Ocaliva (obeticholic acid tablets)

Transcription

1 Ocaliva (obeticholic acid tablets) Policy Number: Last Review: 11/2018 Origination: 11/2016 Next Review: 11/2019 Policy Blue Cross and Blue Shield of Kansas City (Blue KC) will provide coverage for Ocaliva (obeticholic acid) tablets when the following criteria are met. When Policy Topic is covered FDA-Approved Indications 1. Primary Biliary Cholangitis (PBC) [also known as Primary Biliary Cirrhosis]. A) Initial Therapy. Approve for 6 months if the patient meets the following criteria (i, ii, iii, and iv): i. Patient is 18 years of age 1 ; AND ii. Ocaliva is prescribed by or in consultation with a gastroenterologist, hepatologist, or liver transplant physician; AND iii. Patient has a diagnosis of primary biliary cholangitis (PBC) as defined by TWO of the following criteria (a, b, and/or c) according to the prescribing physician 4 : a) Alkaline phosphatase (ALP) elevated above the upper limit of normal as defined by normal laboratory reference values; AND/OR b) Positive anti-mitochondrial antibodies (AMAs); AND/OR c) Histologic evidence of primary biliary cholangitis (PBC) from a liver biopsy; AND iv. Patient meets ONE of the following criteria 1 (a or b): a) Patient has been receiving ursodiol therapy (e.g., ursodiol generics, Urso 250,Urso Forte, Actigall ) for 1 year and has had an inadequate response according to the prescribing physician; OR b) According to the prescribing physician the patient is unable to tolerate ursodiol therapy. B) Patients Currently Receiving Therapy. Approve for 1 year if the patient meets the following criteria (i, ii, and iii): i. Patient is 18 years of age 1 ; AND ii. Ocaliva is prescribed by or in consultation with an gastroenterologist, hepatologist, or liver transplant physician; AND iii. The patient has responded to Ocaliva therapy as determined by the prescribing physician (e.g., improved biochemical markers of primary biliary cholangitis [PBC] {e.g., alkaline phosphatase (ALP), bilirubin, gamma-glutamyl transpeptidase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT) levels}). Ocaliva is indicated for the treatment of PBC in combination with UDCA in adult patients with an inadequate response to UDCA or as monotherapy in adults unable to tolerate UDCA. 1 PBC is a chronic, progressive, cholestatic liver disease. 3 The serologic hallmark of PBC is the finding of AMAs in the serum AMA is a highly disease-specific autoantibody found in most, but not all patients with PBC (90% to 95%). The biochemical hallmark of PBC is an elevated ALP level.5 Per current guidelines, a diagnosis of PBC can be made if a patient meets two of the following criteria: 1) biochemical evidence of cholestasis based on ALP elevation; 2) presence of AMA; or 3) histologic evidence of

2 nonsuppurative destructive cholangitis and destruction of interlobular bile ducts. 3-4 The current standard of care for the treatment of PBC is UDCA (available in the US as ursodiol). FDA-approved brands of ursodiol specifically indicated in PBC are Urso 250 and Urso Forte. 3-4,7 UDCA at a dose of 13 to 15 mg/kg/day has demonstrated the ability to improve biochemical markers of PBC, as well as delay histologic progression of the disease and improve survival without liver transplantation. 4 A patient s response to UDCA is measured using biochemical markers; 90% of the improvement in these markers will occur within the first 6 to 9 months of UDCA therapy. In approximately 20% of patients, liver biochemistries normalize in the first 2 years of therapy; an additional 15% to 35% of patients report normalization in the first 5 years of therapy. However, it is estimated that up to 40% of patients with PBC will have an inadequate response to UDCA, which results in an increased risk of liver transplantation and death. 8 The Ocaliva prescribing information provides dosing recommendations for Ocaliva for adult patients with PBC who have not achieved an adequate response to an appropriate dosage of UDCA therapy for at least 1 year or who are intolerant to UDCA. 1 However, an inadequate response is not defined. In the opinion of an expert physician reviewing the data, we have adopted these criteria. When Policy Topic is not covered Ocaliva has not been shown to be effective, or there are limited or preliminary data or potential safety concerns that are not supportive of general approval for the following conditions. Rationale for noncoverage for these specific conditions is provided below. (Note: This is not an exhaustive list of Conditions Not Recommended for Approval.) Investigational 1. Alcoholic Liver Disease. There are no data available to support the use of Ocaliva in patients with alcoholic hepatitis. Ocaliva is not FDA-approved for this indication and current alcoholic liver disease guidelines do not make recommendations regarding therapy with Ocaliva. 1,12 Additional well-controlled studies are needed. 2. Nonalcoholic Fatty Liver Disease (NAFLD), including Nonalcoholic Fatty Liver (NAFL) or Nonalcoholic Steatohepatitis (NASH). There are limited data available evaluating the efficacy of Ocaliva in patients with NAFLD and NASH Ocaliva is not FDA-approved for this indication and current NAFLD guidelines do not make recommendations regarding therapy with Ocaliva. 1,16 Additional well-controlled studies are needed. Considerations Prior authorization is recommended for prescription benefit coverage of Ocaliva. Because of the specialized skills required for evaluation and diagnosis of patients treated with Ocaliva as well as the monitoring required for adverse events and long-term efficacy, approval requires Ocaliva to be prescribed by or in consultation with a physician who specializes in the condition being treated. This Blue Cross and Blue Shield of Kansas City policy Statement was developed using available resources such as, but not limited to: Food and Drug Administration (FDA) approvals, Facts and Comparisons, National specialty guidelines, Local medical policies of other health plans, Medicare (CMS), Local providers. Ocaliva is a specialty pharmacy benefit. Description of Procedure or Service OVERVIEW Ocaliva is indicated for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA or as monotherapy in adults unable to tolerate UDCA. 1 Ocaliva was approved for this indication under accelerated approval based on reduction in alkaline phosphatase (ALP). An improvement in survival or PBC-related symptoms has not been established. The prescribing information notes that continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

3 Ocaliva is structurally similar to an endogenous bile acid, with the addition of an ethyl group in the 6- alpha position (6α-ethyl-CDCA), which makes it a 100-fold more potent agonist at the Farnesoid X receptor (FXR), a nuclear receptor expressed in the liver and intestine. 1-2 FXR is a key regulator of bile acid, inflammatory, fibrotic, and metabolic pathways. 1 Activation of FXR reduces the intracellular concentrations of bile acids in hepatocytes by suppressing de novo synthesis from cholesterol and by increased transport of bile acids out of the hepatocytes. In general, these mechanisms limit the amount of circulating bile acid, while promoting choleresis, and therefore reduce hepatic exposure to bile acids. Primary Biliary Cholangitis [also known as Primary Biliary Cirrhosis] PBC is a chronic, progressive, cholestatic liver disease in which autoimmune destruction of small and medium intrahepatic bile ducts leads to cholestasis. 3-4 Cholestasis eventually progresses to advanced fibrosis, cirrhosis, and liver failure. 3-5 The disease primary affects women (75% to 90% of cases) and is more common in Caucasian patients of Northern European descent. The diagnosis of PBC generally is made between the fourth and sixth decades of life, with an average age at presentation of approximately 50 years. 3-4,6 The exact prevalence of PBC in the US is unknown, but estimates suggest 4.5 women and 0.7 men out of every 100,000 persons are affected. The serologic hallmark of PBC is the finding of AMAs in the serum.3-4 AMA is a highly disease-specific autoantibody found in most, but not all patients with PBC (90% to 95%). The biochemical hallmark of PBC is the finding of an elevated ALP level. 5 Significant elevations in GGT, IgM, ALT, AST, lipid levels, cholesterol levels and an increase erythrocyte sedimentation rate may also be observed, depending on the stage of disease progression.3-4 Other abnormalities, such as elevated bilirubin level and prolonged prothrombin time may also be present if the disease has progressed to cirrhosis. The current standard of care for the treatment of PBC is UDCA, available as ursodiol; Urso 250 and Urso Forte (brand and generics) are FDA-approved for the treatment of patients with PBC. 3-4,7 However, it is estimated that up to 40% of patients with PBC will have an inadequate response to UDCA, which results in an increased risk of liver transplantation and death. 8 Rationale Ocaliva Clinical Efficacy in PBC The efficacy of Ocaliva was established in one pivotal, 52-week, Phase III, randomized, double-blind, placebo-controlled, multicenter, pivotal trial called POISE (available as an abstract) [n = 216], which involved adult patients with PBC who either had an inadequate response to UDCA therapy (93% of patients) or were unable to tolerate UDCA (7% of patients).2 Patients were randomized (1:1:1) to receive Ocaliva 5 mg (option to titrate to 10 mg at Month 6), Ocaliva 10 mg, or placebo once daily (QD) for 12 months. 2 The primary efficacy endpoint was a composite of an ALP level < 1.67 times the upper limit of normal (ULN), a 15% reduction in ALP, and a total bilirubin ULN at Month 12. At Month 12, 47% of patients (n = 34) in the Ocaliva 10 mg group achieved the composite endpoint compared with 10% of patients (n = 7) receiving placebo (P < ). A similar proportion of patients in the Ocaliva 5 mg (titration) group also met the composite endpoint (46% of patients), which was also significantly better than placebo (P < ). There were significant reductions in ALP with both Ocaliva groups vs. placebo; these reductions were observed early in treatment and sustained throughout the study. Bilirubin levels were normal at baseline, but increased in the placebo group despite continued treatment with UDCA; levels were stable in patients receiving Ocaliva. Guidelines The American Association for the Study of Liver Disease (AASLD) guidelines for PBC (2009) have not been updated to include recommendations regarding Ocaliva therapy.3 UDCA at a dose of 13 to 15 mg/kg/day orally is the recommended treatment for patients with PBC who have abnormal liver enzyme values regardless of histologic stage (Class I, Level A). The guidelines also note that other drugs have been investigated for the treatment of PBC, but none given as monotherapy have been found to be of benefit. The European Association for the Study of the Liver (EASL) Clinical Practice Guidelines: Management of Cholestatic Liver Diseases (2009) make similar recommendations as the AASLD guidelines. 11 Patients with PBC (both symptomatic and asymptomatic disease) should be treatment with UDCA at 13 to 15 mg/kg/day on an ongoing basis. Biochemical response to UDCA should be evaluated at 1 year of therapy. A good biochemical response is defined as a serum bilirubin

4 1 mg/dl, ALP 3 x ULN, and an AST 2 x ULN or by a decrease of 40% or normalization of serum ALP. The guidelines note that at the time of publication, there was no consensus on how to treat patients with a suboptimal response to UDCA; the guidelines have not been updated since the approval of Ocaliva. REFERENCES 1. Ocaliva tablets [prescribing information]. San Diego, CA: Intercept Pharmaceuticals Inc.; May Intercept Pharmaceuticals. Obeticholic Acid. Briefing document for the Food and Drug Administration Gastrointestinal Drugs Advisory Committee. Meeting Date: April 7, Available at: aldrugsadvisorycommittee/ucm pdf. Accessed on April 21, Pyrsopoulos NT. Primary Biliary Cirrhosis. Medscape Drugs, Diseases & Procedures Reference. Updated June 25, Available at: Accessed on May 9, Lindor KD, Gershwin ME, Poupon R, et al. American Association for the Study of Liver Diseases (AASLD) practice guidelines: primary biliary cirrhosis. Hepatology. 2009;50(1): Silveira MG, Brunt EM, Heathcote J, et al. American Association for the Study of Liver Diseases Endpoints Conference: design and endpoints for clinical trials in primary biliary cirrhosis. Hepatology. 2010;52(1): Hirschfield GM, Mason A, Luketic V, et al. Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterol. 2015;148: Urso 250 tablets and Urso Forte tablets [prescribing information]. Bridgewater, NJ: Aptalis Pharma US, Inc.; June Mousa H, Lleo A, Invernizzi P, et al. Advances in pharmacotherapy for primary biliary cirrhosis. Expert Opin Pharmacother. 2015;16(5): Harms MH, Lammers WJ, Marmon T, et al. Improvement in estimated survival after 1 year of obeticholic acid treatment in primary biliary cholangitis [poster 352]. Presented at: the International Liver Congress 2016, the 51st Annual Meeting of the European Association for the Study of Liver Disease (EASL); Barcelona, Spain; April 13-17, Mayo MJ, Kremer AE, Beuers U, et al. Mitigation of pruritus during obeticholic acid treatment in patients with PBC: strategies and successes [poster 357]. Presented at: the International Liver Congress 2016, the 51st Annual Meeting of the European Association for the Study of Liver Disease (EASL); Barcelona, Spain; April 13-17, European Association for the Study of the Liver (EASL) clinical practice guidelines: management of cholestatic liver diseases. J Hepatol. 2009;51(2): O Shea RS, Dasarathy S, McCullough AJ, et al. Alcoholic liver disease: practice guideline by the American Association for the Study of Liver Diseases and the American College of Gastroenterology. Hepatology. 2010;51(1): Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicenter, randomized, placebo-controlled trial. Lancet. 2015;385: Ratziu V, Sanyal AJ, MacConell L, et al. REGENERATE: a phase 3, double-blind, randomized, long-term, placebo-controlled, multicenter study evaluating the safety and efficacy of obeticholic acid in subjects with nonalcoholic steatohepatitis [poster 488]. Presented at: the International Liver Congress 2016, the 51st Annual Meeting of the European Association for the Study of Liver Disease (EASL); Barcelona, Spain; April 13-17, US National Institutes of Health. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US) [cited 2016 May 17]. Available from: acid&search=search. Search term: obeticholic acid. 16. Chalasani N, Younassi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012;55(6):

5 Billing Coding/Physician Documentation Information NA Specialty pharmacy benefit Additional Policy Key Words Policy number Policy Implementation/Update Information 11/2016 New policy titled Ocaliva (obeticholic acid tablets) 11/2017 Reviewed-no policy statement changes 11/2018 Reviewed-no policy statement changes State and Federal mandates and health plan contract language, including specific provisions/exclusions, take precedence over Medical Policy and must be considered first in determining eligibility for coverage. The medical policies contained herein are for informational purposes. The medical policies do not constitute medical advice or medical care. Treating health care providers are independent contractors and are neither employees nor agents Blue KC and are solely responsible for diagnosis, treatment and medical advice. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, photocopying, or otherwise, without permission from Blue KC.