Mirum Pharmaceuticals' LIVMARLI Study Hits Key Endpoints in Rare Liver Diseases

Key Points

• LIVMARLI met all key endpoints in Mirum’s Phase III EXPAND study, significantly reducing pediatric cholestatic pruritus versus placebo, including a 2.15-point reduction in the biliary atresia subgroup.
• Maralixibat also delivered a 70% reduction in serum bile acids, while its safety profile remained consistent with prior studies and no new safety signals emerged.
• Mirum plans to submit a supplemental New Drug Application in the first half of next year and sees biliary atresia as a major commercial opportunity, potentially comparable to Alagille syndrome.

Mirum Pharmaceuticals NASDAQ: MIRM said its Phase III EXPAND study of LIVMARLI, or maralixibat, met its primary endpoint and all prespecified secondary endpoints in pediatric patients with cholestatic pruritus associated with ultra-rare cholestatic liver diseases.

The placebo-controlled study enrolled 46 pediatric patients with moderate-to-severe pruritus, including a subgroup in which approximately half of participants had biliary atresia. Patients were randomized to maralixibat or placebo during a 20-week treatment period.

Across weeks 13 through 20, patients treated with maralixibat had a mean 1.81-point reduction in pruritus from baseline on a caregiver-reported scale ranging from zero to four. That compared with a 0.83-point reduction for placebo, producing a placebo-adjusted treatment difference of 0.98 points and a P value of 0.0004.

Chief Medical Officer Rob Myers said the magnitude of improvement was notable given the population’s mean baseline pruritus score of 2.65. “EXPAND demonstrated a statistically significant and clinically meaningful improvement in pruritus with maralixibat,” Myers said.

Biliary Atresia Results

Mirum highlighted results in biliary atresia, which was the largest subgroup in the study. The company said there are currently no approved medicines for pruritus in this setting and estimates that roughly 2,000 biliary atresia patients across the U.S. and Europe experience pruritus.

In the prespecified biliary atresia subgroup, maralixibat produced a mean 2.15-point reduction in pruritus from baseline, compared with a one-point reduction for placebo. The placebo-adjusted treatment difference was 1.15 points, with a P value of 0.0002.

Myers said roughly 90% of biliary atresia patients achieved at least a one-point improvement in pruritus, while the response rate in the overall study population was about 80%. He said the results in biliary atresia were consistent with those observed among patients with other cholestatic liver diseases in EXPAND.

The study also showed a 70% reduction in serum bile acids among maralixibat-treated patients, compared with a 3.5% reduction in the placebo group. That represented a treatment difference of 69%, with a P value of less than 0.0001.

Myers said the reduction in serum bile acids was “very clinically meaningful,” adding that similar reductions across multiple cholestatic liver diseases have been associated with clinically meaningful improvements in pruritus.

Safety Profile and Regulatory Plan

Mirum reported that the safety profile in EXPAND was consistent with prior clinical experience for maralixibat and that no new safety signals were identified.

• Treatment-emergent adverse events occurred in 96% of patients in both the maralixibat and placebo groups.
• Serious treatment-emergent adverse events occurred in 20% of maralixibat-treated patients and 18.5% of placebo-treated patients.
• There was one discontinuation in the maralixibat group and none in the placebo group.
• Diarrhea and abdominal pain were the most frequently reported adverse events in maralixibat-treated patients, occurring in 64% and 20% of patients, respectively.

Myers said diarrhea generally occurred early in treatment, was short-lived, and was mild to moderate in all cases. No patient discontinued treatment because of diarrhea, and the study did not use preventive treatment with loperamide, he said.

Chief Executive Officer Chris Peetz said Mirum plans to submit a supplemental New Drug Application for the expanded LIVMARLI use in the first half of next year. He characterized the remaining work as the standard post-readout process of compiling the data and follow-up analyses for the filing.

Peetz also said the company views the application as a candidate for priority review because of the unmet need in the treatment setting, though the ultimate review designation would be determined by the FDA.

Commercial Opportunity

Mirum said it expects potential patients to be concentrated among the same liver specialists and pediatric prescribers who already treat LIVMARLI patients with Alagille syndrome and progressive familial intrahepatic cholestasis, or PFIC. Peetz said the company does not expect incremental commercial investment to identify and reach patients under an expanded label.

President and Chief Operating Officer Peter Radovich said LIVMARLI’s unit pricing is already established, with indication-level pricing determined by dose and consumption. The dosing used in EXPAND was about 50% higher than dosing in Alagille syndrome, for which he cited net annualized pricing of approximately $400,000 to $500,000.

Radovich said the company estimates about 1,000 addressable biliary atresia patients in the U.S. and 2,000 across the U.S. and Europe. Those estimates refer specifically to post-Kasai patients with their native liver who experience pruritus, rather than the broader prevalence of biliary atresia, according to Peetz.

The company said the biliary atresia opportunity could be at least as large as the Alagille syndrome opportunity, citing a comparable addressable population, higher expected dosing and the absence of approved competing therapies in biliary atresia.

Beyond LIVMARLI, Peetz said Mirum expects to begin the launch of ATEBRIOZ in fibrodysplasia ossificans progressiva this month. He also reiterated plans for an upcoming AZURE-4 readout for brelovitug, top-line VANTAGE data for volixibat in primary biliary cholangitis next quarter, and regulatory submissions for brelovitug and volixibat in the first half of next year.

About Mirum Pharmaceuticals (NASDAQ:MIRM)

Mirum Pharmaceuticals, Inc is a biopharmaceutical company focused on developing and commercializing medicines for rare diseases of the liver and gastrointestinal system. The company's work centers on conditions involving impaired bile acid transport and cholestasis, which can cause serious liver damage and debilitating symptoms such as itching.

Mirum's primary commercial product is Livmarli (maralixibat), an oral ileal bile acid transporter inhibitor. In the United States, Livmarli is approved to treat cholestatic pruritus associated with Alagille syndrome and progressive familial intrahepatic cholestasis in eligible pediatric patients.

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