Mirum Pharmaceuticals reported positive topline results from its pivotal phase 3 MARCH study evaluating Livmarli oral solution in 93 patients with progressive familial intrahepatic cholestasis in a broad range of subtypes, age one to 17 years, which met the primary endpoint of improvement in pruritus severity in all PFIC subtypes.
Photo: Chris Peetz, president and CEO at Mirum
“The Livmarli data observed in the MARCH study showcase an unprecedented reduction in pruritus and serum bile acids. These data confirm our thesis that higher doses can result in improved efficacy and better outcomes for these patients,” said Chris Peetz, president and CEO at Mirum.
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. The resulting buildup of bile causes liver disease in affected individuals. Signs and symptoms of PFIC typically begin in infancy. Patients experience severe itching, jaundice, failure to grow at the expected rate (failure to thrive), and an increasing inability of the liver to function (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.
Livmarli (maralixibat) oral solution is an orally administered, once-daily, ileal bile acid transporter (IBAT) inhibitor and the only medication approved by the U.S. Food and Drug Administration for the treatment of cholestatic pruritus in patients with Alagille syndrome one year of age and older.
The primary analysis was conducted in 31 PFIC2 patients enrolled in the MARCH study. The secondary analyses were evaluated in the All-PFIC cohort, which included PFIC2 as well as additional PFIC subtypes (n=64). The Full-Study population included All-PFIC as well as supplemental patients who had previously undergone surgery, had truncating mutations and other patients (n=93).
In both groups, treatment with Livmarli led to statistically significant drop in itching severity and serum bile level. Significant improvements were also seen in total bilirubin and growth versus placebo at six months.
Livmarli’s safety and tolerability profile was comparable to previously published data and no new safety signals emerged in the MARCH study. The most common treatment emergent adverse event was diarrhea, which was predominantly mild, with no severe cases, and transient with a median duration of 5.5 days. One patient had a treatment emergent adverse event of mild diarrhea that led to discontinuation.
Further data from the MARCH study will be presented at an upcoming scientific conference and Mirum plans to submit these data to regulatory agencies.
“The landmark MARCH study represents a significant step forward in the evaluation of therapies for PFIC. Knowing of the impact of itching on the quality of life for children with PFIC, the sustained and clinically significant reduction in itching scores in the Livmarli treatment arm is an important topline result,” said Alexander Miethke, associate professor of pediatrics from the PFIC Research Center at Cincinnati Children’s Medical Center. “Lowered serum bile acids are a prognostic marker for native liver survival, and it is encouraging to see such an impressive response. These data improved upon the compelling results seen in the LIVMARLI Phase 2 study and underscore the strong effect that this IBAT inhibitor can have on patients with all PFIC subtypes when optimally dosed.”
Author: Rare Daily Staff
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