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.

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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 (alpha-IFN).

Technology description Albinterferon alfa-2b (Joulferon) is a recombinant albumin and alpha-IFN fusion . 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 (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 Borne 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. 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 . 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.

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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. Expected - 2010/2011 reporting date Adverse Alb-IFN alfa-2b 900µg, 1,200µg every - effects two weeks, 1,200µg every 4 weeks and peg-IFN respectively: discontinuations due to AEs 9.3%, 18.2% 12.1% and 6.1%. Hematologic reductions were lowest with alb-IFN 4 weekly and comparable across other arms.

Estimated cost and cost impact The cost of albinterferon alfa-2b is yet to be determined. The cost of currently licensed treatments is:

Drug Dose 24 week cost Peginterferon alfa-2a 180µg SC once weekly. £3,168 Peginterferon alfa-2b 100µg SC once weeklye. £3,013

Potential or intended impact – speculative Patients ; Reduced morbidity Reduced mortality or increased ; Improved quality of life for length of survival patients and/or carers Quicker, earlier or more accurate Other: None identified diagnosis or identification of disease

Services Increased use Service reorganisation required Staff or training required

; Decreased use: if the incidence Other: None identified of adverse effects is reduced

Costs Increased unit cost compared to Increased costs: more patients Increased costs: capital alternative coming for treatment investment needed New costs: Savings: ; Other: unknown relative cost.

References

1 National Institute for Health and Clinical Excellence. Peginterferon alfa and ribavirin for the treatment of mild hepatitis C. Technology appraisal TA106. London: NICE; August 2006. 2 National Institute for Health and Clinical Excellence. Interferon alfa and ribavirin for the treatment of chronic hepatitis C - part review of existing guidance no.14. Technology appraisal TA75. London: NICE; January 2004. 3 Department of Health. Hepatitis C: quick reference guide for primary care. January 2009. 4 Royal College of General Practitioners. Guidance for the prevention, testing, treatment and management of hepatitis C in primary care. London: RCGP; May 2007. 5 Scottish Intercollegiate Guidelines Network. Management of hepatitis C. No. 92. Edinburgh: SIGN; December 2006. 6 British Association of Sexual Health and HIV. United Kingdom national guideline on the management of the viral hepatitides A, B & C 2005. London: BASHH; September 2005. eBased on average weight 67.5kg (men and women). 5 August 2009 National Horizon Scanning Centre News on emerging technologies in healthcare

7 British Society of Gastroenterology. Guidance on the treatment of Hepatitis C incorporating the use of pegylated interferons. London: BSG; March 2003. 8 British Society of Gastroenterology. Clinical guidelines on the management of hepatitis C. London: BSG; July 2001. 9 NHS. Hospital episode statistics. NHS, England, 2005-06. http://www.hesonline.nhs.uk. Accessed 9th July 2009. 10 Nelson D, Benhamou Y, Chuang WL et al. Efficacy and safety results of albinterferon alfa-2b in combination with ribavirin in treatment-naïve patients with chronic hepatitis C genotype 2 or 3. Oral presentation. 44th Annual Meeting of the European Association for the Study of the Liver 2009; 25th April. 11 Human Genome Sciences. Human Genome Sciences announces albuferon meets primary endpoint in phase 3 trial in chronic hepatitis C. 2008; 8th December. http://www.hgsi.com/latest/human-genome-sciences- announces-albuferon-meets-primary-endpoint-in-phase-3-trial-in-chronic-hepati-4.html. Accessed 17th July 2009. 12Zeuzem S, Sulkowski M, Lawitz E, et al. Efficacy and safety of albinterferon alfa-2b in combination with ribavirin in treatment-naïve patients with chronic hepatitis C genotype 1. Oral presentation. 44th Annual Meeting of the European Association for the Study of the Liver 2009; 25th April. 13Human Genome Sciences. Human Genome Sciences announces positive results in second of two phase 3 trials of albuferon in chronic hepatitis C. 2009; 9th March. http://www.hgsi.com/latest/human-genome-sciences- announces-positive-results-in-second-of-two-phase-3-trials-of-albuferon-in-chronic-hepati-3.html. Accessed 17th July 2009. 14Neumann A, Pianko S, Zeuzem S. et al. Positive and negative predication of sustained virologic response at weeks 2 and 4 of treatment with albinterferon alfa-2b or peginterferon alfa-2a in treatment naive patients with genotype 1 chronic hepatitis C. Journal of Hepatology 2009; 51: 21-28. 15Zeuzem S, Yoshida EM, Benhamou Y. et al. Sustained virologic response rates with albinterferon alfa-2b plus ribavirin treatment in IFN-naive, chronic hepatitis C genotype 1 patients. Hepatology 2007; 46: A.317A. #180. 16Human Genome Sciences. Human Genome Sciences announces initiation of phase 2b trial of albuferon dosed monthly in chronic hepatitis C. 2009; 12th January. http://www.hgsi.com/latest/human-genome-sciences- announces-initiation-of-phase-2b-trial-of-albuferon-dosed-monthly-in-chronic-hepatit.html. Accessed 17th July 2009. 17Human Genome Sciences. Human Genome Sciences announces completion of enrolment in phase 2b monthly- dosing trial of albuferon. http://www.hgsi.com/latest/human-genome-sciences-announces-completion-of- enrollment-in-phase-2b-monthly-dosing-trial-of-albuf.html. Accessed 17th July 2009.

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The National Horizon Scanning Centre, Department of Public Health and Epidemiology University of Birmingham, Edgbaston, Birmingham, B15 2TT, England Tel: +44 (0)121 414 7831 Fax +44 (0)121 414 2269 www.pcpoh.bham.ac.uk/publichealth/horizon

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