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Faldaprevir with BI 207127 for Chronic Hepatitis C Infection, Genotype 1

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Faldaprevir with BI 207127 for Chronic Hepatitis C Infection, Genotype 1 Horizon Scanning Centre November 2012 Faldaprevir with BI 207127 for chronic hepatitis C infection, genotype 1 SUMMARY NIHR HSC ID: 7688 Faldaprevir is intended to be used in combination with BI 207127 for the treatment of genotype 1 chronic hepatitis infection. If licensed, it would This briefing is provide an additional treatment option for this patient group in a regimen that based on does not include interferon. information The true incidence of hepatitis C infection is unknown, however estimates available at the time suggest that there are approximately 173,000 chronically infected patients in of research and a England and Wales. Around five out of six patients are unaware of their limited literature infection status Approximately 17,000 patients are currently receiving search. It is not treatment, of whom 45% (7,650) are infected with genotype 1. Around 30% intended to be a of infected people develop cirrhosis of the liver within 20-30 years, and some definitive statement of these go on to develop hepatocellular carcinoma. on the safety, efficacy or Current standard of care for genotype 1 patients is a triple combination effectiveness of the therapy of telaprevir or boceprevir in combination with peginterferon alfa and health technology ribavirin. Faldaprevir in combination with BI 207127 is currently in phase II covered and should clinical trials comparing its effect on sustained virological response with and not be used for without ribavirin. commercial purposes or commissioning without additional information. This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health. NIHR Horizon Scanning Centre, University of Birmingham Email: [email protected] Web: http://www.hsc.nihr.ac.uk NIHR Horizon Scanning Centre TARGET GROUP Chronic hepatitis C (HCV) infection: genotype 1. TECHNOLOGY DESCRIPTION Faldaprevir (BI 201335) is a second-generation HCV NS3/4A protease inhibitor with highly potent in vitro activity against GT1a/1b subtypes and pharmacokinetics that permit once daily dosing1. BI 207127 is an orally bioavailable, reversible, thumb pocket 1 non-nucleoside inhibitor (NNI) of the HCV NS5B polymerase with potent and specific antiviral activity in vitro1. Drug resistance studies in cell culture have demonstrated that faldaprevir and BI 207127 have different resistance profiles, and early evidence suggests that using NS3/4A protease inhibitors and NS5B thumb pocket 1 NNI compounds in combination may reduce the selection of drug resistant variants1. Faldaprevir is administered orally at 120mg once daily in treatment naive patients, and at 240mg once daily in treatment experienced patients, in combination with BI 207127 administered orally at 600mg three times daily, both with or without ribavirin. Faldaprevir and BI 207127 are also in phase II and phase III clinical trials for hepatitis C in combination with ribavirin and peginterferon alfa. INNOVATION and/or ADVANTAGES If licensed, faldaprevir with BI 207127 will provide an additional treatment option for this patient group in a regimen that does not include interferon. DEVELOPER Boehringer Ingelheim Limited. AVAILABILITY, LAUNCH OR MARKETING In phase III clinical trials. PATIENT GROUP BACKGROUND HCV is a member of the flaviviridae family of spherical, enveloped, positive-strand RNA viruses. There are six different HCV genotypes; genotype 1 is the most common and the most resistant to treatment2. The virus is acquired primarily through percutaneous exposure to contaminated blood3. Most acute infections with HCV are asymptomatic with only 20% developing overt hepatitis4. Approximately 80% of people who are infected go on to develop chronic HCV3, symptoms of which include malaise, weakness and anorexia4. Chronic HCV is categorised as mild, moderate or severe depending on the extent of liver damage3. Approximately 30% of infected people develop cirrhosis within 20-30 years, and some of these develop hepatocellular carcinoma3. End stage-liver disease or hepatocellular carcinoma may require liver transplantation3. Factors known to increase the rate of 2 NIHR Horizon Scanning Centre progression include age, ethnicity, male sex, excessive alcohol consumption and HIV co- infection5. NHS or GOVERNMENT PRIORITY AREA This topic is relevant to: The Blood Borne Virus Action Plan for Wales 2009-2014. 2008. Improving Outcomes: A Strategy for Cancer (2011). CLINICAL NEED and BURDEN OF DISEASE The true incidence of HCV infection is difficult to establish, however recent estimates suggest that there are 173,000 chronically infected HCV patients in England and Wales6, of whom around 28,833 are diagnosed (five out of six chronic HCV patients are unaware of their infection status)6. Estimates suggest that by 2020, around 4,200 people in England may need a liver transplant as a result of untreated hepatitis C7. Currently, 17,000 patients are receiving treatment, of whom 45% (7,650) are infected with genotype 18. It is estimated that there will be 7,922 genotype 1 chronic HCV patients being treated in 20168. In 2010-11, chronic HCV (ICD-10 B17.1, B18.2) was the primary cause of 2,967 hospital admissions in England, resulting in 2,688 bed days9. In 2010, there were 166 deaths registered in England and Wales10. PATIENT PATHWAY RELEVANT GUIDANCE NICE Guidance NICE technology appraisal in development. Hepatitis C (children and young people) – peginterferon alfa and ribavirin. (ID373). Expected August 201311. NICE technology appraisal. Telaprevir for the treatment of genotype 1 chronic hepatitis C (TA252). April 201212. NICE technology appraisal. Boceprevir for the treatment of genotype 1 chronic hepatitis C (TA253). April 201213. NICE technology appraisal. Peginterferon alfa and ribavirin for the treatment of chronic hepatitis C (TA200). September 20103. NICE technology appraisal. Peginterferon alfa and ribavirin for the treatment of mild chronic hepatitis C (TA106). August 200614. NICE technology appraisal. Interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of chronic hepatitis C (TA75). January 200415. NICE public health guidance in development. Hepatitis B and C – ways to promote and offer testing to people at risk of infection. Expected December 201216. Other Guidance Department of Health. Hepatitis C: quick reference guide for primary care. 200917. Royal College of General Practitioners. Guidance for the prevention, testing, treatment and management of hepatitis C in primary care. 20075. Scottish Intercollegiate Guidelines Network. Management of hepatitis C. (92). 200618. 3 NIHR Horizon Scanning Centre British Association of Sexual Health and HIV. United Kingdom national guideline on the management of the viral hepatitides A, B & C. 200519. British Society of Gastroenterology. Guidance on the treatment of hepatitis C incorporating the use of pegylated interferon. 200320. EXISTING COMPARATORS and TREATMENTS The choice of therapy for HCV is influenced by genotype. Patients with genotype 2 or 3 are usually treated with 24 weeks of peginterferon alfa and ribavirin. Patients with genotype 1 are treated with triple combination therapy for a duration influenced by pre-treatment factors (including cirrhosis) and response to therapy21. All patients with chronic HCV (irrespective of the stage of the disease) are considered for therapy5. Current treatment options include3,12,13: A combination of ribavirin and peginterferon alfa-2a or 2b. Telaprevir in combination with peginterferon alfa and ribavirin. Boceprevir in combination with peginterferon alfa and ribavirin. Successful treatment is usually indicated by a sustained virologic response (SVR), which is defined as undetectable serum HCV RNA 6 months after the end of treatment3. The proportion of people with HCV genotype 1 who show SVR after finishing a course of treatment with peginterferon and ribavirin is about 40% to 50%, compared to approximately 75% to 85% of people with HCV genotype 2 or 3, and 50% to 75% for other genotypes (4,5, and 6)3,14. EFFICACY and SAFETY Trial SOUND-C1, NCT01132313, 1241.21, SOUND-C2; faldaprevir and BI 207127, 2009-018197-66; faldaprevir in with or without ribavirin; phase IIb. combination with BI 207127, with or without ribavirin; phase II. Sponsor Boehringer Ingelheim. Boehringer-Ingelheim. Status Ongoing. Complete. Source of Trial registry22, other database23. Manufacturer24. information Location EU, USA, Australia and New Zealand. Not reported. Design Randomised, active controlled. Randomised. Participants n=513 (planned); aged 18-75 years; n=362; HCV infection; genotype 1. chronic HCV; genotype 1; treatment naive. Schedule Randomised to: Randomised to: Arm 1: faldaprevir, oral, once daily, with BI Arm 1: faldaprevir, 120mg, once daily with 207127, high dose, oral, three times daily, BI 207127, 600mg, three times daily and and ribavirin, for 4 weeks. ribavirin for 16 weeks. Arm 2: faldaprevir, oral, once daily, with BI Arm 2: faldaprevir, 120mg, once daily with 207127, low dose, oral, three times daily, BI 207127, 600mg, three times daily and and ribavirin, for 4 weeks. ribavirin for 28 weeks. Arm 3: faldaprevir, oral, once daily, with BI Arm 3: faldaprevir, 120mg, once daily with 207127, high dose, oral, three times daily, BI 207127, 600mg, three times daily and and ribavirin, for 16 weeks. ribavirin for 40 weeks. Arm 4: faldaprevir, oral, once daily, with BI Arm 4: faldaprevir, 120mg, once daily
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