Mirum’s Livmarli Demonstrates Six-Year Event- and Transplant-Free Survival in Patients with Alagille Syndrome
November 16, 2021
Mirum Pharmaceuticals said that a new analysis comparing pooled Livmarli oral solution clinical trial data with a natural history cohort demonstrated statistically significant improvement in six-year event-free survival and transplant-free survival.
The data was presented at the American Association for the Study of Liver Diseases annual congress. Livmarli (maralixibat) is an oral ileal bile acid transporter (IBAT) inhibitor recently approved by the U.S. Food and Drug Administration for the treatment of cholestatic pruritus in patients with Alagille syndrome (ALGS) one year of age and older.
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. The estimated incidence of ALGS is one in every 30,000 people. 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, according to recent reports, 60 percent to 75 percent of patients with ALGS have a liver transplant before reaching adulthood. Signs and symptoms arising from liver damage in ALGS may include jaundice, xanthomas (disfiguring cholesterol deposits under the skin), and pruritus (itch). The pruritus 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 oral, late-breaking session reported on an analysis independently conducted and presented by Bettina Hansen on behalf of Binita Kamath and the Global Alagille Alliance (GALA) Study Group, which has aggregated the largest global natural history clinical database established for ALGS. The analysis evaluated six years of follow-up from pooled Livmarli studies (n=84) in ALGS and compared it against an external natural history control cohort from the GALA database. The objective of the analysis was to compare the time to first clinical event in Livmarli-treated patients with ALGS versus a natural history cohort, with events defined as liver transplantation, biliary diversion surgery, decompensation events (ascites requiring therapy or variceal bleeding), or death. Additional analyses included transplant-free survival as well as several sensitivity and subgroup analyses to ensure robustness of the findings. The GALA control group was selected based on alignment with eligibility criteria from the Livmarli clinical studies.
The analysis demonstrated a highly significant improvement in six-year event-free survival translating to a 70 percent overall reduction for clinical outcomes with Livmarli. The analysis also showed statistically significant improvements in transplant-free survival.
“Cholestatic pruritus associated with Alagille syndrome has a dramatic and debilitating impact on the lives of patients and is a leading indication for liver transplantation,” said Pam Vig, chief scientific officer and head of R&D at Mirum. “The six-year analysis demonstrates that Livmarli significantly improves event-free survival and transplant-free survival, further supporting the impact of Livmarli in this patient population.”
Also at the meeting, a second presentation of complementary data analyzed predictors of event-free survival and transplant-free survival in 76 patients treated with Livmarli. Variables that were predictive of event-free survival included specific thresholds of week 48 total bilirubin, and week 48 serum bile acids. Change in baseline to week 48 in pruritus was also predictive of event-free survival and transplant-free survival. Sixty out of 76 patients remained event-free at the time of analysis, with up to six years of treatment with Livmarli.
The results of the natural history comparison analysis were included in Mirum’s recent marketing authorization application submission (MAA) to the European Medicines Agency (EMA) for Livmarli in the treatment of cholestatic liver disease in patients with ALGS. The MAA is currently under review and Mirum is preparing for a launch in Europe in the second half of 2022, if approved by the EMA.
Livmarli is currently being evaluated in late-stage clinical studies in other rare cholestatic liver diseases including progressive familial intrahepatic cholestasis and biliary atresia. It has received Breakthrough Therapy designation for ALGS and PFIC type 2 and orphan designation for ALGS, PFIC and biliary atresia.
Author: Rare Daily Staff
Sign up for updates straight to your inbox.