Horizon Scanning Centre November Faldaprevir with BI for chronic hepatitis C infection, genotype 1 SUMMARY NIHR HSC ID: 7688

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1 Horizon Scanning Centre November 2012 Faldaprevir with BI for chronic hepatitis C infection, genotype 1 SUMMARY NIHR HSC ID: 7688 This briefing is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes or commissioning without additional information. Faldaprevir is intended to be used in combination with BI for the treatment of genotype 1 chronic hepatitis infection. If licensed, it would provide an additional treatment option for this patient group in a regimen that does not include interferon. The true incidence of hepatitis C infection is unknown, however estimates suggest that there are approximately 173,000 chronically infected patients in England and Wales. Around five out of six patients are unaware of their infection status Approximately 17,000 patients are currently receiving treatment, of whom 45% (7,650) are infected with genotype 1. Around 30% of infected people develop cirrhosis of the liver within years, and some of these go on to develop hepatocellular carcinoma. Current standard of care for genotype 1 patients is a triple combination therapy of telaprevir or boceprevir in combination with peginterferon alfa and ribavirin. Faldaprevir in combination with BI is currently in phase II clinical trials comparing its effect on sustained virological response with and without ribavirin. 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 nihrhsc@contacts.bham.ac.uk Web:

2 TARGET GROUP Chronic hepatitis C (HCV) infection: genotype 1. TECHNOLOGY DESCRIPTION Faldaprevir (BI ) 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 dosing 1. BI is an orally bioavailable, reversible, thumb pocket 1 non-nucleoside inhibitor (NNI) of the HCV NS5B polymerase with potent and specific antiviral activity in vitro 1. Drug resistance studies in cell culture have demonstrated that faldaprevir and BI 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 variants 1. 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 administered orally at 600mg three times daily, both with or without ribavirin. Faldaprevir and BI 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 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 treatment 2. The virus is acquired primarily through percutaneous exposure to contaminated blood 3. Most acute infections with HCV are asymptomatic with only 20% developing overt hepatitis 4. Approximately 80% of people who are infected go on to develop chronic HCV 3, symptoms of which include malaise, weakness and anorexia 4. Chronic HCV is categorised as mild, moderate or severe depending on the extent of liver damage 3. Approximately 30% of infected people develop cirrhosis within years, and some of these develop hepatocellular carcinoma 3. End stage-liver disease or hepatocellular carcinoma may require liver transplantation 3. Factors known to increase the rate of 2

3 progression include age, ethnicity, male sex, excessive alcohol consumption and HIV coinfection 5. NHS or GOVERNMENT PRIORITY AREA This topic is relevant to: The Blood Borne Virus Action Plan for Wales 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 Wales 6, 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 C 7. Currently, 17,000 patients are receiving treatment, of whom 45% (7,650) are infected with genotype 1 8. It is estimated that there will be 7,922 genotype 1 chronic HCV patients being treated in In , chronic HCV (ICD-10 B17.1, B18.2) was the primary cause of 2,967 hospital admissions in England, resulting in 2,688 bed days 9. In 2010, there were 166 deaths registered in England and Wales 10. PATIENT PATHWAY RELEVANT GUIDANCE NICE Guidance NICE technology appraisal in development. Hepatitis C (children and young people) peginterferon alfa and ribavirin. (ID373). Expected August NICE technology appraisal. Telaprevir for the treatment of genotype 1 chronic hepatitis C (TA252). April NICE technology appraisal. Boceprevir for the treatment of genotype 1 chronic hepatitis C (TA253). April NICE technology appraisal. Peginterferon alfa and ribavirin for the treatment of chronic hepatitis C (TA200). September NICE technology appraisal. Peginterferon alfa and ribavirin for the treatment of mild chronic hepatitis C (TA106). August NICE technology appraisal. Interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of chronic hepatitis C (TA75). January NICE public health guidance in development. Hepatitis B and C ways to promote and offer testing to people at risk of infection. Expected December Other Guidance Department of Health. Hepatitis C: quick reference guide for primary care Royal College of General Practitioners. Guidance for the prevention, testing, treatment and management of hepatitis C in primary care Scottish Intercollegiate Guidelines Network. Management of hepatitis C. (92)

4 British Association of Sexual Health and HIV. United Kingdom national guideline on the management of the viral hepatitides A, B & C British Society of Gastroenterology. Guidance on the treatment of hepatitis C incorporating the use of pegylated interferon 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 therapy 21. All patients with chronic HCV (irrespective of the stage of the disease) are considered for therapy 5. Current treatment options include 3,12,13 : 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 treatment 3. 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, NCT , , ; faldaprevir in combination with BI , with or without ribavirin; phase II. SOUND-C2; faldaprevir and BI , with or without ribavirin; phase IIb. Sponsor Boehringer Ingelheim. Boehringer-Ingelheim. Status Ongoing. Complete. Source of Trial registry 22, other database 23. Manufacturer 24. information Location EU, USA, Australia and New Zealand. Not reported. Design Randomised, active controlled. Randomised. Participants n=513 (planned); aged years; chronic HCV; genotype 1; treatment naive. n=362; HCV infection; genotype 1. Schedule Randomised to: Arm 1: faldaprevir, oral, once daily, with BI and ribavirin, for 4 weeks. Arm 2: faldaprevir, oral, once daily, with BI , low dose, oral, three times daily, and ribavirin, for 4 weeks. Arm 3: faldaprevir, oral, once daily, with BI and ribavirin, for 16 weeks. Arm 4: faldaprevir, oral, once daily, with BI and ribavirin, for 28 weeks. Arm 5: faldaprevir, oral, once daily, with BI Randomised to: Arm 1: faldaprevir, 120mg, once daily with BI , 600mg, three times daily and ribavirin for 16 weeks. Arm 2: faldaprevir, 120mg, once daily with BI , 600mg, three times daily and ribavirin for 28 weeks. Arm 3: faldaprevir, 120mg, once daily with BI , 600mg, three times daily and ribavirin for 40 weeks. Arm 4: faldaprevir, 120mg, once daily with BI , 600mg, twice daily and ribavirin for 28 weeks. Arm 5: faldaprevir, 120mg, once daily with 4

5 Follow-up and ribavirin, for 40 weeks. Arm 6: faldaprevir, oral, once daily, with BI , high dose, oral, twice daily, and ribavirin, for 28 weeks. Arm 7: faldaprevir, oral, once daily, with BI for 28 weeks. Arm 8: faldaprevir, oral, once daily, with BI , high dose, oral, twice daily, and ribavirin, for 16 weeks. Arm 9: faldaprevir, oral, once daily, with BI , very high dose, oral, twice daily, and ribavirin, for 24 weeks. Arm 10: faldaprevir, oral, once daily, with BI , high dose, oral, three times daily, and ribavirin, for 24 weeks. Active treatment up to 40 weeks; follow-up period not reported BI , 600mg, three times daily for 28 weeks. Active treatment period up to 40 weeks; follow-up period not reported. Primary Rapid virological response (RVR); SVR. outcome/s sustained virologic response (SVR). Secondary Time to virological response. Not reported. outcome/s Key results - For arms 1-5 respectively, SVR (%), genotype 1a: 38, 44, 47, 43, 11; genotype 1b: 75, 69, 56, 85, 57. Adverse effects (AEs) - Most common AEs included skin changes (photosensitivity, rash), gastrointestinal disorders (vomiting, diarrhoea), jaundice due to transient benign bilirubin elevation (unconjugated hyperbilirubinemia). Expected reporting date Not reported. - ESTIMATED COST and IMPACT COST The cost of faldaprevir in combination with BI is not yet known. The costs of selected currently licensed treatments for HCV are summarised below 25 : Drug Dose a 12 week cost 48 week cost Peginterferon alfa-2a (Pegasys) 180µg SC once weekly 1, , Peginterferon alfa-2b (ViraferonPeg) 100µg SC once weekly 1, , Ribavirin (Rebetol) 1,000mg daily , Telaprevir (Incivo) 2,250mg daily 22, n/a Bopeprevir (Victrelis) 2,400mg daily 8, ,400 b a Based on an average weight of 77.9kg (men and women). b Indicated for 32 weeks treatment. 5

6 IMPACT - SPECULATIVE Impact on Patients and Carers Reduced mortality/increased length of survival Reduced symptoms or disability Other: potential shortened course of treatment compared to standard of care, without the side effects associated with peginterferon; oral regimen has the potential improve adherence. Impact on Services No impact identified Increased use of existing services Decreased use of existing services Re-organisation of existing services Need for new services Other: IL28b testing may be required to determine suitability for treatment. None identified Impact on Costs Increased drug treatment costs Reduced drug treatment costs Other increase in costs:. Other reduction in costs: Other: uncertain unit cost compared to existing treatments None identified Other Issues Clinical uncertainty or other research question identified: expert opinion suggests there is a lack of data on the comparative efficacy of the directly acting antiviral drugs currently in development. Expert opinion also highlights a lack of data on efficacy in patients previously treated with boceprevir or telaprevir (cross resistance with faldaprevir is reported). c REFERENCES None identified 1 Zeuzem S, Asselah T, Angus P et al. Efficacy of the protease inhibitor BI , polymerase inhibitor BI , and Ribavirin in patients with chronic HCV infection. Gasteroenterology 2011;141(6): Mohsen A, Norris S. Hepatitis C (chronic). Clinical Evidence 2010;02: National Institute for Health and Clinical Excellence. Peginterferon alfa and ribavirin for the treatment of chronic hepatitis C. Technology appraisal TA200. London: NICE; September National Institute for Health and Clinical Excellence. Peginterferon alfa and ribavirin for the treatment of mild chronic hepatitis C. Technology appraisal TA106. London: NICE; August Royal College of General Practitioners. Guidance for the prevention, testing, treatment and management of hepatitis C in primary care. London: RCGP; May Health Protection Agency. Hepatitis C in the UK: 2011 report. London: HPA; July Health Protection Agency. Four thousand people in England may need liver transplants by 2020 due to hepatitis C, HPA warns. yleadtotransplantneeds/ Accessed 5 November c Expert personal communication. 6

7 8 National Institute for Health and Clinical Excellence. Single technology appraisal (STA). Telaprevir for the treatment of genotype 1 chronic hepatitis C. London: NICE; October NHS. Hospital episode statistics. NHS England HES data Office for National Statistics. Mortality Statistics: Deaths registered in England and Wales, series DR National Institute for Health and Clinical Excellence. Hepatitis C (children and young people) peginterferon alfa and ribavirin. Technology appraisal in development ID373. Expected August National Institute for Health and Clinical Excellence. Telaprevir for the treatment of genotype 1 chronic hepatitis C. Technology appraisl TA252. London: NICE; April National Institute for Health and Clinical Excellence. Boceprevir for the treatment of genotype 1 chronic hepatitis C. Technology appraisal TA253. London: NICE; April National Institute for Health and Clinical Excellence. Peginterferon alfa and ribavirin for the treatment of mild chronic hepatitis C. Technology appraisal TA106. London: NICE; August National Institute for Health and Clinical Excellence. Interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of chronic hepatitis C. Technology appraisal TA75. London: NICE; January National Institute for Health and Clinical Excellence. Hepatitis B and C ways to promote and offer testing to people at risk of infection. Public health guidance in development. Expected December Department of Health. Hepatitis C: quick reference guide for primary care. London; Crown; January Scottish Intercollegiate Guidelines Network. Management of hepatitis C. National clinical guideline 92. Edinburgh: SIGN; December British Association of Sexual Health and HIV. United Kingdom national guideline on the management of the viral hepatitis A, B & C London: BASHH; September British Society of Gastroenterology. Guidance on the treatment of Hepatitis C incorporating the use of pegylated interferons. London: BSG; March National Institute for Health Research Horizon Scanning Centre. Simeprevir for chronic hepatitis C infection. Birmingham: NIHR HSC; September ClinicalTrials.gov. Safety, antiviral effect and PK of BI BI /- RBV for 4 up to 40 weeks in patients with chronic HCV genotype 1 infection. Accessed 5 November PharmaProjects. Faldaprevir. Accessed 28 November Boehringer-Ingelheim. Phase 2b data of Boehringer Ingelheim s interferon-free hepatitis C treatment show viral cure achieved in up to 85% of treatment-naïve patients. Accessed 28 November British Medical Association and Royal Pharmaceutical Society of Great Britain. British National Formulary. BNF 64. London: BMJ Group and RPS Publishing, September