Livmarli (maralixibat) / Mirum Pharma, Takeda, CANbridge Pharma - LARVOL DELTA

ABCB11 mRNA therapy for the treatment of Progressive Familial Intrahepatic Cholestasis Type 2 (PFIC2) (ASGCT 2025) - "Current treatment options for PFIC2, including the newly approved small molecule ileal bile acid transporter (IBAT) inhibitors such as Odevixibat and Maralixibat, have limited efficacy and are associated with numerous side effects. Furthermore, administration of ABCB11-mRNA-LNP also improved the conditions and extended the survival of the Abcb11-/- mice challenged by diet enriched in cholic acids. Collectively, our data provides strong preclinical proof-of-concept for systemic mRNA-LNP as a potential disease-modifying therapy for patients with PFIC2."

Late-breaking abstract • Cholestasis • Dermatology • Gene Therapies • Hepatology • Liver Failure • Pruritus • ABCB1

IMPROVEMENTS IN PRURITUS, SERUM BILE ACIDS, AND TOTAL BILIRUBIN FOLLOWING TREATMENT WITH MARALIXIBAT IN PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS (DDW 2025) - "A clinically meaningful reduction in pruritus was observed in 7 patients with PSC treated with MRX, and a substantial reduction in sBA levels was observed in the majority. These findings indicate a potential role for IBAT inhibitors in treating pruritus in PSC."

Clinical • Cholestasis • Dermatology • Hepatology • Immunology • Pediatrics • Pruritus

Mirum Pharmaceuticals to Present Data at Upcoming Medical Congresses (Businesswire) - "Mirum Pharmaceuticals, Inc...announced that it will present data at three upcoming medical congresses. Digestive Disease Week (DDW) will be held in San Diego, May 3-6, 2025. The European Association for the Study of the Liver (EASL) will take place May 7-10 in Amsterdam, the Netherlands. The 57th European Society for Paediatric, Gastroenterology, Hepatology, and Nutrition (ESPGHAN) Annual Meeting will follow May 14-17 in Helsinki, Finland. Data from Mirum’s LIVMARLI...will be highlighted in oral and poster presentations during the congresses."

Clinical data • Cholestasis • Gastroenterology • Genetic Disorders • Pruritus

Understanding treatment efficacies of progressive familial intrahepatic cholestasis via a prospective world-wide registry, TreatFIC (EASL 2025) - "Twenty nine individuals are using odevixibat, 4 individuals used odevixibat in the past, 9 individuals are using maralixibat and 42 individuals are not treated with an IBATi. TreatFIC is rapidly expanding and provides prospective data on the treatments of individuals with PFIC and its efficacy. The number of included individuals has grown rapidly since its initiation in 2023. TreatFIC will allow to assess real-world data on the current treatments for PFIC diseases."

Clinical • Cholestasis • Hepatology • Pediatrics

Mirum’s LIVMARLI Now FDA Approved in Tablet Formulation (Businesswire) - "Mirum Pharmaceuticals, Inc...announced that the U.S. Food and Drug Administration (FDA) has approved a new tablet formulation of LIVMARLI (maralixibat) for the treatment of cholestatic pruritus in patients with Alagille syndrome (ALGS) and Progressive Familial Intrahepatic Cholestasis (PFIC)....LIVMARLI tablets are planned to be available in June through Mirum Access Plus."

FDA approval • Launch US • Cholestasis

LIVMARLI Now Approved in Japan for ALGS and PFIC (Businesswire) - "Mirum Pharmaceuticals, Inc...today announced that its partner, Takeda Pharmaceutical Company Limited, has received approval by the Japanese Ministry of Health, Labour, and Welfare for LIVMARLI (maralixibat) oral solution for the treatment of cholestatic pruritus in patients with Alagille syndrome (ALGS) and Progressive Familial Intrahepatic Cholestasis (PFIC) in Japan."

Japan approval • Cholestasis • Genetic Disorders

MERGE: MRX-800: A Long-Term Safety Study of Maralixibat in the Treatment of Cholestatic Liver Disease in Subjects Who Previously Participated in a Maralixibat Study (clinicaltrials.gov) - P2 | N=52 | Completed | Sponsor: Mirum Pharmaceuticals, Inc. | Active, not recruiting ➔ Completed

Trial completion • Cholestasis • Hepatology

An Extension Study of Maralixibat in Patients with Progressive Familial Intrahepatic Cholestasis (PFIC) (clinicaltrials.gov) - P3 | N=90 | Active, not recruiting | Sponsor: Mirum Pharmaceuticals, Inc. | Trial completion date: Dec 2024 ➔ Mar 2025 | Trial primary completion date: Dec 2024 ➔ Mar 2025

Trial completion date • Trial primary completion date • Cholestasis • Hepatology

RISE: A Study to Evaluate the Safety and Tolerability of Maralixibat in Infant Participants With Cholestatic Liver Diseases Including Progressive Familial Intrahepatic Cholestasis (PFIC) and Alagille Syndrome (ALGS). (clinicaltrials.gov) - P2 | N=27 | Completed | Sponsor: Mirum Pharmaceuticals, Inc. | Active, not recruiting ➔ Completed | N=12 ➔ 27 | Trial primary completion date: Aug 2023 ➔ Dec 2024

Enrollment change • Trial completion • Trial primary completion date • Cholestasis • Hepatology

Maralixibat Reduces Serum Bile Acids and Improves Cholestatic Pruritus in Adolescents With Alagille Syndrome. (PubMed, Liver Int) - "Participants receiving maralixibat in adolescence demonstrated improvements in pruritus and sBA, which persisted through young adulthood."

Journal • Dermatology • Hepatology • Pruritus

Structure-Activity Relationships and Target Selectivity of Phenylsulfonylamino-Benzanilide Inhibitors Based on S1647 at the SLC10 Carriers ASBT, NTCP, and SOAT. (PubMed, J Med Chem) - "The ASBT inhibitors odevixibat, maralixibat, and elobixibat are used to treat intrahepatic cholestasis, cholestatic pruritus, and obstipation. The peptide drug bulevirtide blocks binding of the hepatitis B and D viruses to NTCP and thereby inhibits the virus's entry into hepatocytes...The present study aimed to comparatively analyze a set of newly synthesized and commercially available S1647 derivatives for their transport inhibition against ASBT, NTCP, and SOAT. Structure-activity relationships were systematically analyzed regarding potency and target specificity to elucidate whether this compound class is worth being further developed in preclinical studies for pharmacological ASBT, NTCP, and/or SOAT inhibition."

Journal • Breast Cancer • Cholestasis • Dermatology • Hepatitis B • Hepatology • Infectious Disease • Oncology • Pruritus • Solid Tumor

Evaluation of Maralixibat in Pruritus Associated With General Cholestatic Liver Disease (EXPAND) (clinicaltrials.gov) - P3 | N=90 | Recruiting | Sponsor: Mirum Pharmaceuticals, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Cholestasis • Dermatology • Hepatology • Pruritus

Progress in the treatment of progressive familial intrahepatic cholestasis (PubMed, Zhonghua Gan Zang Bing Za Zhi) - "Odevixibat and maralixibat, inhibitors of the apical sodium ion-dependent bile acid transporter on the intestinal epithelial cells, were approved in European Union and the United States for the treatment of PFIC pruritus in 2021, expanding the treatment options for PFIC. Additionally, personalized treatments for specific mutations and novel gene therapy is promising."

Journal • Review • Cholestasis • Dermatology • Gene Therapies • Hepatology • Pruritus • Transplantation

IMPROVEMENT IN SEQUELAE OF CHRONIC LIVER DISEASE IN PATIENTS WITH ALAGILLE SYNDROME TREATED WITH MARALIXIBAT (AASLD 2024) - " Case 1: 10 year-old male with ALGS (JAG1) complicated by portal hypertension and pruritus managed with ursodeoxycholic acid and rifampin. In both cases, our patients demonstrated a decrease in serum bile acid levels and improved pruritus on marilixibat. In addition, the first patient demonstrated resolution of esophageal varices and the second patient experienced a decreased appearance of xanthomas; both occurred in the absence of additional therapeutic interventions. It is promising that Maralixibat may affect progression and manifestations of chronic liver disease, including portal hypertension and xanthomas, that are often indications for liver transplantation."

Clinical • Cardiovascular • Dermatology • Dyslipidemia • Gastroenterology • Hepatology • Metabolic Disorders • Portal Hypertension • Pruritus • JAG1

THE RELATIONSHIP BETWEEN SERUM BILE ACIDS AND EVENT-FREE SURVIVAL FOLLOWING THE USE OF MARALIXIBAT FOR PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS: DATA FROM MARCH/MARCH-ON (AASLD 2024) - "Consistent with sBA response thresholds from the NAPPED Consortium that are associated with EFS, individuals in MARCH/MARCH-ON who reduced sBA levels below the threshold did not have a clinically meaningful event whereas some individuals who had lower reductions in sBA experienced events. These data support the importance of sBA reduction in PFIC and the potential of maralixibat to facilitate this biochemical change."

Cholestasis • Dermatology • Hepatology • Pruritus

IMPACT OF MARALIXIBAT ON CAREGIVER BURDEN FOR PATIENTS WITH ALAGILLE SYNDROME AND PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS (AASLD 2024) - "67% of caregivers reported their child has mild itch and are currently using ursodiol or rifampin. This study provides early data of caregiver burden in caregivers of patients with ALGS including negative impact on sleep, productivity, employment and mental health. Further longitudinal data is needed to better quantify this impact and determine if MRX can mitigate this concern."

Clinical • Cholestasis • CNS Disorders • Depression • Dermatology • Hepatology • Mood Disorders • Pruritus • Psychiatry • Rare Diseases

REAL-WORLD USE OF MARALIXIBAT IN BILIARY ATRESIA: A CASE SERIES (AASLD 2024) - "All patients were on at least two medications for pruritus; all were receiving ursodiol and rifampin and four patients were receiving an antihistamine. Maralixibat may be effective in patients with BA for the management of cholestatic pruritus, including in patients with significant pruritus and progressive liver disease. This data supports the need for larger studies to systematically evaluate the potential benefit of MRX for the treatment of cholestatic pruritus in BA."

Clinical • Real-world • Real-world evidence • Cholestasis • Dermatology • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Hepatology • Pediatrics • Pruritus • Thrombocytopenia

IMPROVEMENTS IN PRURITUS ARE ASSOCIATED WITH IMPROVEMENTS IN GROWTH IN PATIENTS WITH PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS: DATA FROM THE MARCH-ON TRIAL (AASLD 2024) - "MARCH was a 26-week, randomized, placebo-controlled (PBO), Phase 3 trial of maralixibat (MRX), an ileal bile acid transporter (IBAT) inhibitor, that achieved its primary and key secondary endpoints of pruritus and sBA reduction for individuals across the broadest range of PFIC types studied... These consistent trends in growth for participants who received MRX and were pruritus responders indicate a potential disease-modifying effect of MRX treatment in PFIC."

Clinical • Cholestasis • Dermatology • Hepatology • Pruritus

BILE ACID SUBSPECIES ARE CORRELATED WITH PRURITUS AND BILIRUBIN IMPROVEMENT IN PFIC PATIENTS TREATED WITH MARALIXIBAT: DATA FROM MARCH AND MARCH-ON (AASLD 2024) - "For the All-PFIC cohort on MRX, a decrease in conjugated primary BA (GCDCA, TCDCA, GCA, TCA) and conjugated UDCA (i.e., GUDCA, TUDCA) was correlated with a decrease in both ItchRO(Obs) and DB (Table). Building on prior research demonstrating a correlation between sBA and pruritus, this analysis further identifies changes in BA subspecies that are associated with both pruritus reduction and improvement in DB including positive correlations with conjugated primary BAs and negative correlations with unconjugated primary BAs. This pattern indicates either new BA synthesis in response to reduced BA levels in the liver or increased bacterial action on BAs in the colon. These data further elucidate the pathophysiology of how MRX may influence improvements in both pruritus and underlying liver health in patients with PFIC."

Clinical • Cholestasis • Dermatology • Hepatology • Pruritus

An Extension Study of Maralixibat in Patients with Progressive Familial Intrahepatic Cholestasis (PFIC) (clinicaltrials.gov) - P3 | N=90 | Active, not recruiting | Sponsor: Mirum Pharmaceuticals, Inc. | Trial completion date: Sep 2024 ➔ Dec 2024 | Trial primary completion date: Sep 2024 ➔ Dec 2024

Trial completion date • Trial primary completion date • Cholestasis • Hepatology

Stereoselective Synthesis of Maralixibat via VO(acac)2/Schiff Base-Catalyzed Asymmetric Oxidation of Its Sulfide Intermediate. (PubMed, J Org Chem) - "The stereoselective synthesis of maralixibat was achieved by harnessing the chiral transferring effect of the stereogenic R-sulfoxide functionality, which was obtained via the VO(acac)2/Schiff base-catalyzed asymmetric oxidation of a phenylthiophenol prochiral intermediate. The R-sulfoxide intermediate underwent a ring closure reaction to form the seven-membered ring core structure with the desired stereochemistry, ultimately ensuring the drug's exceptional isomeric purity and synthetic efficiency."

Journal

Management of refractory pruritus in Alagille syndrome with dupilumab treatment: A case report. (PubMed, JAAD Case Rep) - No abstract available

Journal • Dermatology • Hepatology • Pruritus

Evaluation of Maralixibat in Pruritus Associated With General Cholestatic Liver Disease (EXPAND) (clinicaltrials.gov) - P3 | N=90 | Not yet recruiting | Sponsor: Mirum Pharmaceuticals, Inc.

New P3 trial • Cholestasis • Dermatology • Hepatology • Pruritus

Transporter Proteins as Therapeutic Drug Targets-With a Focus on SGLT2 Inhibitors. (PubMed, Int J Mol Sci) - "Sodium taurocholate co-transporting polypeptide (NTCP) serves as virus particles (HBV/HDV) carrier, and inhibition of its function is applied in the treatment of hepatitis B and hepatitis D by myrcludex B. Inherited cholestatic diseases, such as Alagille syndrome (ALGS) and progressive familial intrahepatic cholestasis (PFIC) can be treated by odevixibat and maralixibat, which inhibit activity of apical sodium-dependent bile salt transporter (ASBT). Probenecid can be considered to increase uric acid excretion in the urine mainly via the inhibition of urate transporter 1 (URAT1), and due to pharmacokinetic interactions involving organic anion transporters 1 and 3 (OAT1 and OAT3), it modifies renal excretion of penicillins or ciprofloxacin as well as nephrotoxicity of cidofovir. This review discusses clinically approved drugs that affect membrane/drug transporter function."

Journal • Review • Cardiovascular • Cholestasis • Congestive Heart Failure • Diabetes • Heart Failure • Hepatitis B • Hepatology • Infectious Disease • Inflammation • Metabolic Disorders

ODEVIXIBAT FOR PRURITUS REFRACTORY TO MARALIXIBAT IN PFIC1 (ESPGHAN 2024) - "After a washout period on maintenance therapy of rifampicin and cholestyramine, odevixibat was introduced at 40mg/kg then progressively increased to 120ug/kg over 44 days. In patients with PFIC1 related pruritus refractory to maralixibat treatment, a trial of odevixibat can be considered for symptomatic relief. Treatment emergent elevation in aminotransferase levels should be watched carefully and tolerated if liver function is stable as it may spontaneously resolve."

Cholestasis • Dermatology • Hepatology • Pruritus