WHO MODEL LIST OF ESSENTIAL MEDICINES APPLICATION

Simeprevir 150mg capsule

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS

Abbreviations AE Adverse event BOC CHC Chronic C DAA Direct-acting antiviral agent HBV virus HCV Virus HIV Human immunodeficiency virus

HRQoL Health-related quality of life

IFN

INN International non-proprietary name NAT Nucleic acid test PegIFN Peginterferon PegIFN/RBV Peginterferon alfa and PI inhibitor QALY Quality-Adjusted Life Year RCT Randomized controlled trial RGT Response-guided therapy RNA Ribonucleic acid RBV Ribavirin SOC System Organ Class SOF SMV Simeprevir SVR Sustained virologic response TPV ULN Upper limit of normal WHO World Health Organization

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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 (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.

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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 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.

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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). cNon-response following prior treatment with IFN (pegylated or non-pegylated), with or without RBV. dNo stopping rules apply to the combination of SMV with SOF.

Refer to Table 2 for treatment stopping rules based on HCV RNA levels at weeks 4, 12 and 24 for patients receiving treatment with SMV and PegIFN/RBV.

Treatment discontinuation in patients with inadequate on-treatment virologic response during treatment with SMV and PegIFN/RBV

It is unlikely that patients with inadequate on-treatment virologic response will achieve SVR, therefore discontinuation of treatment is recommended in these patients. The HCV RNA

7 thresholds that trigger discontinuation of treatment (i.e., treatment stopping rules) are presented in Table 2.

Table 2: Treatment stopping rules in patients receiving SMV in combination with PegIFN/RBV with inadequate on-treatment virologic response

HCV RNA Action

Treatment week 4: ≥ 25 IU/ml Discontinue SMV, PegIFN/RBV Treatment week 12: detectablea Discontinue PegIFN/RBV (treatment with (≥25 IU/mL) SMV is complete at week 12) Treatment week 24: detectablea Discontinue PegIFN/RBV (≥25 IU/mL) aRe-evaluation of HCV RNA is recommended in case of detectable HCV RNA ≥25 IU/mL after previous undetectable HCV RNA to confirm HCV RNA levels prior to discontinuing HCV treatment.

There are no virologic treatment stopping rules that apply to the combination of SMV with SOF.

Dosage adjustment or interruption of SMV treatment

To prevent treatment failure, the dose of SMV must not be reduced or interrupted. If treatment with SMV is discontinued because of adverse reactions or inadequate on-treatment virologic response, SMV treatment must not be reinitiated.

Dosage adjustment or interruption of medicinal products used in combination with SMV for the treatment of CHC

If adverse reactions, potentially related to the medicinal products that are used in combination with SMV for the treatment of CHC, require dosage adjustment or interruption of either medicinal product, refer to the instructions outlined in the respective Summary of Product Characteristics for these medicinal products.

If the other medicinal products that are used in combination with SMV for the treatment of CHC are permanently discontinued for any reason, SMV must also be discontinued. When RBV has been added to the combination of SMV and SOF, and RBV needs to be discontinued, consideration can be given to continue treatment of SMV with SOF alone.

Missed dose

If a dose of SMV is missed, and the patient notices within 12 hours of the usual dosing time, the patient should take the missed dose of SMV with food as soon as possible and then take the next dose of SMV at the regularly scheduled time.

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If a dose of SMV is missed by more than 12 hours after the usual dosing time, the patient should not take the missed dose of SMV and should resume dosing of SMV with food at the regularly scheduled time.

Special populations

Elderly (over 65 years of age)

There are limited data on the safety and efficacy of SMV in patients older than 65 years. There are no safety and efficacy data for SMV in patients over the age of 75 years. No dose adjustment of SMV is required in elderly patients.

Renal impairment

No dose adjustment of SMV is required in patients with mild, moderate or severe renal impairment. The safety and efficacy of SMV have not been studied in HCV-infected patients with severe renal impairment (creatinine clearnace below 30mL/min) or end-stage renal disease, including patients requiring dialysis. SMC is highly protein-bound, therefore dialysis is unlikely to result in significant removel of SMV.

Hepatic impairment

No dose adjustment of SMV is required in patients with mild or moderate hepatic impairment (Child-Pugh class A or B). SMV exposure is significantly increased in patients with severe hepatic impairment (Child-Pugh class C) and no dose recommendation can be given for these patients. The safety and efficacy of SMV have not been studied in HCV-infected patients with moderate or severe hepatic impairment (Child-Pugh class B or C); therefore particular caution is recommended when prescribing SMV to HCV-infected patients with moderate or severe hepatic impairment.

Race

No dose adjustment is neccesary based on race.

Pediatric population

The safety and efficacy of SMV in children aged below 18 years have not yet been established. No data are available.

HCV/HIV-1 co-infection

No dose adjustment of SMV is required in HCV/HIV-1 co-infected patients.

SMV in combination with PegIFN/RBV: HCV/HIV-1 co-infected patients, irrespective of prior HCV treatment history, should be treated in the same way as HCV mono-infected patients,

9 except for co-infected patients with cirrhosis who should receive 36 weeks of treatment with PegIFN/RBV after completing 12 weeks of treatment with SMV and PegIFN/RBV (total treatment duration of 48 weeks).

It is not recommended to use SMV in combination with , delavirdine, etravirine or nevirapine, darunavir/, any HIV PI, or cobicistat-containing medicinal products.

Use in patients with other HCV genotypes

Clinical data are insufficient to support the use of SMV in patients with HCV genotypes 2, 3, 5 or 6.

Interactions with medicinal products Co-administration of SMV with substances that moderately or strongly induce or inhibit cytochrome P450 3A (CYP3A) is not recommended as this may lead to significantly lower or higher exposure of SMV, respectively.

HBV co-infection

The safety and efficacy of SMV for the treatment of HCV infection in patients co-infected with HBV have not been studied.

Organ transplantation

The safety and efficacy of SMV have not been established in organ transplant patients. Co-administration of SMV with cyclosporine is not recommended as this leads to significantly higher exposure of SMV.

Method of administration

SMV must be taken orally once a day with food. The capsule should be swallowed as a whole.

9.2 Reference to existing WHO and other clinical guidelines

WHO recently published for the first time a set of Hepatitis C treatment guidelines;2 these guidelines indicate that:

SMV, given in combination with pegylated interferon and ribavirin, is recommended for persons with genotype 1b HCV infection and for persons with genotype 1a HCV infection without the Q80K polymorphism rather than pegylated interferon and ribavirin alone. (Strong recommendation, high quality of evidence).

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9.3 Need for special diagnostics, treatment or monitoring facilities and skills

The diagnosis and clinical management of HCV infection requires sophisticated laboratory capacity. Diagnosing HCV infections requires serologic testing followed by nucleic acid tests (NAT) to confirm the presence of chronic infection. Assessment for treatment requires NAT to measure HCV and to determine HCV genotype, and the detection of the Q80K polymorphism in HCV genotype 1.

It is not anticipated that the use of SMV will add any additional staff, monitoring or administration costs. Patients receiving treatment with SMV are more likely to require shorter treatment duration with PegIFN/RBV compared with existing treatments; hence total monitoring costs should be lower. There are no additional requirements over and above the standard monitoring regimen for patients treated with either triple (e.g., BOC or TPV + PegIFN/RBV) or dual (PegIFN/RBV) therapy.

10. Summary of comparative effectiveness in a variety of clinical settings:

10.1 Identification of clinical evidence (search strategy, systematic reviews identified, reasons for selection/exclusion of particular data)

A systematic literature review described elsewhere,12 together with the publications from Janssen’s clinical development program (PILLAR, QUEST-1, QUEST-2, ASPIRE, PROMISE, COSMOS and ATTAIN) constitute the primary evidence base. A clinical study report was used as the primary source for the unpublished RESTORE study.

The evidence base for genotype 1 patients consists of two Phase IIb studies and four Phase III trials that compare SMV with comparator treatments relevant to the scope. One of the Phase IIb, dose-finding studies was conducted in a treatment-naïve population (PILLAR) and the other in a treatment experienced population (ASPIRE). Two Phase III trials explored the efficacy and safety of SMV compared to PegIFN/RBV in treatment-naïve patients (QUEST-1 and -2) and two further studies have been conducted in treatment-experienced patients (PROMISE and ATTAIN); the comparator in the former is PegIFN/RBV and in the latter is TPV/PegIFN/RBV. A further analysis has pooled the results from the Phase III trials in naïve patients (QUEST-1 and -2).13 Table 3 presents the study details for each of the relevant randomized controlled trials (RCTs).

Three other non-randomized single arm studies also provide efficacy and safety data for genotype 4 patients (RESTORE),14 HIV co-infected patients (C212)15 and the effectiveness of SMV when used in combination with SOF (SMV/SOF +/- PegIFN/RBV) (COSMOS).16

These details of these studies are provided in Table 4.

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Table 3: List of relevant RCTs

Trial no. Intervention Comparator Study type Population Primary (acronym) study ref.

PILLAR17 SMV 75 mg + PegIFN/RBV for 12 weeks followed by PegIFN/RBV for 36 weeks (n=78) Placebo + Phase IIb Patients with CSR (C205) n=309 SMV 75 mg + PegIFN/RBV for 24 weeks followed by PegIFN/RBV for 24 weeks (n=75) PegIFN/RBV Dose finding genotype 1 Fried, 2013 for 48 weeks chronic HCV who NCT00882908 SMV 150 mg + PegIFN/RBV for 12 weeks followed by PegIFN/RBV for 36 weeks (n=77) (n=77) had not been

SMV 150 mg + PegIFN/RBV for 24 weeks followed by PegIFN/RBV for 24 weeks (n=79) previously treated (Response guided treatment (RGT) allowed patients to stop treatment at 24 weeks) for HCV ASPIRE 18 SMV 100 mg + PegIFN/RBV for 12 weeks followed by PegIFN/RBV for 36 weeks (n=66) Placebo + Phase IIb Patients with CSR (C206) n=396 SMV 100 mg + PegIFN/RBV for 24 weeks followed by PegIFN/RBV for 24 weeks (n=65) PegIFN/RBV Dose finding genotype 1 Zeuzem, 2013 for 48 weeks chronic HCV who NCT00980330 SMV 100 mg + PegIFN/RBV for 48 weeks (n=66) (n=66) failed prior

SMV 150 mg + PegIFN/RBV for 12 weeks followed by PegIFN/RBV for 36 weeks (n=66) PegIFN/RBV SMV 150 mg + PegIFN/RBV for 24 weeks followed by PegIFN/RBV for 24 weeks (n=68) therapy SMV 150 mg + PegIFN/RBV for 48 weeks (n=65) (No RGT) QUEST-119 SMV 150 mg + PegIFN/RBV for 12 weeks followed by PegIFN/RBV for 36 weeks Placebo + Phase III Patients with CSR (C208) n=264 (RGT allowed patients to stop treatment at 24 weeks) PegIFN/RBV genotype 1 Jacobson, (n=130) chronic HCV who NCT01289782 2014 had not been previously treated for HCV QUEST-220 SMV 150 mg + PegIFN/RBV for 12 weeks followed by PegIFN/RBV for 36 weeks Placebo + Phase III Patients with CSR (C216) n=257 (RGT allowed patients to stop treatment at 24 weeks)Either PegIFNα-2a or PegIFNα-2b could be PegIFN/RBV genotype 1 Manns, 2014 (n=134) chronic HCV who NCT01290679 administered) had not been previously treated for HCV PROMISE21 SMV 150 mg + PegIFN/RBV for 12 weeks followed by PegIFN/RBV for 36 weeks Placebo + Phase III Patients with CSR (HPC 3007) (RGT allowed patients to stop treatment at 24 weeks) PegIFN/RBV genotype 1 Forns, 2014 n=260 (n=133) chronic HCV who relapsed after NCT01281839 previous interferon-based therapy ATTAIN22 SMV (150 mg od) + telaprevir placebo (tds) + PegIFN/RBV for 12 weeks, followed by Telaprevir Phase III Patients with CSR (HPC3001) PegIFN/RBV for 36 weeks (n=379) (750 mg tds) genotype 1 Reddy, 2014 n=763 (No RGT) + SMV chronic HCV who placebo (od) have previously + failed pegylated PegIFN/RBV interferon for 12 weeks, (null/prior followed by responders) PegIFN/RBV for 36 weeks (n=384): 12

Table 4: List of relevant non-RCTs

Trial no. Intervention Population Objective Primary Justification for (acronym) study ref. inclusion RESTORE14 Treatment-naïve patients and prior HCV Efficacy, RESTORE Genotype 4 (HPC3011) relapsers (n=57) genotype 4 safety CSR 2013 patients are NCT01567735 SMV 150 mg + PegIFN/RBV for 12 patients and study specified in the Scope for this n=107 weeks, followed by PegIFN/RBV for 36 Treatment- protocol appraisal and are weeks. naïve and treatment- relevant to the Poster: experienced decision problem (RGT allowed patients to stop treatment Moreno et al. This study at 24 weeks) (2014) provides evidence for the efficacy Prior non-responders (null and partial) and safety of and patients with METAVIR F4 cirrhosis SMV in this (regardless of treatment experience) patient population (n=50)

SMV 150 mg + PegIFN/RBV for 12 weeks, followed by PegIFN/RBV for 36 weeks. (No RGT) C21215 Treatment-naïve subjects and prior HCV Efficacy, C212 CSR This study NCT01479868 relapsers (n=61) genotype 1 safety 2013 and provides evidence patients co- study protocol for the efficacy n=106 infected with and safety of SMV 150 mg + PegIFN/RBV for 12 HIV SMV in this weeks, followed by PegIFN/RBV for 36 Oral patient population weeks. Treatment- presentation: naïve and which has been (RGT allowed patients to stop treatment Dieterich et treatment- defined as a at 24 weeks) al. (2013) experienced subgroup in the Scope for this Prior non-responders (null and partial) appraisal and patients with cirrhosis regardless of treatment experience (n=45)

SMV 150 mg + PegIFN/RBV for 12 weeks, followed by PegIFN/RBV for 36 weeks. (No RGT) COSMOS16 SMV 150 mg + SOF 400 mg + RBV Treatment Efficacy, COSMOS This study (HPC2002) (1,000/1,200 mg) for 24 weeks (n=54) naïve safety Topline report provides evidence NCT01466790 SMV 150 mg + SOF 400 mg for 24 (METAVIR 2014 and for the efficacy score F3-F4) study protocol and safety of n=167 weeks (n=31) SMV (plus SOF SMV 150 mg + SOF 400 mg + RBV Null ± RBV) in an (1,000/1,200 mg) for 12 weeks (n=54) responders Publication: (METAVIR IFN-free regimen SMV 150 mg + SOF 400 mg for 12 Lawitz et al. score F0-F4) weeks (n=28) (2014) and Sulkowski et

al. (2014)

RGT, response-guided therapy.

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10.2 Summary of available data

In treatment-naïve HCV genotype-1 infected patients:

 The Phase III QUEST-1 and QUEST-2 trials showed that SMV plus PegIFN/RBV was associated with significantly higher SVR12 rates than PegIFN/RBV alone (80.0% in QUEST-1 and 81.0% in QUEST-2) compared with PegIFN/RBV (50.0% in QUEST-1 and 50.0% in QUEST-2). These results are similar to those seen with TPV or BOC triple therapy compared with PegIFN/RBV (75% vs 44% in ADVANCE23 for TPV plus PegIFN/RBV vs PR; and 63% vs 38% in SPRINT-224 for BOC plus PegIFN/RBV vs PegIFN/RBV).

 The Q80K mutation has been identified as predictor of response for SMV plus PegIFN/RBV therapy. In a pooled analysis of QUEST-1 and QUEST-2, lower SVR12 rates were observed in the SMV group among genotype 1a patients with Q80K compared with those without Q80K (58% vs 84%, respectively).13

 Subgroup analysis in QUEST-1 and QUEST-2 showed that the efficacy of SMV plus PegIFN/RBV was consistently higher than for PegIFN/RBV alone, regardless of subject demographics, HCV geno/subtype (1a/1b genotype), baseline HCV RNA level and METAVIR score.

In HCV genotype 1-infected patients who failed prior treatment (including relapsers, partial responders and null responders):

 In the Phase III PROMISE trial SVR12 rates for prior relapsers treated with SMV plus PR were 79.2% (78.5% when Q80K+ patients are screened out) vs 36.1% for those treated with placebo plus PegIFN/RBV. These finding are similar to the efficacy seen with existing PI-based triple therapy (83% vs 24% with TPV plus PegIFN/RBV in REALIZE;25 59–66% vs 21% with BOC plus PegIFN/RBV in RESPOND-2).26

 The Phase II ASPIRE trial demonstrated that SMV plus PegIFN/RBV was more effective than PegIFN/RBV plus placebo:

. 77% of prior relapsers achieved SVR24 vs 37% for PegIFN/RBV; 65% of prior partial responders achieved SVR24 vs 9% for PR; 53% of prior null responders achieved SVR24 vs 19% for PegIFN/RBV.

 The Phase III ATTAIN trial showed that in prior non-responders the combination of SMV plus PegIFN/RBV is non-inferior to TPV plus PegIFN/RBV:22

. SMV plus PegIFN/RBV was associated with SVR rates of 69.7% in prior partial-responders and 43.6% in prior null-responders (vs 68.5% and 46.2%, respectively, for TPV plus PegIFN/RBV). 14

 Subgroup analysis in PROMISE and ASPIRE showed that the efficacy of SMV plus PegIFN/RBV was consistently higher than for PegIFN/RBV alone, regardless of patient demographics, HCV geno/subtype (1a/1b genotype), baseline HCV RNA level and METAVIR score:

. In ASPIRE, higher SVR24 rates were observed in SMV-treated patients with cirrhosis (31-82%), compared with PegIFN/RBV (0%).

. The indirect comparison of proportion of patients achieving SVR in SMV- and TPV-treated patients shows statistically higher SVR rates for TPV, driven by differences in the PegIFN/RBV/placebo differences between the studies. It should be noted that the TPV trial (REALIZE) was not powered to assess SVR in each sub-population but rather in treatment-experienced patients overall.

 Subgroup analysis from the Phase III ATTAIN study also showed similar efficacy for SMV plus PegIFN/RBV and TPV plus PegIFN/RBV across subgroup analyses.

In genotype 1 patients (treatment-naïve and treatment-experienced) with HIV co-infection, SMV plus PegIFN/RBV has superior efficacy to PegIFN/RBV alone.

 In the Phase III C212 trial in HIV-co-infected patients 79.2% of treatment-naïve patients, 86.7% prior relapsers, 70.0% prior partial-responders and 57.1% prior null-responders achieved SVR.

Overall, indirect comparisons performed in the global trial population showed that SMV-based therapy achieves similar or better SVR rates in treatment-naïve and treatment-experienced population to BOC plus PegIFN/RBV and TPV plus PegIFN/RBV. This is in addition to the direct comparison with TPV plus PegIFN/RBV from ATTAIN, described previously.

In genotype 4 patients, SMV plus PegIFN/RBV has improved results compared to dual (PR) therapy alone

 In patients with HCV genotype 4 (treatment-naïve and treatment-experienced) SMV plus PegIFN/RBV has better efficacy than PegIFN/RBV alone:

. In the RESTORE trial in genotype 4 patients, 82.9% of treatment-naïve patients, 86.4% of prior relapsers, 60.0% of prior partial-responders and 40.0% of prior null-responders achieved SVR.

. In comparison, reported SVR rates for PegIFN/RBV alone are typically in the region of 50–60%.27-31

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SMV plus SOF presents an effective option for all-oral regimens

 Patients with CHC who are either intolerant to or ineligible for treatment with IFN-based regimens represent a patient group with high unmet clinical need.

 The COSMOS study assessed the safety and efficacy of the IFN-free combination of 12 or 24 weeks treatment with SMV plus SOF with or without RBV in treatment-naïve patients (F3-F4) and prior null responders (F0-F4) with HCV genotype 1. SVR rates were consistently above 90%, regardless of fibrosis stage. SMV plus SOF is associated with higher SVR rates than IFN-based regimens, even in patient groups that are regarded as hard to treat such as prior null responders with advanced fibrosis/cirrhosis. In these patients, existing therapy achieves at best SVR rates of 34% (SMV/PegIFN/RBV in ATTAIN) after 48 weeks of therapy. As such, this 12-week duration IFN-free regimen represents a significant medical advance for these patients.

Shortened duration of therapy

 In both treatment-naïve and treatment-experienced (prior relapse) genotype 1 and 4 HCV patients, treatment with SMV and PegIFN/RBV can be reduced to 24 weeks of treatment. This simplified recommendation on the treatment duration was based on the observation from the program that a high proportion of patients who met response-guided therapy (RGT) criteria and shortened their exposure to PegIFN/RBV from 48 weeks to 24 weeks reached SVR. The high SVR rate combined with stopping rules described in the SMV label and Q80K screening resulted in the recommendation for a general treatment duration of only 24 weeks in treatment-naïve and prior relapser patients.

. In the Phase III QUEST-1 and QUEST-2 trials in treatment-naïve patients, 85–91% of patients in the SMV group met the criteria for RGT, of whom 86– 91% achieved SVR12.

. In the Phase III PROMISE trial in prior relapsers 92.7% of patients in the SMV-treated group met the criteria for RGT and 83% of these patients achieved SVR12.

 In HCV genotype 1-infected prior null responders with METAVIR fibrosis score F0-F2 (Cohort 1 COSMOS), or treatment-naïve and prior null responder patients with METAVIR fibrosis score F3-F4 and compensated liver disease (Cohort 2 COSMOS), SMV plus SOF achieved high efficacy in 12 weeks. For prior null responders, this is a significant reduction vs the current standard of 48 weeks PegIFN/RBV-based triple therapy.

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10.3 Summary of available estimates of comparative effectiveness: clinical studies

Direct evidence from the head-to-head ATTAIN study vs TPV plus PegIFN/RBV

 In the ATTAIN study in prior non-responders, treatment with SMV plus PegIFN/RBV was non-inferior to TPV plus PegIFN/RBV:

. In patients treated with SMV plus PegIFN/RBV, SVR was achieved in 69.7% prior partial responders (vs 68.5% for TPV plus PR) and 43.6% prior null- responders (vs 46.2% for TPV plus PegIFN/RBV.

 SVR rates for SMV plus PegIFN/RBV for patients with genotype 1a (without Q80K) and genotype 1b were comparable to those with TPV plus PegIFN/RBV:

. For patients with genotype 1a (without Q80K) the SVR rate was 43.5% for SMV plus PegIFN/RBV vs 39.8% for TPV plus PegIFN/RBV.

. For patients with genotype 1b the SVR rate was 63.7% for SMV plus PegIFN/RBV vs 66.8% for TPV plus PegIFN/RBV.

 Higher SVR rates were obtained for both SMV plus PegIFN/RBV and TPV plus PegIFN/RBV in patients with METAVIR F0-F2 than in patients with METAVIR F3-F4:

. In patients with METAVIR F0–F2 the SVR rate for SMV plus PegIFN/RBV was 61.3% (vs 59.8% for TPV plus PegIFN/RBV).

 In patients with METAVIR F3 or F4 the SVR rate for SMV plus PegIFN/RBV was 53.1 and 35.1% (vs 50.5 and 37.3% for TPV plus PegIFN/RBV).

Indirect evidence based on unadjusted side-by-side comparison with published trials

 In treatment-naïve HCV genotype 1 patients, SMV plus PegIFN/RBV has comparable efficacy, as evidenced by SVR rates in Phase III trials, with other protease inhibitors (BOC and TPV) in combination with PegIFN/RBV.

 In both treatment-naïve and treatment-experienced patients, SMV plus PegIFN/RBV has a better safety profile and improved tolerability with lower discontinuation rates due to AEs, and a lower risk of anemia and rash vs BOC- and TPV-based triple therapy. No significant safety issues beyond PegIFN/RBV were observed (due to reduced time with PegIFN/RBV toxicities).

 In both treatment-naïve and prior-relapser patients, treatment with SMV plus PegIFN/RBV is associated with a higher proportion of patients able to shorten exposure to PegIFN/RBV from 48 weeks to 24 weeks compared with other protease inhibitor regimens:

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. SMV is associated with less fatigue from Week 24 onwards, in comparison with BOC- or TPV-based triple therapy.

 Compared with BOC or TPV, the good tolerability and once daily, one-pill dosing profile of SMV/PR that allows a lower pill burden, may lead to improved adherence, and this may in turn influence efficacy.

11. Summary of comparative evidence on safety:

11.1 Estimate of total patient exposure to date

Use with PegIFN/RBV

The overall safety profile of SMV in combination with PegIFN/RBV in patients with HCV genotype 1 infection who were treatment-naïve or who failed prior IFN therapy with or without RBV is based on the pooled data from 2 clinical Phase IIb studies (studies PILLAR and ASPIRE) and 3 clinical Phase III studies (studies QUEST-1, QUEST-2 and PROMISE). The pooled data from the Phase IIb and Phase III studies included 1,486 patients who received SMV in combination with PegIFN/RBV (of whom 924 patients received SMV 150 mg once daily for 12 weeks) and 540 patients who received placebo with PegIFN/RBV.

In the pooled Phase III safety data, the majority of the adverse reactions reported during 12 weeks treatment with SMV were Grade 1 to 2 in severity. Grade 3 or 4 adverse reactions were reported in 2.8% of patients receiving SMV with PegIFN/RBV vs 0.5% of patients receiving placebo with PegIFN/RBV. Serious adverse reactions were reported in 0.3% of SMV-treated patients (2 photosensitivity events requiring hospitalization) and in none of the patients receiving placebo with PegIFN/RBV.

During the first 12 weeks of treatment, the most frequently reported adverse reactions (incidence ≥5%) were nausea, rash, pruritus, dyspnea, blood increase and photosensitivity reaction.

Discontinuation of SMV due to adverse reactions occurred in 0.9% of patients receiving SMV with PegIFN/RBV.

The safety profile of SMV is comparable between patients with HCV genotype 4 infection and genotype 1 infection.

Use with SOF with or without RBV

In the COSMOS study, assessing SMV in combination with SOF with or without RBV, no new safety findings were identified other than those observed with SMV in combination with PegIFN/RBV; the most common (>10%) AEs reported during 12 weeks treatment with SMV in combination with SOF were fatigue (25%), headache (21%), nausea (17%), insomnia (14%) and

18 pruritus (11%). Patients who received RBV in combination with SMV and SOF had an increase in frequency (>10%) of rash (15%) and anemia (11%) compared with those who did not receive RBV (4% and 0%, respectively). Other selected AEs reported were photosensitivity reactions (7% in patients receiving SMV in combination with SOF vs 6% in patients receiving SMV in combination with SOF and RBV) and increased bilirubin (0% vs 9%, respectively).

Cumulative and interval patient exposure from marketing experience

Based on the cumulative post-marketing data as available to date, no previously unrecognized adverse reactions with SMV have been identified and the safety profile of SMV remains similar to that established in clinical trials.

11.2 Description of adverse effects/reactions

Tabulated list of adverse reactions

Adverse reactions are reported in Table 5. The adverse reactions are listed by System Organ Class (SOC) and frequency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000).

Table 5: Adverse reactions of SMV in combination with PegIFN/RBV reported in adult patients with HCV genotype 1 infection (pooled phase 3 studies QUEST-1, QUEST-2 and PROMISE; first 12 weeks of treatments; Intent-To-Treat analysis set)

System Organ Class Frequency SMV + PegIFN/RBV category N=781

Respiratory, thoracic and Very common Dyspneaa mediastinal disorders Gastrointestinal disorders Very common Nausea Common Constipation Hepatobiliary disorders Common Blood bilirubin increaseda Skin and subcutaneous Very common Rash,a pruritusa tissue disorders Common Photosensitivity reactiona aSee section below for further details.

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Description of selected adverse reactions

Rash and pruritus

During the 12 weeks treatment with SMV, rash and pruritus were observed in 21.8% and 21.9% of SMV-treated patients, compared to 16.6% and 14.6% in patients treated with placebo, PegIFN/RBV, respectively (all Grades; pooled Phase III). Most of the rash and pruritus events in SMV-treated patients were of mild or moderate severity (Grade 1 or Grade 2). Grade 3 rash or pruritus occurred in 0.5% and 0.1% of SMV-treated patients, respectively. Discontinuation of SMV due to rash or pruritus occurred in 0.8% and 0.1% of SMV-treated patients, compared to 0.3% and no patients treated with placebo, PegIFN/RBV, respectively.

Blood bilirubin increased

During the 12 weeks treatment with SMV, ‘blood bilirubin increased’ was reported in 7.4% of SMV-treated patients, compared to 2.8% in patients treated with placebo, PegIFN/RBV (all Grades; pooled Phase III). In 2% and 0.3% of the SMV-treated patients Grade 3 or Grade 4 ‘blood bilirubin increased’ was reported, respectively (pooled Phase III studies). Discontinuation of SMV due to ‘blood bilirubin increased’ was rare (0.1%; n=1). During administration of SMV with PegIFN/RBV, the elevations in direct and indirect bilirubin were generally not associated with elevations in liver transaminases and normalized after end of treatment.

Photosensitivity reactions

During the 12 weeks treatment with SMV, photosensitivity reactions were reported in 4.7% of SMV-treated patients compared to 0.8% in patients treated with placebo, PegIFN/RBV (all Grades; pooled Phase III). Most photosensitivity reactions in SMV-treated patients were of mild or moderate severity (Grade 1 or 2); 0.3% of the SMV-treated patients experienced serious reactions leading to hospitalization (see section 4.4).

Dyspnea

During the first 12 weeks treatment with SMV, dyspnea was reported in 11.8% of SMV-treated patients, compared to 7.6% in patients treated with placebo, PegIFN/RBV (all Grades; pooled Phase III). Only Grade 1 and 2 events were reported and there were no events leading to discontinuation of any of the study . In patients aged >45 years, dyspnea was reported in 16.4% of SMV-treated patients compared to 9.1% in patients treated with placebo and PegIFN/RBV (all Grades; pooled Phase III).

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Laboratory abnormalities

There were no differences in hemoglobin, neutrophils or platelets between both treatment groups. Treatment-emergent laboratory abnormalities that were observed at a higher incidence in SMV-treated patients than in patients treated with placebo and PegIFN/RBV are given in Table 6.

Table 6: Treatment-emergent laboratory abnormalities (World Health Organization [WHO] worst toxicity Grades 1 to 4) observed at a higher incidence in patients treated with SMV in combination with PegIFN/RBV (pooled Phase III studies QUEST-1, QUEST-2 and PROMISE; first 12 weeks of treatments; Intent-To-Treat analysis set)

Laboratory parameter WHO toxicity range SMV + PegIFN/RBV N=781 n (%) Chemistry Alkaline phosphatase Grade 1 ≥ 1.25 to ≤ 2.50 x ULN 26 (3.3%) Grade 2 > 2.50 to ≤ 5.00 x ULN 1 (0.1%) Hyperbilirubinemia Grade 1 ≥ 1.1 to ≤ 1.5 x ULN 208 (26.7%) Grade 2 > 1.5 to ≤ 2.5 x ULN 143 (18.3%) Grade 3 > 2.5 to ≤ 5.0 x ULN 32 (4.1%) Grade 4 > 5.0 x ULN 3 (0.4%) ULN, Upper Limit of Normal.

11.3 Identification of variation in safety due to health systems and patient factors

Patients co-infected with HIV-1

The safety profile of SMV in combination with PegIFN/RBV is comparable between HCV genotype 1-infected patients with and without HIV-1 co-infection.

Hepatic impairment

SMV exposure is significantly increased in patients with severe hepatic impairment. A trend for a higher incidence of increased bilirubin levels with increasing SMV plasma exposure was observed. These increases in bilirubin levels were not associated with any adverse liver safety finding. A higher incidence of anemia in patients with advanced fibrosis has been reported.

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11.4 Summary of comparative safety against comparators

In the Phase III ATTAIN study, SMV plus PegIFN/RBV was associated with a better safety and tolerability profile than TPV plus PegIFN/RBV, as demonstrated by lower incidence of serious AEs, AEs leading to permanent discontinuation, and AEs related to PIs.

 During the first 12-weeks of treatment, SMV plus PegIFN/RBV was associated with the following AEs of special/clinical interest:

. Lower rates of rash (21.4% vs 31.0%), pruritus (32.2% vs 44.3%) and anemia (13.5% vs 37.5%).

. Similar rates of neutropenia (18.2% vs 13.5%), dyspnea (7.1% vs 9.4%) and increased bilirubin (7.9% vs 7.3%).

. Higher rates of photosensitivity conditions (2.1% vs 0.3%).

 For Grade 3 to 4 AEs of special/clinical interest during the first 12 weeks of treatment, SMV plus PegIFN/RBV was associated with lower rates of pruritus (0% vs 1.0%). No Grade 3/4 photosensitivity reactions were reported. There were no clinically meaningful differences between the treatment groups in terms of increased bilirubin concentrations. The rate of Grade 3 rash was 0.5% in the SMV plus PegIFN/RBV group and 1.3% in the TPV plus PegIFN/RBV group; one Grade 4 rash was reported in the TPV plus PegIFN/RBV group. The incidence of Grade 3 anemia was 1.3% vs 5.2% in the SMV plus PegIFN/RBV and TPV plus PegIFN/RBV groups, respectively. Grade 4 anemia occurred in 1.3% patients in the TVR plus PegIFN/RBV group.

 AEs leading to permanent discontinuation of PI occurred in 1.8% of patients treated with SMV plus PegIFN/RBV compared with 8.3% of TPV plus PR-treated patients.

12. Summary of available data on comparative cost and cost-effectiveness within the pharmacological class or therapeutic group:

12.1 Range of costs of the proposed medicine

The US list price for SMV is $790 per capsule/$66,360 per 12-week treatment course. In the European Union and Nordic countries, published prices for SMV range from €295–€472 per capsule, or €24,750–€39,623 per 12-week treatment course. The price in Canada is CAD 435 per capsule/CAD 36,502 per treatment course.

It is not Janssen’s usual practice to communicate prices prior to local regulatory approval and reimbursement discussions with local governments, and consequently, there are currently no public prices for low and middle income countries. In those settings where HCV is a public health concern and SMV has a role in therapy, Janssen is committed to affordable pricing.

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12.2 Comparative cost-effectiveness (presented as range of cost per routine outcome) (e.g., cost per case, cost per cure, cost per month of treatment, cost per case prevented, cost per clinical event prevented, or, if possible and relevant, cost per quality-adjusted life year [QALY] gained)

 A systematic literature review for cost-effectiveness data encompassed studies assessing SMV triple therapy and/or intended comparators to SMV (triple therapy TPV and BOC as well as dual therapy PegIFN/RBV.

 From the systematic literature review, a total of 43 economic evaluations of interest were identified.

 Of the studies which included dual therapy with PegIFN/RBV, all studies except one concluded that the intervention was cost-effective compared to no treatment and IFN with ribavirin at the £20,000 threshold.32 An incremental cost-effectiveness ratio of £28,409 for PegIFN/RBV vs no treatment in patients with mild chronic hepatitis C was reported.

 Treatment guidance for CHC33 released by the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) in the United States offers two options for IFN-ineligible/intolerant individuals with genotype 1 infection: SOF/ribavirin for 24 weeks or SOF/SMV for 12 weeks. A 24-week course of SOF/ribavirin costs approximately US$169,000, with SVR rates ranging from 52% to 84%; 12 weeks of SOF/SMV costs approximately $150,000, with SVR between 89% and 100%.

 In a cost-effectiveness analysis using a Markov model with lifetime horizon and societal perspective, SOF/SMV dominated SOF/RBV in a modeled 50-year-old cohort of treatment-naïve and -experienced subjects, excluding those who failed earlier therapy with TPV or BOC. SOF/SMV yielded lower costs and more QALYs for the average subject, compared to SOF/RBV ($165,336 and 14.69 QALYs vs $243,586 and 14.45 QALYs, respectively). In base-case cost analysis, the SOF/SMV treatment strategy saved $91,590 per SVR, compared to SOF/RBV. Under all one-way sensitivity scenarios, SOF/SMV remained dominant and resulted in cost savings.34

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13. Summary of regulatory status of the medicine (in country of origin, and preferably in other countries as well) (Table 7).

Table 7: Summary of regulatory status of SMV

Country Approval date Japana 27 Sept 2013 Canada 18 Nov 2013 United States 22 Nov 2013 Russia 27 Feb 2014 European Union 14 May 2014 Norway 23 May 2014 Iceland 5 June 2014 Mexico 19 Jun 2014 Australia 10 Jul 2014 Kuwait 30 Oct 2014 a100 mg capsules.

Simeprevir has been submitted for regulatory approval in the following countries as of 30 November 2014:

WHO African Region:

South Africa

WHO Americas Region

Bolivia, Brazil, Colombia, Costa Rica, Chile, Dominican Republic, Guatemala, Panama, Paraguay, Peru, Trinidad & Tobago, Uruguay

WHO Eastern Mediterranean Region:

Egypt, Morocco, United Arab Emirates, Saudi Arabia

WHO European Region

Israel, Kazakhstan, Ukraine, Serbia, Switzerland

WHO Western Pacific Region

New Zealand

14. Availability of pharmacopoeial standards (British Pharmacaopoeia, International Pharmacopoeia, US Pharmacopeia)

There are no compendial monographs established at this time.

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15. Proposed (new/adapted) text for the WHO model formulary

Treatment of Hepatitis C

SMV 150mg capsules*

*To be used in combination with PegIFN/RBV, or in combination with SOF with or without RBV.

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