Rare Daily Staff

Mirum Pharmaceuticals reported that results from the long-term extension of the phase 2b ICONIC study demonstrate the durability of treatment effect and disease-modifying potential of maralixibat in children with Alagille syndrome.

Alagille syndrome (ALGS) is a rare genetic disorder in which bile ducts are abnormally narrow, malformed, and reduced in number, which leads to bile accumulation in the liver and ultimately progressive liver disease. In patients with ALGS, multiple organ systems may be affected by the mutation, including the liver, heart, kidneys and central nervous system. The accumulation of bile acids prevents the liver from working properly to eliminate waste from the bloodstream and leads to progressive liver disease that may require liver transplantation. The severe itching, known as pruritus, that is experienced by patients with ALGS is among the most severe in any chronic liver disease and is present in most affected children by the third year of life.

“The new analyses of years of treatment with maralixibat support the disease-modifying potential of the medicine in children with Alagille syndrome and PFIC2,” said Chris Peetz, president and CEO of Mirum.

At the conclusion of the 48-week treatment period of the placebo-controlled phase 2b ICONIC study of maralixibat in children with ALGS, 23 participants entered into the long-term extension. At the time of the new analysis, 15 remained on study with duration of up to 4 years. Consistent with results reported after 48 weeks of treatment with maralixibat, reductions in serum bile acids and pruritus were statistically significant and further improved in the participants who remained on maralixibat through 191 weeks of treatment compared to baseline.

In addition, clinician scratch scale scores continued to improve and xanthomas continued to diminish with long-term treatment. Improvements were also seen in the PedsQL Multidimensional Fatigue Scale score. Children taking maralixibat exhibited a clinically meaningful and statistically significant acceleration in height growth as measured by height z-score. The growth acceleration continued in those children who took 400 µg/kg maralixibat twice daily. Maralixibat was generally well tolerated at doses of up to 800 µg/kg day. During the extension phase, four patients withdrew consent, two had liver transplants, one had renal failure unrelated to maralixibat and one had ALT elevation as of the week 191 data cutoff.

Maralixibat is a novel, minimally-absorbed, orally administered experimental drug being evaluated in several rare cholestatic liver diseases for pediatric populations. Maralixibat inhibits the apical sodium dependent bile acid transporter, which results in more bile acids being excreted in the feces, leading to lower levels of bile acids systemically, thereby potentially reducing bile acid mediated liver damage and related effects and complications. Maralixibat has Breakthrough Therapy designation for the treatment of pruritus associated with Alagille syndrome in patients one year of age and older from the U.S. Food and Drug Administration.

The data will be presented at the annual meeting of the American Association of the Study of Liver Diseases in Boston. The company will also present data from the long-term extension of the phase 2 INDIGO study of maralixibat in children with progressive familial intrahepatic cholestasis demonstrating the durability of multi-parameter treatment response in afflicted children, as well as correlation of treatment response to non-truncating bile salt export pump mutations and increased bile acid synthesis as a result of ASBT inhibition.

Progressive familial intrahepatic cholestasis (PFIC) is a rare genetic disorder that causes progressive liver disease typically leading to liver failure. In people with PFIC, liver cells are less able to secrete bile, resulting in its buildup in the liver. Signs and symptoms of PFIC typically begin in infancy and include severe itching, jaundice, failure to grow at the expected rate, and eventually liver failure. The disease is estimated to affect one in every 50,000 to 100,000 births in the United States and Europe. Six types of PFIC have been genetically identified, all of which are similarly characterized by impaired bile flow and progressive liver disease The PFIC2 patient population accounts for approximately 60 percent of the PFIC patient population. PFIC2 is caused by a mutation in the ABCB11 gene, which normally encodes a bile salt export pump protein that moves bile acids out of the liver.

An analysis of the long-term extension of the phase 2 INDIGO study demonstrated that response to maralixibat in children with bile salt export pump (BSEP) deficiency, or PFIC2, is maintained and is correlated to the non-truncating mutations. Of the 25 children with BSEP deficiency, 19 had non-truncating mutations (mild and moderate) and 6 children had truncating mutations (severe).

Half of the children with moderate mutations experienced clinically meaningful long-term multi-parameter responses, as defined by a greater than 70 percent reduction or normalization in serum bile acids and a greater than 1.0 reduction in ItchRO(Obs) score, a measure of pruritus. Increased bile acid synthesis was shown to correlate with maralixibat treatment response, offering physiologic and mechanism-based elucidation in responders vs. non-responders.

Photo: Chris Peetz, president and CEO of Mirum

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