Albinterferon alfa-2b (Joulferon) for hepatitis C with compensated liver disease August 2009 This technology summary 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. The National Horizon Scanning Centre Research Programme is part of the National Institute for Health Research August 2009 National Horizon Scanning Centre News on emerging technologies in healthcare Albinterferon alfa-2b (Joulferon) for hepatitis C with compensated liver disease Target group • Hepatitis C (HCV): genotypes 1, 2 and 3; chronica with compensated liver diseaseb; no prior treatment with alpha interferon (alpha-IFN). Technology description Albinterferon alfa-2b (Joulferon) is a recombinant albumin and alpha-IFN fusion protein. The precise mechanism of action of alpha-IFN is not fully understood however research has demonstrated that it has direct antiviral activity as well as immune-modulating effects. Albinterferon alfa-2b is intended as a substitute for peginterferon alfa-2a or 2b. Albinterferon alfa-2b is administered by subcutaneous (SC) injection once every two weeks in combination with ribavirin (RBV). In phase III trials patients with HCV genotypes 2 and 3 had 24 weeks treatment whilst those with HCV genotype 1 had 48 weeks treatment. Innovation and/or advantages Conjugation to human albumin prolongs the action of alpha-IFN which reduces the dosing frequency and may reduce the incidence of adverse events. Developer Novartis Pharmaceuticals UK Ltd. and Human Genome Sciences. Availability, launch or marketing dates, and licensing plans: In phase III clinical trials. NHS or Government Priority area This topic is relevant to The Blood Borne Virus Action Plan for Wales 2009-2014 2008; Hepatitis C Action Plan for England 2004; Getting Ahead of the Curve: a Strategy for Combating Infectious Diseases (Including Other Aspects of Health Protection) 2002; and The Hepatitis C Strategy for England 2002. Relevant guidance • NICE technology appraisal. Peginterferon alfa and ribavirin for the treatment of mild hepatitis C. 20061. • NICE technology appraisal. Interferon alfa and ribavirin for the treatment of chronic hepatitis C - part review of existing guidance no.14. 20042. • Department of Health. Hepatitis C: quick reference guide for primary care. 20093. • Royal College of General Practitioners. Guidance for the prevention, testing, treatment and management of hepatitis C in primary care. 20074. • SIGN. Management of hepatitis C. 20065. • British Association of Sexual Health and HIV. United Kingdom national guideline on the management of the viral hepatitides A, B & C. 20056. • British Society of Gastroenterology. Guidance on the treatment of hepatitis C incorporating the use of pegylated interferons. 20037. • British Society of Gastroenterology. Clinical guidelines on the management of hepatitis C. 20018. aChronic HCV is defined as persistent detectable serum HCV RNA for a period greater than 6 months. bCompensated liver disease indicates a diseased or cirrhotic, but functional liver. 2 August 2009 National Horizon Scanning Centre News on emerging technologies in healthcare Clinical need and burden of disease Complications of HCV infection include cirrhosis, compensated and decompensated liver disease, and hepatocellular carcinoma. About 30% of those who are infected with HCV develop cirrhosis within 20–30 years and some people with end-stage liver disease or hepatocellular carcinoma may need liver transplantation1,2. Factors associated with disease progression include: older age at acquisition; male sex; co-infection with HIV, hepatitis B virus, or both; coexisting liver disease; and excessive alcohol consumption4. As diagnosis of HCV infection is often the result of active screening - the true incidence of HCV is difficult to establish. Recent estimates suggest that approximately 200,000 to 500,000 people are infected with HCV in England and Wales1. In 2005, the Department of Health estimated that only 47,000 people with HCV infection had been diagnosed and only 7,000 had been treated1. Chronic HCV was the primary cause of 3,367 admissions to hospitals in England in 2005-06, resulting in 3,709 bed days9. In 2004 an estimated 2,000 people received some form of interferon or peginterferon alfa therapy for HCV2. Existing comparators and treatments The genotype of the infecting hepatitis C virus and the viral load affect the choice and duration of treatment - typically 24 weeks treatment for HCV genotypes 2 and 3 and 48 weeks treatment for HCV genotype 1. Current treatment options include: • A combination of ribavirin and peginterferon alfa-2a (Pegasys; Roche) or peginterferon alfa-2b (ViraferonPeg; Schering-Plough). • Peginterferon alfa-2a or peginterferon alfa-2b as monotherapy - used if ribavirin is contra-indicated or not tolerated. • Interferon alfa as monotherapy or combination therapy – used only if neutropenia and thrombocytopenia are a particular risk Efficacy and safety Trial ACHIEVE 2/3, NCT00411385; ACHIEVE 1, NCT00402428; alb-IFN albinterferon (alb-IFN) alfa-2b with RBV alfa-2b with RBV vs peg-IFN alfa-2a with vs peginterferon (peg-IFN) alfa-2a with RBV; phase III. RBV; phase III. Sponsor Human Genome Sciences and Novartis. Human Genome Sciences and Novartis. Status Oral presentation10, press release11. Oral presentation12, press release13. Location EU (inc UK), USA, Canada and other EU (inc UK), USA, Canada and other countries. countries. Design Randomised, active control. Randomised, active control. Participants n=933; adults; HCV genotypes 2 and 3; n=1,331; adults; HCV genotype 1; and schedule compensated liver disease; interferon compensated liver disease; interferon naive. naive. Randomised to alb-IFN alfa-2b 900 or Randomised to alb-IFN alfa-2b 900 or 1,200µg every 2 weeks or peg-IFN alfa- 1,200µg every 2 weeks or peg-IFN alfa- 2a 180µg weekly. All patients received 2a 180µg weekly. All patients received RBV 800mg daily. In January 2008, RBV 800mg daily. In January 2008, patients receiving 1,200µg alb-IFN alfa- patients receiving 1200µg alb-IFN alfa-2b 2b had dose modified to 900µg every 2 had dose modified to 900µg every 2 weeks. weeks. Follow-up Treatment for 24 weeks. 24 weeks post Treatment for 48 weeks. 24 weeks post treatment period. treatment period. 3 August 2009 National Horizon Scanning Centre News on emerging technologies in healthcare Primary Sustained virologic response (SVR) c at SVR at week 72. outcome week 48. Secondary Rapid virologic response, early virologic Rapid virologic response, early virologic outcome response, undetectable HCV RNA, response, undetectable HCV RNA, normalisation of ALT, quality of life, normalisation of ALT, quality of life, safety. safety. Key results Alb-IFN alfa-2b 900µg vs peg-IFN alfa- Alb-IFN alfa-2b 900µg vs peg-IFN alfa- 2a respectively: SVR 79.8% vs 84.8% 2a respectively: SVR 48.2% vs 51.0%. (p=0.0086 for non-inferiority). Alb-IFN (p=0.0008 for non-inferiority). Alb-IFN alfa-2b 1,200µg vs peg-IFN alfa-2a alfa-2b 1,200µg vs peg-IFN alfa-2a respectively: SVR 80.0% vs 84.8% respectively: SVR 47.3% vs 51.0% (p=0.0059 for non-inferiority). (p=0.0029 for non-inferiority). Adverse Alb-IFN alfa-2b 900µg, 1,200µg and peg- Alb-IFN alfa-2b 900µg, 1,200µg and peg- effects IFN alfa-2a respectively: serious and/or IFN alfa-2a respectively: serious and/or severe AEs 17.3%, 16.8% and 17.5%; severe AEs 24.0%, 28.3% and severe and/or serious pulmonary 23.1%; serious and/or severe pulmonary infections 0.6%, 1.3% and 0.6%; severe infections 1.8%, 3.2% and 1.1%; serious and/or serious respiratory, thoracic or and/or severe respiratory, thoracic or mediastinal disorders 1.0%, 1.6% and mediastinal disorders 2.5%, 3.0% and 1.3%. Discontinuations due to AEs 4.8%, 0.5%. Discontinuation due to AEs 10.4%, 5.5% and 3.6%. 10.0% and 4.1%. Trial ALFR-HC-04, NCT00115908; alb-IFN CABF656B2202, NCT00759200; alb-IFN alfa-2b with RBV vs peg-IFN alfa-2a with alfa-2b with RBV vs peg-IFN alfa-2a with RBV; phase II. RBV, phase II. Sponsor Human Genome Sciences. Human Genome Sciences and Novartis. Status Published14,15. Ongoing16,17. Location EU, Canada, Australia and Israel. EU (inc UK), Canada and other countries. Design Randomised, open label, active control. Randomised, open label, active control. Participants n=458; adults; HCV genotype 1; n=391; adults; HCV genotypes 2 and 3; and schedule interferon naive; compensated liver interferon naive. disease. Randomised to alb-IFN alfa-2b 900, Randomised to alb-IFN alfa-2b 900 or 1,200 or 1,500µg every 4 weeks or peg- 1,200µg every 2 weeks, alb-IFN alfa-2b IFN alfa-2a 180µg weekly. All patients 1,200µg every 4 weeks or peg-IFN alfa- received RBV at 800mg daily. 2a 180µg once weekly. All in combination with weight-based RBV 1,000-1,200mg daily. Follow-up Treatment for 48 weeks. 24 weeks post Treatment for 24 weeks. treatment period. 24 weeks post treatment period. Primary SVR at 24 weeks post treatment. SVR at week 48. outcome Secondary Virologic responsed at week 4, early Viral load. outcome virologic response at week 12, end of treatment response, quality of life (QOL). Key results Alb-IFN alfa-2b 900 and 1,200µg every 2 - weeks, 1,200µg every 4 weeks and peg- IFN alfa-2a weekly, respectively: SVR 66.7%, 65.4%, 54.2% and 64.3% (no significant difference). QOL and missed cDefined as HCV RNA <10IU/ml. dDefined as undetectable HCV RNA or a >2-log reduction in HCV RNA. 4 August 2009 National Horizon Scanning Centre News on emerging technologies in healthcare work was significantly more favourable for the alb-IFN 900µg every 2 weeks arm.