Maralixibat Treatment Significantly Reduces Pruritus and Serum Bile Acids in Patients with Alagille Syndrome: Results from a Randomized Phase II Study with 4 Years of Follow-Up

Background: Alagille syndrome (ALGS) is a rare genetic disease that often presents with severe cholestasis and pruritus. There are no approved drugs for management. Maralixibat, an apical sodium-dependent bile acid transport inhibitor, prevents enterohepatic bile acid recirculation. We evaluated the safety and efficacy of maralixibat for children with cholestasis in ALGS. Methods: ICONIC was a randomized, placebo-controlled, drug-withdrawal, Phase IIb study with open-label extension in children with ALGS (NCT02160782). Eligible participants had >3x normal serum bile acid (sBA) levels and intractable pruritus. After 18 weeks of maralixibat 380 μg/kg once daily, participants were randomized 1:1 to continue maralixibat or receive placebo for 4 weeks. Subsequently, all participants received open-label maralixibat to Week 48. During the long-term extension (204 weeks reported), doses were increased up to 380 μg/kg twice daily. The primary endpoint was the mean sBA change during the randomized withdrawal in participants with ≥50% sBA reduction by Week 18. Cholestasis was assessed using pruritus (observer-, patient- and clinician-rated; 0-4 scale), growth and liver function. Findings: Between October 2014 and August 2015, 31 participants (mean age: 5.4 years) were enrolled and 28 analyzed at Week 48. In the randomized-withdrawal period, participants switched to placebo experienced significant increases in sBA (+94 µmol/L; p=0.0130) and pruritus (+1.7 pts; p<0.0001), whereas those continuing maralixibat maintained treatment response. From Baseline to Week 48, sBA (‑96 µmol/L; p=0.0058), pruritus (-1.6 pts, p<0.0001), xanthomas (-0.9 pts; p=0.0006), height (+0.18 z-score; p=0.0704) and quality of life (+9 pts; p=0.0200) improved. In those continuing to Week 204 (n=15) all improvements were maintained. Throughout, no increase in adverse event frequency or severity was observed. Interpretation: In children with ALGS, maralixibat is the first agent to demonstrate significant, durable, and clinically meaningful improvements in cholestasis. Maralixibat represents a new treatment paradigm for chronic cholestasis in ALGS. Trial Registration: NCT02160782 Funding: Funded by Mirum Pharmaceuticals. Declaration of Interests: EG has received consultancy fees from Mirum Pharmaceuticals, Albireo, and Laboratoires CTRS. AB has received grants and research support from Mirum Pharmaceuticals. ES has received consultancy fees from Mirum Pharmaceuticals and Albireo and has received travel support from Albireo. KDRS has received consultancy fees from Retrophin and Sanitarium Health and Wellbeing Company and is a stockholder in Asklepion Pharmaceuticals, LLC, Ausio Pharmaceuticals, LLC, and Aliveris s.r.l. CK and TJ are shareholders in Mirum Pharmaceuticals. NKD is a stockholder in and employee of Takeda. PV and AJW are stockholders in and employees of Mirum Pharmaceuticals. EJ has received consultancy fees from Laboratoires CTRS and is a stockholder of Laboratoires CTRS and Vivet Therapeutics AD was an employee of Lumina Pharmaceuticals and has received personal fees from Shire Pharmaceuticals. WH, MS, LH, AL, FL, AL, and JS have no conflicts of interest to declare. Ethics Approval Statement: This study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines and approved by institutional review boards and ethics committees. Informed consent (and assent) was obtained from the participant or their legal guardian.