Mirum is developing transformative medicines for rare cholestatic liver diseases, including progressive familial intrahepatic cholestasis (PFIC), Alagille syndrome (ALGS), biliary atresia (BA), primary sclerosing cholangitis (PSC) and intrahepatic cholestasis of pregnancy (ICP).
Cholestasis is characterized by impaired flow of bile, resulting in accumulation of toxic levels of bile acids in the liver. This leads to liver injury, progressive liver disease and, if left untreated, can result in fibrosis, cirrhosis, liver failure and death. Patients with cholestatic liver disease typically experience debilitating itching (pruritus), which dramatically impacts quality of life and can lead to scarring, sleep deprivation, significant fatigue and psycho-social effects.
Mirum’s therapies are selective inhibitors of the apical sodium-dependent bile acid transporter (ASBT). ASBT is present in the small intestine and mediates the uptake of bile acids in the intestines, recycling them back to the liver. ASBT inhibition results in more bile acids being excreted in the feces, leading to lower levels of bile acids systemically, thereby reducing bile acid mediated liver damage. This leads to improvements in liver function, pruritus and other symptoms of cholestatic liver diseases.
Redirects bile acid flow by inhibiting reuptake by ASBT
Interrupts recirculation of bile acids to the liver
Increases fecal bile acid excretion
| Program | Disease | Status |
|---|---|---|
| Maralixabat | Progressive Familial Intrahepatic Cholestasis (PFIC) | Enrolling Phase 3 |
| Maralixabat | Alagille Syndrome (ALGS) | Phase 2b Complete |
| Maralixabat | Biliary Atresia (BA) | Planning Clinical Program |
| Volixabat | Intrahepatic Cholestasis of Pregnancy (ICP) | Planning Clinical Program |
| Volixabat | Primary Sclerosing Cholangitis (PSC) | Planning Clinical Program |
Maralixibat’s safety profile has been well validated, having been evaluated in more than 1,500 human subjects, including nearly 120 children.
Maralixibat is a novel, oral, minimally-absorbed therapy being evaluated as a treatment for children with rare cholestatic liver diseases, including Alagille syndrome (ALGS) and progressive familial intrahepatic cholestasis (PFIC). Both of these cholestatic diseases involve an interruption in the flow of bile acid from the liver, resulting in excess bile acid in the liver and systemically. This leads to liver disease and a variety of severe and life-altering symptoms, including stunted growth and chronic and severe itch. Maralixibat works by inhibiting an important carrier protein known as the apical sodium dependent bile acid transporter (ASBT), thereby reducing systemic levels of bile acids.
Maralixibat is currently being evaluated in the Phase 3 MARCH-PFIC Study in children with PFIC, and Mirum is in discussion with regulatory agencies with regard to bringing a much needed solution to children with ALGS. Mirum also is exploring maralixibat as a treatment for other cholestatic liver diseases including biliary atresia with potential plans to initiate a clinical program in 2020.
In the Phase 2 INDIGO clinical trial of maralixibat, children with PFIC2 experienced a multi-parameter response, including reduced pruritus, reductions in serum bile acids, normalization of liver enzymes and improved quality of life scores. A long-term analysis of the INDIGO clinical trial showed an improvement in growth for those patients who had a significant response in sBA and pruritus. Maralixibat has breakthrough therapy designation for the treatment of PFIC2.
In the Phase 2b ICONIC clinical trial of maralixibat in ALGS, children taking maralixibat had statistically significant reductions in pruritus and serum bile acids compared to placebo. At the 48-week measurement, pruritus and serum bile acid reductions were maintained and improvements in xanthomas (disfiguring and often debilitating buildup of lipid deposits) and quality of life were also observed.
Volixibat is an oral, minimally-absorbed investigational therapy designed to selectively inhibit ASBT, a protein that is primarily responsible for recycling bile acids from the intestine to the liver. We believe that volixibat may offer a novel approach in the treatment of adult cholestatic diseases by blocking recycling of bile acids, thereby reducing bile acids systemically. Data from Phase 1 and Phase 2 clinical trials of volixibat demonstrated decreases in LDL cholesterol, increases in C4 and increases in fecal bile acid content, all markers of ASBT inhibition. We plan to initiate Phase 2 clinical trials in primary sclerosing cholangitis (PSC) and intrahepatic cholestasis of pregnancy (ICP) in 2020.
An important intestinal transporter that regulates the enterohepatic circulation of bile acids and cholesterol homeostasis: The apical sodium-dependent bile acid transporter (SLC10A2/ASBT)
Xiao, L & Pan, G, Clinics and Research in Hepatology and Gastroenterology (2017) 41, 509—515
Role of the Intestinal Bile Acid Transporters in Bile Acid and Drug Disposition
Dawson, PA, Handb Exp Pharmacol. 2011;(201):169-203
