know about maralixibat, but also the potential to connect them to other services that are out there and then specialty pharmacy and medical information services. So that was really highlighting one particular activity that we've spent a lot of time on in getting ready for launch, but there's a whole bunch of activities going on at Mirum. I mean I'm not going to go through all of these, but just to say that we're quite busy and well on track to be ready to launch in the United States. Internally, we're planning for a Q3 2021 launch readiness and still with the guidance of approval anticipated in the second half of 2021. And we've really brought on substantially all of our senior leadership and commercial and medical affairs who are really carrying all the water to make this happen. And really excited about the team we built here. As was mentioned at the outset, have built a really great diverse team. We've launched over 50 products in orphan, ultra-orphan diseases, liver diseases, other specialty markets and really bring a rich experience. We've aligned ourselves closely with several collaborators, including the patient advocacy community who really -- just so impressed with their passion and commitment to these families. It's really an honor to work with them as well as others who can really do -- help us out to do everything we can to introduce this product to the market next year. And finally, partnering with people like Dr. Williamson and Dr. Rosenthal, who spent their whole career dedicated to these patients and families and a lot of interactions with them across a lot of fronts on the R&D side and the educational side. So I've spent most of my time here talking about the text in red, which is the Alagille syndrome and PFIC which, as I reviewed earlier, is approximately 20,000 or greater than 20,000 patients worldwide, who, we believe, are addressable patients. And these are the indications where we already have breakthrough designation and marketing applications underway. But really excited about the potential to fully exploit this mechanism of action of targeting bile acids and more broadly, both in pediatric and adult settings where we have the opportunity to increase the addressable patient population, pending the result of these clinical trials by greater than 20-fold. So really exciting opportunity to pursue this mechanism of action to its fullest extent. And just to summarize, this is only the beginning for Mirum. Today, we're busy with launch prep, as I've been reviewing with you just now and building a team and getting ready. In the near future, next year, we look forward to launching maralixibat, if approved and expanding indications -- clinical indications as well as global expansion. And in the future, the very exciting indications that were reviewed today that volixibat is pursuing to hopefully help as many patients as we can with this strategy and build for investors really what we believe will be a very viable economic value proposition and for Mirum to lead the way in rare liver disease. So with that, I'd like to hand it back over to Chris Peetz.

Great. Thanks, Peter, and thanks to all the speakers today for contributing. I hope that we've conveyed our excitement and why we believe Mirum is leading the way in rare liver disease and the tremendous impact that our programs can have across a number of different settings. And so to recap here, I'd like to take stock of where Mirum sits at the end of 2020, heading into what we believe is a very bright future with the maralixibat programs poised to launch in Alagille syndrome and PFIC. Starting first with Alagille, where we're in the midst of completing our rolling NDA submission with all of the clinical and nonclinical modules submitted. Those modules, including the 5-year follow-up with pronounced and durable reductions in pruritus and other markers of cholestasis. Targeting launch readiness in Q3, thanks to all of the great work from the team. And then in PFIC, where the MAA has been submitted and validated, including 5-year transplant-free survival data as well as the event-free survival data conducted with natural history comparisons. And an ongoing Phase III for label expansion opportunities of the higher doses of maralixibat as well as additional PFIC subtypes. We've talked a lot about the new programs that we're rolling out with an exciting biliary atresia study for maralixibat beginning and volixibat being an important growth driver with adult cholestatic indications launching into intrahepatic cholestasis of pregnancy and PSC. All of this being enabled by a team that I couldn't be more proud of that have brought experts from rare disease and small company launches all together in one great platform for advancing new medicines for patients in need. What that means for the year ahead is a milestone-rich calendar. Starting in the first quarter of next year, we expect to complete our rolling NDA submission and initiate the studies that we talked about here today in biliary atresia, ICP and PSC. In Q2, we expect to complete enrollment of the MARCH-PFIC Phase III study, followed by the launch of maralixibat in Alagille syndrome. Year-end data in -- from that Phase III study in PFIC and moving into 2022, where we'll start to see data from the volixibat program and additional filings for the pediatric settings across the U.S. and Europe. So an exciting calendar ahead and really appreciate all of the interest and time that everyone has spent with us here today. And I'd like to pause for any questions. Operator, would you please open the line for any questions.

[Operator Instructions] Our first question comes from the line of Yasmeen Rahimi from Piper Sandler.

Thank you, first of all, for a great R&D Day and also sharing some of the journey that the patients experienced, very helpful. I have actually 4 questions, and I'm going to go in the order of presenters, and I'll go one by one. The first question is targeted for Dr. Rosenthal. Can you kindly help us understand what are the number 1 and number 2 reasons for PFIC and Alagille patients to go on transplant surgery? And what percentage of patients end up on the transplant surgery due to itch? And then my second question will be to Dr. Tucker and also to Dr. Rosenthal.

Yes. Dr. Rosenthal?

Thanks for that question. I would say that in Alagille syndrome, a very high percentage are likely getting a liver transplant because of their quality of life issue and their severe itching and sleeplessness. PFIC, however, is more progressive. And I would say the majority of those patients are getting liver transplants as a result not because of the itch alone but actually because they develop portal hypertension and bleeding esophageal varices as a result, which can be life-threatening. Now there are some Alagille patients who also progress and go on to develop cirrhosis and portal hypertension. But PFIC also has the problems with hepatocellular carcinoma occurring a lot earlier than in patients with Alagille, there is that risk also in these patients. So I hope I've tried to answer your question. I can't give you exact numbers because I don't think those are available anywhere, but I would say the majority of the PFIC patients is because of end-stage liver disease and the majority of patients with Alagille is because of their quality of life and itching.

Another question for you and Dr. Tucker is, what is the natural occurrence of liver transplantation occurrence in biliary atresia infants who are below the age of 3 months? And the question directed to Dr. Tucker is, is there a possibility to use bilirubin as a surrogate endpoint post Phase II for Subpart H approval?

Thanks for the question. Dr. Rosenthal, you want to speak to transplant in biliary atresia to kick it off?

Yes. So I would say that very rarely is a liver transplant in biliary atresia needed less than 3 months of age. Usually, most of the patients have just had their Kasai procedure by around 60 days of age. So the likelihood of needing a liver transplant that early is low. However, the likelihood of needing a liver transplant before 2 years of age, especially if the Kasai fails is pretty high, as I've shown you. So I would say that there definitely is a need for those patients whose Kasai is not working very well to see if they can get an extension on their need for a liver transplant by using IBAT inhibitors. And for those patients who are doing very well, again, those patients still are at risk for needing a liver transplant down the road when they're older. And again, whether an IBAT inhibitor would help protect them is an unknown question begging for an answer.

Now, Ed, if you can speak a bit to the second part of the question about our study design?

Yes. Sure. So this is the first study with maralixibat in the setting of biliary atresia. As Dr. Rosenthal had presented earlier, the indicators for improved liver or transplant-free survival have been demonstrated both with the serum bile acids and also serum bilirubin. So we want to get a look at really how maralixibat performs in this disease to understand if maralixibat can actually bend the curve on some of those outcomes. So we will be exploring bilirubin as the primary endpoint, and that should give us line of sight as to whether maralixibat can influence the transplant-free survival curve, which is really the goal, as was alluded to by Dr. Rosenthal earlier.

And then my third question is for Dr. Catherine Williamson. Can you kindly shed some lights on how does serum bile acid change over the time of pregnancy? And how important is it to catch patients early in their stages of pregnancy to lower bile acids?

Thank you for the question. Bile acid concentrations seem to rise gradually with advancing gestation. Interestingly, there are no large reliable studies on this. We're actually designing one at present, and I hope within a few weeks, we'll have much more data. But there's no doubt, as one follows either women with cholestasis or even normal pregnancy, pregnancy itself causes women to have a mild increase in bile acids, which is why the upper end of the reference range is a little bit higher in normal pregnancy and then in the susceptible women, they go up further. And I think this also explains why the condition typically presents in the second and third trimester.

And then my last question is to Dr. Pam Vig. Just if she could kindly remind us what was the magnitude of itch response in bile acid suppression that we have seen to date with volixibat. And thank you, again, for reminding us on the CAMEO results on maralixibat.

Yes. So the bile acid response of volixibat has not been studied yet in cholestasis. So you wouldn't expect in healthy volunteer studies during the previous NASH study that was conducted for those patients to have elevated serum bile acids as they have a normal bile flow. But really the point to look at in this is the pharmacodynamic markers of fecal bile acid excretion and 7 alpha C4 increases, which show that there is a reduction of fecal bile acids, which would then inform for reductions in serum bile acids. And we see this, as you mentioned, in the CAMEO results using maralixibat, where in this setting, particularly, there is a significant reduction in serum bile acids, which then refers to the significant reduction we see in pruritus.

Our next question comes from the line of Josh Schimmer from Evercore ISI.

Really interesting overview. Maybe to start with the ICP indication. Just a couple of questions around that. Are we confident that the maternal bile acid levels mimic and are in equilibrium with the fetal levels? And this feels like a little bit of a different mechanism of elevated bile acids compared to the other conditions. Maybe you can elaborate a little bit more on your confidence in the IBAT inhibition mechanism for this particular disease in light of what you've seen with some of the other programs and what we've seen with the Urso study?

Thanks for the question, Josh. Yes. I think just one quick note, then I'll pass it on to Professor Williamson to speak to some of those aspects. Just from the work we've done with volixibat, that gives us confidence that we are at quite active doses, which is, of course, the first step. Then as we start to map the mechanism of ASBT against the disease pathology and progression. So with that, Professor Williamson, do you care to elaborate?

Yes. Of course. So firstly, to answer your question about maternal and fetal bile acid concentrations, it's an interesting and good question. What is certain, all the studies that have looked at fetal bile acid concentrations unpaired maternal bile acid concentrations, and it has to be borne in mind that these are normally assessed taking umbilical venous or umbilical arterial blood at the time of delivering the baby and a matched maternal sample at the same time. It's certainly clear, and I think consistent across studies, that the gradient is from fetus to mother in non-cholestatic pregnancy and the other way in cholestatic pregnancy. The other interesting observation in ICP, the principal bile acids that are raised are the primary bile acids and these are the -- the same bile acids are identified in the fetal circulation. So I think it's very, very likely looking at the patterns that the elevated bile acids in the fetal compartment are of maternal origin. Although, of course, there will be a small proportion that are likely to be synthesized by the fetus, but I sometimes wondered given that a proportion of women have pathological mutations in ABCB11, ABCB4, but 1 in 5 do. Could the occasional fetus be at risk of having PFIC? And I'm sure the very occasional fetus is, but that's not typically what is seen at all. So typically, it looks like it's the maternal bile acids crossing into the fetal circulation. In terms of mechanism, obviously, this -- we have thought about this and the mechanism has to be different because there isn't -- certainly, the mechanism is different to, for example, Alagille or biliary atresia. There is a loss of function, I think, of biliary transporters in gestational cholestasis. In some women, this may be because of genetic variation, causing some loss of function, but also because of the reproductive hormones. But it seems to me very logical that it's likely that an IBAT inhibitor would reduce bile acid reabsorption in the intrahepatic circulation, which does not seem to be appreciably impaired. So therefore, I think it's very plausible that it would be of benefit.

Got it. That's really helpful. Maybe another question on the PSC program and the confidence that pruritus is a suitable primary endpoint for approval. Are there key secondary endpoints that you expect you'll need to demonstrate in terms of liver health or stability of liver pathology to support pruritus? And is that part of the trial? I missed if you had commented on that.

Yes. Thanks again for the question. I'll touch on the regulatory aspects and then ask Pam to speak about some of the endpoints and long-term follow up that's included in the study. And from a regulatory perspective, we did discuss the study design with the FDA and so have incorporated their feedback on the use of pruritus as an outcome to be the basis for full approval. That's really a learning we've had across these cholestatic settings in our interactions with FDA. And so you'll see this as a theme in the Alagille syndrome program as well as PFIC and ICP, where the FDA has had a focus on the pruritus endpoints and what that can mean for an early look at an outcome in these settings. Pam, would you like to speak to the long-term endpoints from the PSC study?

Absolutely. Thank you for the question. So for PSC, we -- the underlying disease is marked and characterized by the accumulation of bile acids. And that is the underlying cholestasis is really what drives damage to the liver and bile ducts and fibrosis and cirrhosis, et cetera. So with the reduction of cholestasis with an ASBT inhibitor like volixibat, you would expect to see reduction of bile salts in the hepatocytes and subsequent reductions of serum bile acids in the systemic circulation, which would then hopefully point to an improvement in the underlying liver health. So it remains to be seen. But in the long-term extension, we'll be looking at markers of disease progression, fibrosis biomarkers as well as transient elastography, as patients continue with maralixibat long term. So more to follow up there.

Got it. And maybe one last question, if I may. You've laid out some of the new indications that you're pursuing with volixibat. Are there others that you're considering? Are there large additional diseases of cholestasis to pursue that you'll be exploring in the years to come? And if so, when might we hear about those programs?

Thanks again for the question. Yes, there are a number of other settings. And I think the one that's most noteworthy, not in our materials here today that we are considering is the potential to address pruritus in PBC as well. So that's one that we're considering what a program might look like and the implications. More to come on that as we get into next year, we'll share our thinking and plans on that setting.

Our next question comes from the line of Steve Seedhouse from Raymond James.

I had a few questions, maybe for Dr. Rosenthal to start. In the data that you highlighted from ICONIC and ITCH and IMAGO, it doesn't really look like the rate of diarrhea in the maralixibat patients is much higher than placebo during some of the randomized portions. But of course, as you noted, that is an on-target side effect. So I'm just hoping you could characterize in your experience how uncomfortable is the diarrhea really relative to the clearly severe, debilitating itching that the drugs are intending to treat in the first place? Is it even close from a quality of life standpoint?

Thanks for that question. It's a very important issue. I'm happy to tell you that at least in my experience of using this, that the diarrhea is not as bad as the itching is. The itching is really the predominant issue in these patients. I will mention, however, that after liver transplant in patients with PFIC, because PFIC1, as I earlier mentioned, affects the intestines, there have been case reports of patients having quite a bit of diarrhea when their itching has resolved as a result of the liver transplant. So the good news is that itching in Alagille's patients is the predominant issue and the diarrhea is minimal even with maralixibat. And in PFIC, so far, at least in PFIC2, predominantly, the itching is the predominant issue and the diarrhea is a lesser issue.

Got it. And maybe just a follow-up for you, Dr. Rosenthal. So thinking about the overall course of disease for Alagille patients and how maralixibat would fit into that? I was hoping you could just comment on the other organ involvement. And in your experience, some of the extrahepatic symptoms that were mentioned. How are those impacted by liver transplant, first of all? And then how are they impacted by IBAT inhibitors? And just wondering sort of beyond maralixibat, like what proportion of the overall treatment paradigm here is the treatment of these patients' itch, if you can quantify that in any way?

Yes. So what I would say to you is that, as I mentioned earlier, JAG1 and NOTCH genes are developmental genes. So if there are problems in the heart, like peripheral pulmonic stenosis or aortic stenosis, which are developmental, maralixibat clearly isn't going to do anything for that. And many of those patients wind up needing cardiac surgery to correct those abnormalities. Vertebral abnormalities, such as hemivertebrae or vertebral or butterfly vertebrae in the vertebrae, again, those occur at the time of birth, those are not going to be affected by an IBAT inhibitor. To answer your question about the itching, the itching is really quite significant. And I would say that probably greater than 50% of the patients with Alagille syndrome have moderate-to-severe itching. It's only the minority of patients in my experience that have mild itching. And again, with time, many of those patients have sort of a peak in their itching that once they can get past it, it may improve, but the problem is that up until the time that they get old enough that their itching might improve they are having a horrendous quality of life, and we have really nothing at the moment in our armamentarium to treat them with. And that's where I am so excited about the opportunity to potentially have IBAT inhibitors to make their lives much better.

That's very helpful. I appreciate that. Maybe for the company then, just following up. The epidemiology data that you updated today, is that specific to Alagille and specific to the U.S., obviously, where this will be launching initially, is the identified Alagille patients based on your survey work, those that would be candidates for an itch therapy? Or is that overall Alagille? And if it's all right, I have just maybe 1 or 2 quick follow-ups for the company as well.

Thanks, Steve. Yes, happy to take those. And I'll ask Peter to speak to some of the epidemiology work and market research we've done recently.

Yes. Thanks for the question. Yes, the 2,500 diagnosed prevalent Alagille patients that are pre-transplant, that's an overall population. And I think as Dr. Rosenthal articulated, the vast majority of those patients have liver involvement. And probably, we estimate at least 2/3 of them have moderate-to-severe pruritus that's not adequately controlled by the available therapies. The other 1/3, I think, would probably be a population that I think there's a lot of interest in, but -- and certainly, those patients have high serum bile acids and do have mild-to-moderate itch. But we would anticipate at the initial approval that 2/3 would be the target population that would be considered.

Very helpful. Appreciate that. And just one quick one maybe on ICP. So how long typically would a patient be a candidate for or be seeking treatment either through pregnancy or postpartum and how easily or quickly would this typically self resolve with time without treatment? Just trying to understand if this is like a weekly treatment or if this is going to go on for months or years? And then also just curious, generally speaking, across all the programs that you highlighted today, there are different dosing schemes, some flat dosing, some weight-based, obviously, some adults on pediatric, but there's a pretty clean dose response in terms of fecal bile acid excretion with this mechanism, and you guys have elucidated that. So I was hoping you could just comment on generally on dose selection and your comfort across the programs that you highlighted.

Yes, thanks for the question. And I'll ask Professor Williamson to speak to the ICP portion first, and then we'll move on to talk about our dosing.

Thank you very much for the question. In terms of how long women would be likely to be treated with volixibat, as I mentioned, the condition typically comes on in the second or third trimester. The average gestational week of presentation is somewhere around 30, 32. I would envisage that if women have a response, they would require treatment until the end of pregnancy, but they're very unlikely to need treatment for much longer than that. The reproductive hormone concentrations in the blood drop quite rapidly in terms of the cholestatic reproductive hormones that we're aware of very soon after delivery and most women report a marked improvement in symptoms, and they have a gradual improvement in the biochemistry over a small number of the symptoms days, the biochemistry weeks. So I would say from the time of diagnosis until the end of pregnancy is the likely duration of treatment.

And then I'd ask Pam to speak to what we know about some of the pharmacodynamic markers that have informed our dose decisions and how that plays out across the indications.

Yes, sure. Thanks. So maralixibat is used in pediatrics. This is the weight-based dosing, as you referred to. And this is only for pediatrics. And it maps to adult equivalents, and that's how we've really got it dialed in on maralixibat at -- over many years of study at several different doses. So I think that's quite clear. When it comes to volixibat, this is not weight-based dosing, of course, different formulation, different ASBT inhibitor. And the fecal bile acid excretion and the dose proportionality of 7 alpha C4 that we see we feel very confident that we've now got the right target doses that we're taking forward into our Phase IIb studies for ICP and PSC.

Our next question comes from the line of Joel Beatty from Citi.

Thanks for the great presentation today. The first question is on Alagille syndrome and PFIC. How much do you anticipate your therapy will impact need for surgeries, hospitalizations and transplants in patients?

Thanks, Joel. I appreciate the question. And I'll give a bit of a comment, and then it would be great to hear from Dr. Rosenthal on his thoughts. And as we think about the impact on potential need for surgery and the role for maralixibat in this setting, we do see it as addressing some of the same clinical issues that are in consideration when you look at surgical decisions. Importantly, we are collaborating with a natural history effort called GALA that has now accumulated a database of well over 1,000 Alagille syndrome cases and tracks longitudinal outcomes. That data is being compiled now. And we'll be looking at analyses of our 3 long-term Alagille syndrome studies against that cohort in different matched or paired group analyses to ask that very question. So something that we hope to have more data on next year. But with that said, I'd ask Dr. Rosenthal to give his perspective on what we know from the data to date.

So I would say that from what we know, and what I anticipate, I think that there will be certainly decreased surgical interventions as a result of using IBAT inhibitors. In PFIC, you know that most patients get a biliary diversion, and that's usually done early on like a few months of age. And I think if I was as a clinician to present to a family, the option is for your child that's been newly diagnosed with PFIC, you can have a surgical biliary diversion, potentially with an ostomy bag hanging out to collect bile or you could have a medicine that your child would take, I think most families will opt for the medical management initially and assuming maralixibat works well, they will avoid the surgery. Obviously, if there are patients where the surgery does not work, then perhaps they would then opt to do a biliary diversion at a later point. As for Alagille syndrome, in the past, we did do biliary diversions like we do for PFIC. That has decreased considerably. And I would say that it may be a little harder to show a statistically significant difference between biliary diversions now going on and especially decreasing with the use of the IBAT inhibitors. But I'm pretty certain that surgical procedures, including transplant, where I showed data that's very encouraging that there were 5 years of no liver transplants in some of those patients. And the fact that diversions will probably decrease is likely. And as a result, those will probably have decreases in hospitalizations.

Great. That's helpful. And maybe another question on the 2,500 pediatric patients with Alagille syndrome that were mentioned today in the epidemiology data. Could you discuss how easy it will be to identify those patients for treatment if maralixibat is approved? And are those patients maybe relatively concentrated at a handful of centers? Or are they more spread out?

Thanks, Joel, for the question. I'll ask Peter to give a little color on some of the ways that we have to identify these patients and the work that we're doing now up through the launch as well.

Great. Yes. Thanks, Joel, for the question. We do believe that the care delivery for Alagille is quite concentrated. We think there's -- we've done a fair bit of kind of commercial analytics work to look at claims and prescriptions to see where these patients are being cared for. And it does appear to us that -- there are 60 centers in the United States, for example, that have active liver transplant programs. And even if that's 60 -- a subset of that 60 are the ones that are the most active, probably 20 or 30. And then if one takes a little bit broader lens and looks at other tertiary centers, children's hospitals that maybe don't have a liver transplant program, you could think about kind of medium or smaller-sized cities, geographies, you could get -- we get up to about 125 accounts that we feel will represent -- will be the ones that are delivering care to the vast majority of the diagnosed patients today. And we do think, though, there could be more patients out there that are kind of not in care. So we have various kind of nonpersonal promotion activities planned to try to raise awareness of these diseases with neonatologists and maybe even to some extent, pediatricians and families themselves. And then I think as we kind of move into next year and move up to our anticipated approval date, we kind of hope to do more profiling work. There already has been a fair bit of profiling work done by our medical affairs team of these centers, but do a fair bit more so that we really understand the patients that are being followed, how the referral networks are functioning in each geography, et cetera.

And then maybe one last question from me and it's on ICP. Could you discuss if there's outcomes, endpoints that you could assess in a clinical trial? For example, I imagine something like pruritus would be relatively easy to assess in a clinical trial and for outcomes, endpoints, there may be some endpoints that are really important, but rare enough that it could be hard to assess in a clinical trial, but are there maybe some other outcomes, endpoints that could be assessed?

Thanks, Joel, for the question. I'll ask Professor Williamson to talk about her experience, both on prior studies and on the OHANA study.

Yes. In terms of outcomes, as you say, pruritus is relatively easy to quantify and is a symptom that can be very, very distressing for women in pregnancy and have a major impact on quality of life. Serum bile acids are a very important outcome because they are clearly associated with the risk of adverse outcome. 10% of women have serum bile acids greater than 100 micromoles per liter. And this group have a markedly increased risk of stillbirth, which seems to go up from 35 to 36 weeks of gestation. So a reduction in bile acids is very important. And the risk of spontaneous preterm birth goes up with serum bile acids greater than 40, which affects about 25% of women with ICP. In terms of clinical outcomes, which I think was also part of your question. For the PITCHES trial that we published in the Lancet last year, we had a composite of adverse pregnancy outcomes that included preterm birth, increased perinatal mortality and admission to the neonatal unit for more than 4 hours. For the OHANA trial, we're also going to have a composite of adverse outcomes that we will consider as well as, of course, looking at individual outcomes. And I think it becomes a little complex because aside from the real risk of spontaneous preterm birth, clinicians quite frequently decide to deliver early because of concerns about the risk of stillbirth and occasionally also because the pruritus is so distressing to women. And so this is a slightly more complex outcome. But if pruritus is improved and serum bile acids don't rise, then clinician concern will be reduced. So I think they are complex outcomes, but I think they're very, very important and likely to have an impact. I hope that answers your question sufficiently, and I wonder maybe if another member of the team may want to add anything to that, or I'm happy to come back on it.

I think from my perspective, I think, as usual, quite comprehensive answer. Joel, any other follow-ups from that?

No, that's all for me.

Our next question comes from the line of Etzer Darout from Guggenheim Securities.

Great. Thank you for a very informative event. First question to Dr. Williamson, a two-part question. I guess, part 1, based on sort of the UDCA study you highlighted and sort of the itch score produced there, do you have a sense on the magnitude in itch score change you would consider clinically meaningful for volixibat? And then sort of on the safety side, any additional considerations in pregnant patients in these studies relative to previous trials for the bile acid programs?

Thank you for the question. Firstly, what itch score is clinically meaningful is an absolutely important question. Prior to the trial we published last year and the pilot before that, we surveyed both clinicians and women with ICP through the patient charities to ask them what they would perceive to be a clinically meaningful reduction in pruritus. And we ask them to assume that a woman would start at 60, and we were fascinated. Of course, there was a spread of answers. But overall, both maternal medicine clinicians and women with ICP thought that a reduction of 30 millimeters on an itch analogue score would be a clinically meaningful difference. Now of course, a decision about that may depend if a woman still has the pruritus, and it may just depend how severe her pruritus is. And in the clinic, I often have women say to me that if they could just reduce the pruritus, they know about the 7-or-so percent reduction from the PITCHES trial, they say, "That 7 millimeters is enough to enable me to sleep. That would be important for me." So I think quality of life is also very, very important when considering this. So in terms of pruritus score and being meaningful, I think these are the most useful data we have. Your second question was about safety. Now the easiest answer, I would say, as a clinician, is I find it very, very reassuring that volixibat has negligible systemic absorption because something we always worry about is potential teratogenicity. But do remember, cholestasis presents in the second half of pregnancy. So teratogenicity isn't an issue. However, absorption and possible transfer to the fetus one always think about, but I believe this will be highly unlikely. And even if there is a tiny amount of maternal absorption, it's even more unlikely that there would be any fetal exposure. But of course, we'll be able to establish this in an initial trial. So this is the safety consideration that I think would first come to people's mind. Otherwise, my own personal belief, if there's a reduction in maternal serum bile acid concentrations and particularly the primary bile acids, then I think there's very likely to be an improvement in risk and not be a safety issue. So theoretically, I feel very encouraged and very, very enthusiastic about this trial as a clinician who looks after these women. I hope I've answered your question about safety. And again, I'm happy for you to ask more if you want to.

That was very helpful. My second question is for Dr. Rosenthal and maybe the management team as a result of the survey. So I guess you highlighted a number of diagnosis methods for testing for Alagille, for example. And how early in algorithm is genetic testing being performed? And is genetic testing, I guess, limiting at all in areas where you're seeing low diagnosis of Alagille?

Thanks for the question. I would just make one kind of comment and then interested to hear Dr. Rosenthal's thoughts, but in the effort to address some of these diagnoses challenges, there is an industry consortium that's come together to provide a free genetic panel for any cholestatic child in the U.S. We help support this. That's been available for the past 5 years. So there are efforts such as that to help proactively reduce some of the barriers to get earlier an accurate diagnosis.

I just was going to say that indeed, there are several different genetic panels, the one that Chris is referring to, it comes from Emory University. And there's a neonatal cholestasis panel that includes about 65 different genes that cause cholestasis. If you remember my slide, it had many different diseases that can cause cholestasis, and many of those are picked up on a genetic screen. The thing that needs to be done when a patient presents in the first few weeks of life with cholestasis jaundice is to make sure that they do not have biliary atresia. Because we know from many studies that the earlier the Kasai portoenterostomy is performed, the more likely it's to be successful. But once the biliary atresia has been ruled out on a patient, then it becomes necessary to determine what really is wrong with the patient. And that's where genetic testing has become much more frequently utilized than has been mentioned, it's possible to get this genetic screen done for free as a result of the collaborations between these different companies, all interested in rare cholestatic liver disorders, which now that there are treatments for will make it possible to do something when these diseases are found and diagnosed. So I hope that answers your question.

Our next question comes from the line of Ed Arce from H.C. Wainwright.

This is Thomas Yip asking a couple of questions for Ed. Thank you very much for a very comprehensive webcast today. First question is for Dr. Rosenthal. For the MARCH-PFIC study for the specifically supplemental cohort with other PFIC subtypes, what type of response will you consider that to be a win in these PFIC patients? Would that be based on the metrics similar to PFIC2 patients?

Thanks for the question, Thomas. Maybe I'll give a little -- a couple of thoughts on the MARCH-PFIC design to kick us off here. And so as you've mentioned, the MARCH-PFIC study has 2 cohorts: the primary cohort focused on PFIC2 as well as a supplemental cohort that largely enrolls all other PFIC subtypes. So we are seeing PFIC1, 3 and 4 patients randomized into that portion of the study. In essence, it is a parallel randomized, placebo-controlled study. So we'll have all of the same observations in those patients on pruritus, serum bile acids. Those patients will also roll on to open-label therapy and the long-term follow-up. So really opportunity for rich data generation ahead from the MARCH study. So with that as backdrop, just on the study design, Dr. Rosenthal, anything to add in terms of what expectations you might have in the other PFIC subtypes?

So what I would comment along those lines is that I think the other PFICs will probably have a lower likelihood of success than PFIC2 is at the moment. But having said that, I think, as I showed you in the slides, PFIC2 or BSEP has 3 different categories of mild, moderate and severe, dependent upon non-truncating and truncating gene defects. And I think as we utilize these drugs more commonly in the other PFIC, we're going to also be able to tease out genetically if there are subcategories within those PFICs of mild, moderate and severe likelihoods of response to the drugs. So I guess the best thing to do would be to stay tuned and let's see what the results show us.

That sounds good. Next question for Dr. Williamson switching gears for volixibat, specifically for the OHANA study and ICP, can you tell us the significance of going with a serum bile acid over pruritus as the primary endpoint? And also, would a future pivotal study compare UDCA as a baseline?

In terms of the choice of bile acid reduction over pruritus, it's always a tricky decision to decide what is the most important primary endpoint. But last year, the paper that we published in The Lancet did very clearly show that maximum serum bile acid concentration in pregnancy in women with ICP is associated with adverse pregnancy outcomes. Pruritus is very, very distressing, and it's a very important symptom for many women. But women and clinicians managing them worry so much about stillbirth and spontaneous preterm birth, that reduction in bile acids, I think, is equally important. I would like to see if maybe Dr. Tucker or another member of the team wants to say any more about the choice of primary endpoint and also a comparison of ursodeoxycholic acid.

Yes. So I do think that the selection of the serum bile acid as the primary endpoint is the most meaningful for the changes in standard of care within ICP as described by Professor Williamson. So if we can demonstrate that volixibat can positively influence those levels of serum bile acid, it's highly likely that that's going to confer a clinical improvement, both for the maternal outcomes but also for the fetal outcomes as well. So that was really the decision on the selection of the primary endpoint. I think with regards to comparing with UCDA (sic) [ UDCA ], I think that's always a difficult question. Because this is not an approved indication for this disease. And therefore, we would be trialing one investigational study against -- one investigational product against another. Within the OHANA study, we do allow stable doses of UDCA to be included within the study, which reduces the level of noise around the introduction of rescue meds should these patients need them. But I think what you've seen from Professor Williamson is that the benefits of urso is relatively marginal for most patients. And so I don't think it warrants a head-to-head clinical trial in the future.

Okay. Thank you for your clarification. Perhaps turning back to the Mirum team, specifically for commercial -- on the commercial side for Peter. You outlined 125 accounts to focus on for U.S. Alagille syndrome market. How many sales rep on top of the 10 sales rep to address the payers do you think are sufficient to address the whole -- the total U.S. market? And what about PFIC in EU? What's the plan there so far?

Great. Thanks for the question. So to comment on the U.S., yes, we do feel that the 10 representatives can cover these 125 accounts pretty adequately without much concern. There'll be some travel involved, of course, but it's a big country, but we think that can be done. On the payer side, it's -- we're imagining a small national accounts team, even smaller than that, kind of on the order of 3 or 4 to cover commercial and Medicaid payers. And there'll be -- there may be some support in the peri-launch stage because that's always when things are the most busy when new indications are being evaluated. But we feel pretty confident that, that scale of the team -- the focused kind of scale of the team can handle that lift. And then transitioning to Europe. Yes, we're envisioning really a very flexible commercial operation in Europe. The company already has a small clinical development team based in Switzerland, where a lot of the commercial talent for Europe exists. And we're kind of envisioning sort of a direct presence in a handful of key Western European markets. And I think the care delivery in Western European countries is just as, if not even more concentrated than the U.S. So it just would be a pretty small flexible team focused on kind of the core Western European markets, which we're still defining. But I don't think it would be that atypical from what you see from other rare disease launches. And then partnerships with distributors more broadly, maybe in Central and Eastern Europe as well as Middle East, Turkey, places like that.

Okay. One final question from me is for Ian. Can you give us some idea on the Oberland financing in terms of royalty rates and caps on the total payments to Oberland in ALGS? And does the financing involve other indications or programs beyond maralixibat in ALGS?

Sure. Happy to take that for you, Thomas. So in terms of the structure of the deal, up to $210 million, as we outlined earlier in the press release. From the perspective of the royalty rates, we haven't disclosed those. There is a tiering involved in the repayments via those revenue streams. And those revenue streams are based on maralixibat and the indications that we're launching in, as you think about both PFIC and Alagille. Did that cover the question from you?

Yes, yes. Yes, that really helps. Congratulations on obtaining the financing. And thank you again for taking our questions and looking forward to a very busy 2021.

Our next question comes from the line of Brian Skorney from Baird.

Both of mine are for Dr. Rosenthal. I guess to start, it looks like there's the potential for 2 IBAT inhibitors to get approval over the next year. And I was just wondering if you could kind of provide your sort of expertise to compare and contrast between maralixibat and odevixibat? And how do you ultimately think about utilizing each as they inevitably start to overlap in terms of indications? And then on Alagille specifically, maybe I was hoping you could help us understand kind of a little bit about the waxing and the waning of the liver pruritus manifestations versus the non-liver pruritus manifestations? And would you expect commercialization and utility to be limited initially to patients with pruritus and some threshold of LFTs? And how do you think about sort of the ebb and flow of keeping these patients on treatment, if ultimately, you see some waning of these symptoms?

Thanks for the question, Brian. Dr. Rosenthal, I'll let you comment on a couple of these aspects.

On your first question about the different IBAT inhibitors, I think it's very likely that maralixibat is going to get approval for Alagille before odevixibat. And I think odevixibat may likely get approval for their PFIC indication before maralixibat does. But having said that, I am happy to use whatever IBAT inhibitor I can get my hands on since there is currently no treatment available at all for these patients. So that's how I would answer your first question. As far as head-to-head, that will take quite a while to accumulate that information to say which seems to win. But I'm hopeful that access to both of these drugs is really important for my patients. And as a clinician, that's what I'm most interested in. Now the waxing and waning of itching is the reason why there are ItchRO scores where people get their itching measured morning and evening daily, then weekly, then monthly and even yearly because indeed, depending upon the weather, depending upon in a young child, whether or not it's the father or the mother who's reporting their results, I think there is going to be quite a significant difference in the severity of the itch in any particular day. And that's why it's really important to look over time as to whether or not the itching is improving with the use of the drug or not. If obviously, itching is not improving, then clearly, there may not be a need to continue using the drug. And if the itching significantly improves, as I showed you in many of those slides, then clearly, at the moment, that is going to be the way to proceed because, as has been mentioned numerous times today, the itching is quite severe. It's not just a little itch, it's a significant itch. So I hope that answers your question.

Yes. And maybe if I could just throw one more additional question on biliary atresia. How should we be thinking about the markers of bilirubin? And any sort of threshold that would be very compelling in terms of clinical benefit. Do you think of it as a percentage reduction in bilirubin from baseline? Or is it meeting a certain threshold in terms of the upper limit of normal, like is 2x upper limit of normal, very predictive? And what other LFTs should we -- be considered here on top of bilirubin to be meaningfully predictive?

So first of all, we show it from our children's network that if your bilirubin 3 months after your Kasai is less than 2, that's a good prognostic sign. And if it's 2 to 6 or greater than 6, that's not a good prognostic sign. So that's the magic number for bilirubin. You need to realize that 2 is about twice the upper limit of normal for bilirubin, mg per dL. Bile acids will be useful also because we know from Sonny Harpavat's work from our children's network also that not just bilirubin but bile acids predict outcomes for Kasais. Obviously, if the transaminases are going up and not going down, that's not a good sign. GGT, alk phos, those are the routine liver function tests that we utilize that give us an idea about biliary obstruction. So briefly, those are the things that I would be looking at.

And this does conclude the question-and-answer session of today's program. I'd like to hand the program back to Chris for any further remarks.

Thank you, and thanks, everyone, for all the time and attention and great questions today. I hope we've conveyed our excitement about Mirum and the programs we've developed and the future ahead of us, the team we've assembled, leading the way in rare liver disease, working to bring life-changing medicines to patients in need. Heading into 2021, we have exciting developments on the maralixibat program with the upcoming potential for launch in Alagille syndrome and PFIC, with 5-year data sets and a really transformative clinical potential in those indications as well as the pipeline expanding what we've learned from those first settings into other indications with far greater reach in terms of number of patients impacted, all of this building on this track record of success to build a bright future for Mirum. Thank you for your time and look forward to future interactions.

Thank you, ladies and gentlemen, for your participation in today's conference. This does conclude the program. You may now disconnect. Good day.