During its recent fourth-quarter and full-year earnings report, Foster City, Calif.-based Mirum Pharmaceuticals Inc. provided an update on the apical sodium dependent bile acid transporter (ASBT) inhibitor maralixibat for Alagille syndrome (ALGS), which will be the subject of a rolling NDA starting in the third quarter of 2020. And setting up a duel of sorts in the rare genetic disorder is another candidate in the same class for the condition: odevixibat, due to undergo a pivotal program in the hands of Albireo Pharma Inc., of Boston.

ALGS causes liver problems that result from having fewer small bile ducts, which leads to bile buildup, then scarring and damage. Signs and symptoms are generally noticed in infancy or early childhood, though the earmarks and their severity vary greatly, even among people in the same family. Liver trouble may surface first, and can include jaundice. Other signs are itchy skin; dermal bumps caused by deposits of cholesterol and fats (xanthomas); pale, loose bowel movements; and poor growth. But the affliction can strike other parts of the body, including the heart, brain, kidneys, blood vessels, eyes, face and bones. People with ALGS may have distinctive facial features, including a broad, prominent forehead, deep-set eyes, and a small, pointed chin, according to the NIH.

Specifically, ALGS, for which there’s no cure, is caused by changes or mutations in the JAG1 and NOTCH2 genes. Inheritance is autosomal dominant, but in about half of cases the mutation occurs de novo. Treatments include drugs that boost the flow of bile and management of diet to handle nutritional effects. Still, some patients end up with liver transplants. ALGS belongs to a class of illnesses called cholestatic liver diseases, which include intrahepatic cholestasis of pregnancy and the somewhat better known primary sclerosing cholangitis; cholestasis is any condition in which substances normally excreted into bile are retained.

Maralixibat came to Mirum by way of Dublin-based Shire plc, and the former pulled down $120 million in a series A financing to pursue work with the compound in ALGS as well as progressive familial intrahepatic cholestasis (PFIC). A phase III study in PFIC is ongoing, with results possibly available by the end of 2020. Albireo has work in progress in PFIC as well; whereas Mirum has the lead in ALGS, Albireo is “slightly ahead” in PFIC, Evercore ISI analyst Josh Schimmer said in a report in the summer of 2019, when he started coverage of Mirum with an outperform rating. Blocking ASBT represents “a rational mechanism of action for certain cholestatic liver diseases,” in his view, and Shire conducted “a number of studies for maralixibat in indications including PFIC and ALGS,” with results “supportive of a benefit in lowering bile acids and also improving key related symptoms, including pruritus. The wealth of data from clinical trials provides important insights into appropriate doses and target populations,” in his view. “Albireo is the key competitor to track, though the universe of indications should be large enough to support both players,” he said. In ALGS, Mirum will be first to market and estimates a target of as many as 2,500 patients with symptomatic disease accompanied by severe pruritus, which could support the chance of more than $300 million of revenues in the U.S. In Europe, the company plans to lead with a filing in PFIC.

During Albireo’s March 2 conference call on earnings, Chief Medical Officer Patrick Horn declined to provide details about the design of the ALGS effort. “I think we want to wait until we have clearance with the FDA and have those regulatory discussions before we really start to release much about that,” he said. More questions had to do with PFIC, where Jefferies analyst Eun Yang wanted to know whether the study was enrolling patients with or without partial external biliary diversion (PEBD) surgery and, once the drug is approved, how many patients who have undergone PEBD surgery would be eligible for the treatment. CEO Ronald Cooper said that, “like usual, the challenge in this space – rare orphan diseases – there [are] no published data on your question, nor are there any registries. In our phase III study, we had patients who were before-PEBD surgery [and] others who had PEBD surgery but still fulfilled our entry criteria. It's going to be difficult for us to actually estimate the number of patients that would be eligible,” but between 8,000 and 10,000 people in the U.S. and Europe have PFIC, “and they're in various stages of treatment, so [it’s a] big opportunity,” he said.

Separately, Albireo recently hit full patient enrollment in its phase II trial testing elobixibat, a first-in-class, once-daily, orally available ileal bile acid transporter inhibitor for the treatment of nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD). The firm is on track to roll out top-line results in mid-2020. Albireo expects results from a second NASH/NAFLD trial with elobixibat, sponsored by its partner EA Pharma Co. Ltd., of Tokyo, late in 2020 or early in 2021. The two proof-of-concept studies are designed to assess the combination of improvements in liver function and cardiovascular risk parameters with what’s hoped to be a favorable gastrointestinal tolerability profile. The combined data from both studies will inform next steps for Albireo, the company noted. Wainwright analyst Ed Arce wrote in a March 2 report that “mid-2020 is building up to be a crucial period for Albireo,” with the NASH data and the results from the pivotal phase III experiment with odevixibat in PFIC.

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