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EP-3266457-B1 - BILE ACID RECYCLING INHIBITORS FOR TREATMENT OF PEDIATRIC CHOLESTATIC LIVER DISEASES

EP3266457B1EP 3266457 B1EP3266457 B1EP 3266457B1EP-3266457-B1

Inventors

  • GEDULIN, BRONISLAVA
  • GREY, Michael
  • O'DONNELL, NIALL

Dates

Publication Date
20260506
Application Date
20121026

Claims (15)

  1. A composition comprising an apical sodium-dependent bile acid transporter inhibitor (ASBTI) which is or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, for use in a method of treating a pediatric cholestatic liver disease in a human pediatric patient aged between 0 and 18 years of age, wherein the pediatric cholestatic liver disease is selected from the group consisting of progressive familial intrahepatic cholestasis (PFIC), PFIC type 1, PFIC type 2, PFIC type 3, Alagille syndrome, biliary atresia, post-Kasai biliary atresia, post-liver transplantation biliary atresia, pediatric primary sclerosing cholangitis, benign recurrent intrahepatic cholestasis (BRIC), BRIC type 1, BRIC type 2 and BRIC type 3, and wherein the composition comprising the ASBTI is administered orally.
  2. The composition for use according to claim 1, wherein the composition is a liquid dosage form suitable for treating a human pediatric patient.
  3. The composition for use according to claim 2, wherein the liquid dosage form is selected from a solution, syrup, suspension, and elixir.
  4. The composition for use according to any of claims 1-3, wherein the composition decreases the patient's level of serum bile acids or hepatic bile acids.
  5. The composition for use according to any of claims 1-4, wherein the composition decreases at least 20% of the patient's serum bile acid or hepatic bile acid levels.
  6. The composition for use according to any of claims 1-5, wherein the pediatric cholestatic liver disease is progressive familial intrahepatic cholestasis (PFIC), PFIC type 1, PFIC type 2, PFIC type 3 or Alagille syndrome.
  7. The composition for use according to any of claims 1-6, wherein the pediatric cholestatic liver disease is progressive familial intrahepatic cholestasis (PFIC), PFIC type 1, PFIC type 2, or PFIC type 3.
  8. The composition for use according to any of claims 1-6, wherein the pediatric cholestatic liver disease is Alagille syndrome.
  9. The composition for use according to any of claims 1-8, wherein the pediatric cholestatic liver disease is characterized by one or more symptoms selected from the group consisting of pruritis, hypercholemia, increased serum concentration of bile acids, xanthomas, and anorexia.
  10. The composition for use according to any of claims 1-9, wherein the dosage of the ASBTI is between 1 µg/kg/day and 10 mg/kg/day.
  11. The composition for use according to claim 10, wherein the dosage of the ASBTI is between 5 µg/kg/day and 1 mg/kg/day.
  12. The composition for use according to claim 10, wherein the dosage of the ASBTI is between 10 µg/kg/day and 300 µg/kg/day.
  13. The composition for use according to any of claims 1-9, wherein the dosage of the ASBTI is between 0.5 mg/day and 40 mg/day.
  14. The composition for use according to any of claims 1-13, wherein less than 10% of the ASBTI is systemically absorbed.
  15. The composition for use according to claim 2, wherein the liquid dosage form is an oral suspension and the pharmaceutically acceptable excipient is a solvent, a taste-masking agent, an antioxidant, a filler, an acidifier, an enzyme inhibitor, or combinations thereof.

Description

BACKGROUND OF THE INVENTION Pediatric cholestatic liver diseases affect a small percentage of children, but therapy results in significant healthcare costs each year. Currently, many of the pediatric cholestatic liver diseases require invasive and costly treatments such as liver transplantation and surgery. An effective and less invasive treatment that is suitable for the pediatric population is not available. It is well understood and accepted that the therapeutic needs of children are sufficiently different than those of adults as to require specific studies of medications in children. For example, oral administration of a solid dosage form of medication is painless and simple for most adult patients, but for the pediatric patient population, swallowing an oral solid dosage form produced for adults can be problematic. In addition, the drugs used in solid dosages often have an unpleasant taste. More importantly, oral administration of adult medication targeting cholestatic liver diseases may result in side effects such as diarrhea and intestinal discomfort. Such problems pose a safety risk and affect compliance. Effective and acceptable forms of pediatric medication for pediatric cholestastatic liver diseases are needed. US 2005/009805 A1 describes benzothazepine compounds as being useful for treating and preventing hyperlipidemia, cholestasis-accompanying hepatopathy, and obesity and fatty liver. Homg-Chih Huang et al. describe certain substituted benzothiepines as being apical sodium-codependent bile acid transport inhibitors in "Discovery of Potent, Nonsystemic Apical Sodium-Codependent Bile Acid Transporter Inhibitors (Part 2)", JOURNAL OF MEDICINAL CHEMISTRY, vol. 48, no. 18, 1 September 2005, pages 5853-5868. US 2002/061888 A1 describes HMG Co-A reductase inhibitors and one or more ASBT inhibitors selected from a specific group, and combinations thereof as useful in the treatment and/or prophylaxis of a hyperlipidemic condition or disorder in a subject. SUMMARY OF THE INVENTION The present invention is defined by the scope of the appended claims. In particular, the invention provides a composition comprising an apical sodium-dependent bile acid transporter inhibitor (ASBTI) which is or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, for use in a method of treating a pediatric cholestatic liver disease in a human pediatric patient aged between 0 and 18 years of age, wherein the pediatric cholestatic liver disease is selected from the group consisting of progressive familial intrahepatic cholestasis (PFIC), PFIC type 1, PFIC type 2, PFIC type 3, Alagille syndrome, biliary atresia, post-Kasai biliary atresia, post-liver transplantation biliary atresia, pediatric primary sclerosing cholangitis, benign recurrent intrahepatic cholestasis (BRIC), BRIC type 1, BRIC type 2 and BRIC type 3, and wherein the composition comprising the ASBTI is administered orally. Provided herein are therapeutic compositions for use in methods for treating or ameliorating a pediatric cholestatic liver disease or pediatric cholestasis. In certain embodiments, provided herein are compositions for use in methods for treating or ameliorating a pediatric cholestatic liver disease comprising non-systemically administering to a pediatric patient a therapeutically effective amount of a composition comprising an Apical Sodium-dependent Bile Transporter Inhibitor (ASBTI) or a pharmaceutically acceptable salt thereof. In certain embodiments, provided herein are compositions for use in methods for treating or ameliorating a pediatric cholestatic liver disease comprising administering to an individual in need thereof a therapeutically effective amount of a composition comprising a non-systemically absorbed ASBTI or a pharmaceutically acceptable salt thereof. In certain embodiments, provided herein are pediatric dosage forms for use in methods for treating or ameliorating a pediatric cholestatic liver disease comprising non-systemically administering to a pediatric patient a therapeutically effective amount of a pediatric dosage form comprising an Apical Sodium-dependent Bile Transporter Inhibitor (ASBTI) or a pharmaceutically acceptable salt thereof. In certain embodiments, provided herein are pediatric dosage forms for use in methods for treating or ameliorating a pediatric cholestatic liver disease comprising administering to an individual in need thereof a therapeutically effective amount of a pediatric dosage form comprising a non-systemically absorbed ASBTI or a pharmaceutically acceptable salt thereof. In certain embodiments, provided herein are pediatric dosage forms comprising a pediatric dosage of a non-systemically absorbed Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTI) or a pharmaceutically acceptable salt thereof. Disclosed are pediatric dosage forms comprising any non-systemically absorbed ASBTI or a pharmaceutically acceptable salt thereof and a second agent described he