Regulatory Decision Summary for Livmarli

This New Drug Submission (NDS) was filed to obtain market authorisation for the use of Livmarli (maralixibat) in the treatment of cholestatic pruritus in patients with Alagille syndrome (ALGS). The submission was filed under the Priority Review policy.

Alagille syndrome (ALGS) is a rare, genetic, complex multisystem disorder characterised by the occurrence of cholestasis due to intrahepatic bile duct paucity with an incidence of 1 in 70,000. Maralixibat is a selective inhibitor of the ileal bile acid transporter (IBAT), an important mediator of conjugated bile acid uptake. Maralixibat is minimally absorbed and therefore minimizing its systemic exposure. Maralixibat blockade of intestinal reabsorption of bile acids by IBAT interrupts their enterohepatic circulation, increasing fecal bile acid excretion and lowering serum bile acid (sBA) levels.

The safety and efficacy of maralixibat in the treatment of pruritus in patients with ALGS over the age of 12 months were assessed in one pivotal trial conducted in 31 patients, with a median treatment exposure to maralixibat of 714 days. This study consisted of an 18-week open-label treatment period followed by a 4-week, double-blind, placebo-controlled randomized drug withdrawal period followed by a subsequent 26-week open-label treatment period, and finally, a long-term open label extension period. The recommended dose was 400µg/kg (380 µg/kg free base equivalent) daily with a maximum daily dose of 28.5mg.

The primary endpoint was the change in sBA during the 4-week second phase of the study, from Week 18 to Week 22, in patients who were considered responders (those achieving a sBA reduction of ≥50% from baseline at either Week 12 or Week 18 in the first phase of the study. This occurred in 5 patients randomised to the maralixibat arm and 10 patients randomised to the placebo arm. This primary endpoint was met with a p-value of 0.046. Several secondary pruritus endpoints, including the Itch Report Outcome-Observer [ItchRO(Obs)], Itch Report Outcome-Patient [ItchRO(Pt)], and Clinician Scratch Score (CSS), were assessed at multiple time points in all patients. The protocol and statistical analysis plans did not prespecify a single primary pruritus endpoint and did not specify a method to protect the study-wise type I error rate. Therefore, the statistical analysis and p-values from the secondary endpoints, including analyses of pruritus, were considered nominal but clinically relevant. The pruritus and sBA analysis during all study phases in all patients were in favour of maralixibat. Maralixibat is approved for use in adults despite no adults in the pivotal study due to the rarity of the disease in adults, about 25% will survive to adulthood with their native liver. Further, the pathophysiology and mechanism of action is expected to be the same as the patients in the study. Adult patients with ALGS who either present with new onset pruritus secondary to ALGS or responded to treatment as children and have turned 18 years or older would also likely benefit from access to treatment. Long-term effect is however unknown.

A summary of an interim report of the ongoing study MRX-801 was included in the submission to support the inclusion of patients 2-12 months of age. This study includes 2 cohorts of patients: patients with ALGS and patients with another pediatric cholestatic disease. The report was limited to 6 patients with ALGS in whom maralixibat was administered for more than 13 weeks, and provided only limited quantification of maralixibat’s effects in this condition. No results were presented for the patients with the other cholestatic disease. These data did not establish the safety and efficacy in these patients as the data was insufficient. However, the information provided did not identify any additional safety concerns that were not identified in the pivotal trial. Further, the pathophysiology and the mechanism of action of the drug is expected to be the same. These patients with intractable pruritus would most likely benefit from treatment at a young age as intractable pruritus is an independent indication for liver transplantation in this condition. Therefore, given the substantial unmet medical need for effective treatment of pruritus in patients with ALGS in these younger patients, the rarity of this disease, and taking into account the demonstrated benefits of maralixibat in ALGS patients over the age of 12 months, an indication without an age range with qualifiers in the pediatric indication section of the Product Monograph was considered to be acceptable. The sponsor has also committed to submit the full study report of Study MRX-801 for our review, when available.

The safety of maralixibat treatment was acceptable, given the high incidence of background adverse events observed that were considered attributable to the underlying disease. Gastrointestinal adverse events (AE), including diarrhea and abdominal pain, were the most common AE in the pivotal study. They were mostly limited to mild to moderate severity and self-limited in nature. Increases in hepatic transaminases were observed, while some decreases were also observed, but given the universal elevations of these biomarkers in these patients due to underlying hepatic disease, the extent that hepatotoxicity may occur with maralixibat treatment is unclear. Headache was an AE reported to occur at an incidence of > 10% in both the initial OL and post-RDW OL study phases. Additionally, fat-soluble vitamin deficiencies have been noted in patients treated with maralixibat, but it remains unclear if maralixibat treatment predisposes to this risk or rather, if its occurrence remains due to the underlying condition. Serious adverse events included gastrointestinal events at 9.3% (including 5.8% due to diarrhea, abdominal pain or vomiting), and 3.5% of gastrointestinal bleeding. All these risks are included in the Livmarli Product Monograph.

In summary, the benefit-risk-uncertainty profile of maralixibat was favorable in the treatment of cholestatic pruritus in patients with Alagille syndrome.