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1 Who Model List of Essential Medicines Application

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1 Who Model List of Essential Medicines Application WHO MODEL LIST OF ESSENTIAL MEDICINES APPLICATION Simeprevir 150mg capsule 1 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS Abbreviations AE Adverse event BOC Boceprevir CHC Chronic hepatitis C DAA Direct-acting antiviral agent HBV Hepatitis B virus HCV Hepatitis C Virus HIV Human immunodeficiency virus HRQoL Health-related quality of life IFN Interferon INN International non-proprietary name NAT Nucleic acid test PegIFN Peginterferon PegIFN/RBV Peginterferon alfa and ribavirin PI Protease inhibitor QALY Quality-Adjusted Life Year RCT Randomized controlled trial RGT Response-guided therapy RNA Ribonucleic acid RBV Ribavirin SOC System Organ Class SOF Sofosbuvir SMV Simeprevir SVR Sustained virologic response TPV Telaprevir ULN Upper limit of normal WHO World Health Organization 2 1. Summary statement of the proposal for inclusion, change or deletion: Inclusion of the once a day oral medication Simeprevir (SMV) is proposed for use in combination with other medicinal products for the treatment of chronic hepatitis C (CHC) in adult patients (including those co-infected with human immunodeficiency virus [HIV]) with genotype 1 and 4 hepatitis C virus (HCV). The principal reasons for requesting this inclusion are as follows: 1. There is significant burden of hepatitis C disease among adults living in resource-limited settings. 2. Treatment of hepatitis C will be improved with wider availability of this direct acting antiviral (DAA) agent. 3. SMV is a potent and selective inhibitor of the HCV NS3/4A protease. It has activity against HCV genotypes 1, 2, 4, 5 and 6.1 4. Evidence supports the use of SMV in either a triple therapy regimen with peginterferon (PegIFN) and ribavirin (RBV) or in combination with other DAAs as part of an all-oral interferon (IFN)-free regimen such as SMV + sofosbuvir (SOF). 5. SMV has the lowest pill burden of currently available protease inhibitor (PI) treatments (one capsule once a day). When used in treatment-naïve patients and prior relapsers, SMV in combination with PegIFN/RBV will halve the time on therapy from 48 weeks to 24 weeks, and reduce the number of PegIFN injections required for most patients on currently available treatments. 6. Efficacy and safety have been established for SMV in combination with PegIFN/RBV in genotype 1 or 4 HCV/HIV co-infected patients. 7. When used in combination with SOF, SMV provides a short (12-week), efficacious and well tolerated all-oral regimen for treatment of CHC in patients with HCV genotype 1 and 4. 8. Recent WHO Guidelines for the treatment of Hepatitis C indicate that treatment with SMV + PegIFN/RBV is preferred to treatment with PegIFN/RBV alone.2 2. Name of the focal point in WHO submitting or supporting the application: Stefan Wiktor, Team Leader, Global Hepatitis Programme, Department of HIV/AIDS. 3 3. Name of the organization(s) consulted and/or supporting the application: Janssen Pharmaceutica N.V. Turnhoutseweg 30, Beerse, 2340 Belgium Contact: Mercè Caturla, Global Regulatory Affairs Janssen Infectious Diseases BVBA Turnhoutseweg 30 Beerse, 2340 Belgium. 4. International non-proprietary name (INN, generic name) of the medicine: Simeprevir. 5. Formulation proposed for inclusion; including adult and pediatric (if appropriate): Adult: Hard capsule (capsule). White gelatin capsule of approximately 22 mm in length, marked with “TMC435 150” in black ink. Pediatric: none as of yet. 6. International availability – sources, if possible manufacturers and trade names: Manufacturer: Janssen Cilag SpA, Via C. Janssen, Borgo San Michele, 04100 Latina, Italy. Trade name: OLYSIOTM. 7. Whether listing is requested as an individual medicine or as an example of a therapeutic group: Individual medicine. 8. Information supporting the public health relevance: 8.1 Epidemiological information on disease burden Hepatitis C is a transmittable disease that may gradually impact liver function and results from chronic infection with the HCV; it is estimated that >185 million people worldwide are 4 chronically infected with HCV.1 CHC is categorized as mild, moderate or severe depending on the extent of liver damage. Rate of progression from mild to severe disease is slow but variable, with a time lag of approximately 10–30 years from the time of infection.3,4 CHC infections are a leading cause of liver disease and liver cancer (hepatocellular carcinoma), as well as the leading indication for liver transplantation in many settings. Of the six genotypes of HCV, genotype 1 is the most common and is found across most world regions. Genotype 4 is the most prevalent genotype in the Middle East and Africa, and the dominant genotype in Egypt.5,6 Genotype 4 is also becoming increasingly common in a number of Southern European countries including France, Spain and Greece due to variations in population structure, immigration and routes of transmission. Unlike HIV and hepatitis B virus (HBV), HCV infection can be cured. Achievement of sustained virologic response (SVR), defined as undetectable levels of HCV RNA 12 (SVR12) or 24 (SVR24) weeks after end of treatment, is the objective of antiviral treatment (SVR12 is becoming increasingly used as an endpoint and strong concordance exists between SVR12 and SVR24).7 For patients who achieve SVR, this is considered a virologic ‘cure’ as follow-up studies have shown that 93–100% of patients who achieve SVR maintain their response. The duration of treatment for HCV infection with PegIFN/RBV-based regimens is 24–48 weeks, depending on virologic response during treatment (Week 4 and 12), compared with long-term antiviral treatment for HIV or HBV. New IFN-free treatment options enable treatment duration to be shortened to 8–12 weeks for some patients. Currently available treatments for HCV genotype 1-infected patients include triple therapy with either boceprevir (BOC) or telaprevir (TPV) in combination with PegIFN/RBV, or dual therapy with PegIFN/RBV alone. Recently, new treatment options have become available in the form of SMV or SOF that can be used in combination with PegIFN/RBV (SOF also in combination with RBV alone) or in combination with other DAAs . There are several new DAAs currently in development that are likely to be approved for use in 2014–2015. As part of the new treatment options, SMV brings improved patient outcomes: In genotype 1-infected patients, SMV plus PegIFN/RBV has comparable efficacy compared with treatment with TPV-based triple therapy, while shortening duration of therapy in a large proportion of patients and improving tolerability. In genotype 4-infected patients, SMV plus PegIFN/RBV has SVR rates >80%. For patients eligible for an IFN-free regimen, SMV in combination with SOF results in SVR rates >90%, including in prior null responders. Published evidence indicates that although HCV is portrayed as asymptomatic, it is far from a silent disease, and even patients presenting with mild CHC have markedly reduced health-related quality of life (HRQoL) due to symptoms such as fatigue, weakness and depression,8-10 and 5 experience impairment in the ability to perform daily activities including work. As liver disease progresses to more advanced stages, HRQoL deteriorates further.9,11 Antiviral treatment, in particular the associated incidence of adverse events (AEs) and the overall treatment duration, can impact on HRQoL including symptom severity and impairment in daily activities. 8.2 Assessment of current use Cumulative exposure in clinical trials Overall, an estimated 6,924 subjects have been enrolled in the SMV clinical program, of which approximately 5,302 subjects have received SMV. Cumulative and interval patient exposure from marketing Approximately 60,000 patients have been treated to date using SMV. 8.3 Target population Adults with genotype 1 or 4 CHC infection: • Who have not been previously treated. • Who have relapsed following prior treatment with IFN (pegylated or non-pegylated) +/- RBV. • Who have not responded to prior treatment with IFN (pegylated or non-pegylated) +/- RBV. 9. Treatment details: 9.1 Dosage regimen, duration The recommended dosage of SMV is one capsule of 150 mg once daily for 12 weeks, taken with food. SMV must not be administered as monotherapy. SMV must be used in combination with other medicinal products for the treatment of CHC. When considering SMV combination treatment with PegIFN/RBV in HCV genotype 1a patients, patients should be tested for the presence of virus with the NS3 Q80K polymorphism before starting treatment. Q80K positive patients should consider alternative treatment options. 6 The recommended co-administered medicinal product(s) and treatment duration for SMV combination therapy are provided in Table 1. Table 1: Recommended co-administered medicinal product(s) and treatment duration for SMV combination therapy Patient population Regimen and Treatment Duration SMV in combination with PegIFN and RBV Treatment-naïve and prior relapsea patients with HCV genotype 1 or 4 With or without cirrhosis, who 12 weeks of SMV in combination with PegIFN/RBV are not coinfected with HIV followed by an additional 12 weeks of PegIFN/RBV Without cirrhosis, who are (total treatment duration of 24 weeks)b coinfected with HIV 12 weeks of SMV in combination with PegIFN/RBV With cirrhosis, who are followed by an additional 36 weeks of PegIFN/RBV coinfected with HIV (total treatment duration of 48 weeks)b Prior non-responderc patients (including partial and null responders) with HCV 12 weeks of SMV in combination with PegIFN/RBV genotype 1 or 4, with or without followed by an additional 36 weeks of PegIFN/RBV cirrhosis, with or without HIV (total treatment duration of 48 weeks)b coinfection SMV in combination with SOF Treatment-naïve, prior relapsea patients and prior non-responderc patients (including partial and null responders) 12 weeks of SMV + SOFd with HCV genotype 1 or 4, with or without cirrhosis, who are not coinfected with HIV aRelapse following prior treatment with IFN (pegylated or non-pegylated), with or without RBV. bRecommended duration of treatment provided that patient does not meet a stopping rule (see Table 2).
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