Maviret (Glecaprevir/Pibrentasvir) 2019 Application for Inclusion on WHO Model List of Essential Medicines

Application for Inclusion of Maviret (Glecaprevir/Pibrentasvir) on the WHO Model List of Essential Medicines (EML) General items

1.0 Summary statement of the proposal for inclusion, change or deletion.

Maviret (glecaprevir/pibrentasvir) is being proposed for inclusion on the core WHO Model List of Essential Medicines (EML) as a treatment for adult patients with chronic hepatitis C virus (HCV) genotypes (GT) 1-6. Maviret is a second-generation HCV fixed-dosed combination regimen of two direct-acting antiviral agents (DAAs), which includes glecaprevir (GLE), an HCV nonstructural (NS) 3/4A protease inhibitor (PI) and pibrentasvir (PIB), an HCV NS5A inhibitor. GLE and PIB each demonstrates potent antiviral activity against HCV GTs 1, 2, 3, 4, 5, and 6, with little or no loss of potency against common HCV NS3 and NS5A resistance associated substitutions, respectively, in vitro. Both drugs have negligible (< 1%) renal excretion, allowing administration of GLE and PIB in subjects with any stage of renal function, including subjects with severe renal impairment and end-stage renal disease (ESRD). GLE and PIB are coformulated into a fixed-dose combination tablet (GLE/PIB), which provides patients a treatment regimen consisting of three 100 mg/40 mg tablets (300 mg/120 mg) taken once daily (QD) with food.

The principal reasons for requesting inclusion of Maviret in the core WHO Model List of Essential Medicines are as follows:

● Chronic Hepatitis C (CHC) is one of the most common chronic viral infections affecting the global population and is associated with substantial morbidity, mortality societal and health economic burden across countries with limited resources as well as resource-richer countries.1,3,4,5,11,23,24,30,41

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● Maviret is effective and indicated for CHC treatment of all six major HCV genotypes (GT1-6, pangenotypic) in adults. ● As the vast majority of adults with CHC are treatment naïve non-cirrhotic,1 Maviret is the only pangenotypic regimen indicated for CHC treatment of these subjects with a short, 8-week treatment duration. ● Other treatment regimens for CHC may be restricted to treatment of a few HCV genotypes in subjects with severe renal impairment, or ESRD (Zepatier, Viekirax/Exviera), and require the addition of ribavirin (RBV) in subsets of patients, Maviret is the only pangenotypic (GT1-6) treatment for CHC in adults with severe renal impairment and those with ESRD, including subjects on dialysis. ● Maviret's 8-week duration for treatment-naïve (TN), non-cirrhotic adult subjects with CHC with GT1-6 extends to subjects with severe renal impairment, ESRD, human immunodeficiency virus (HIV)/HCV coinfection, and also includes pegylated interferon (pegIFN)/RBV-, interferon (IFN)-/RBV- sofosbuvir (SOF)-/pegIFN, SOF/IFN-, and SOF/RBV-experienced subjects with CHC GT 1, 2, 4, 5, or 6 infection. ● Maviret is also indicated for adults with CHC GT1-6 and compensated liver cirrhosis. ● GT1 is the most prevalent of all HCV genotypes with a wide geographic distribution spanning resource limited and resource-richer countries,1,66 and the majority of treatment failures are GT1 CHC. Maviret provides a re-treatment option for those GT1 subjects who failed a prior NS3/4A PI, or who failed a prior NS5A inhibitor containing regimen, but not both in several countries globally. In Japan, as well as Turkey and New Zealand, Maviret is additionally indicated for retreatment of GT1 to GT6 subjects who failed a prior PI/NS5A inhibitor regimen. ● The majority of current new HCV infection are through blood by risky injection practices and needle sharing among people who inject drugs (PWIDs)12,25 and high-risk sexual practices, including men who have sex with men (MSM). Maviret has been studied in PWIDs and subjects on opioid-substitution therapy (OST) with similar effectiveness when compared to the non-PWID population studied in the Maviret registration program.67

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The safety and efficacy of the pangenotypic Maviret regimen in HCV TN and/or treatment-experienced (TE) HCV GT1- to GT6-infected subjects with compensated liver disease (with or without cirrhosis), including subjects with severe renal impairment or ESRD (chronic kidney disease [CKD] Stages 4 or 5), subjects coinfected with HIV, and subjects with recent or past history of injection drug use or on OST, were demonstrated in 8 registrational studies and 3 supportive Phase 2 studies resulting in regulatory approvals in 58 countries globally to date. Those studies demonstrated that treatment-naïve non-cirrhotic subjects can be treated for 8 weeks. In multiple countries across the globe, Maviret is also indicated for the treatment of adult patients with HCV GT1 infection who previously have been treated either with a regimen containing an HCV NS5A inhibitor or an NS3/4A PI, but not both. Further, in Turkey, New Zealand, and Japan, Maviret is also indicated for the treatment of adult patients with HCV GT1 to GT6 infection who previously have been treated with a regimen containing an HCV NS5A inhibitor, an NS3/4A PI, or both.

2.0 Relevant WHO technical department and focal point (if applicable).

Global Hepatitis Programme, Department of HIV/AIDS

3.0 Name of organization(s) consulted and/or supporting the application.

World Hepatitis Alliance (support) and World Health Organization (consulted)

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4.0 International Nonproprietary Name (INN) and Anatomical Therapeutic Chemical (ATC) code of the medicine. glecaprevir

(3aR,7S,10S,12R,21E,24aR)-7-tert-butil-N-{(1R,2R)-2-(difluorometil)-1-[(1- metilciclopropano-1-sulfonil)carbamoil]ciclopropil}-20,20-difluoro-5,8-dioxo- 2,3,3a,5,6,7,8,11,12,20,23,24a-dodecahidro-1H,10H-9,12- metanociclopenta[18,19][1,10,17,3,6]trioxadiazaciclononad ecino[11,12-b]quinoxalina- 10-carboxamida

C38H46F4N6O9S

4 Maviret (Glecaprevir/Pibrentasvir) 2019 Application for Inclusion on WHO Model List of Essential Medicines

pibrentasvir

N,N'-([(2R,5R)-1-{3,5-difluoro-4-[4-(4-fluorofenil)piperidin-1-il]fenil}pirrolidina-2,5- diil]bis{(6-fluoro-1H-benzimidazol-5,2-diil)[(2S)-pirrolidina-2,1-diil][(2S,3R)-3-metoxi- 1-oxobutano-1,2-diil]})dicarbamato de dimetil

C57H65F6N10O8

ATC code: J05AP57 (glecaprevir and pibrentasvir)

5.0 Dose forms(s) and strength(s) proposed for inclusion; including adult and age-appropriate paediatric dose forms/strengths (if appropriate).

Maviret is a fixed-dose combination product containing 100 mg of GLE and 40 mg of PIB. The tablets are pink, oblong-shaped, film-coated, and debossed with "NXT" on one side. The recommended adult dosage of Maviret is three tablets (total daily dose: GLE 300 mg and PIB 120 mg) taken orally once daily with food. This coformulated fixed-dose

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tablet is the only formulation currently available on the market and recommended for administration at the total daily dose of 300/120 mg of Maviret.

Maviret is not presently recommended for patients < 18 years of age because its safety and efficacy in children and adolescents (< 18 years) have not yet been established. Thus, no pediatric formulation is proposed for inclusion and its potential for use in children will not be discussed further in this application.

6.0 Whether listing is requested as an individual medicine or as representative of a pharmacological class.

The Essential Medicines Listing for Maviret is being requested as an individual essential medicine within the class of DAA medicines for the treatment of HCV infection. Glecaprevir is a representative of the NS3/4A PI pharmacological class of DAAs and PIB is a representative of the NS5A inhibitor pharmacological class of DAAs – Maviret (GLE/PIB).

Treatment details, public health relevance and evidence appraisal and synthesis

7.0 Treatment details (requirements for diagnosis, treatment and monitoring).

WHO estimates that in 2015, 71 million persons were living with chronic hepatitis C virus (HCV) infection worldwide and that 399,000 died from cirrhosis or hepatocellular carcinoma caused by HCV infection. In May 2016, the World Health Assembly endorsed the Global Health Sector Strategy (GHSS) on viral hepatitis, which proposes to eliminate viral hepatitis as a public health threat by 2030 (90% reduction in incidence and 65% reduction in mortality). Elimination of viral hepatitis as a public health threat requires 90% of those infected to be diagnosed and 80% of those diagnosed to be treated.13

Since the last update to the WHO Guidelines was issued in 2016, three key developments have prompted changes in terms of when to treat and what treatments to use. First, the

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use of safe and highly effective direct-acting antiviral (DAA) regimens for all persons improves the balance of benefits and harms of treating persons with little or no fibrosis, supporting a strategy of treating all persons with chronic HCV infection, rather than reserving treatment for persons with more advanced disease. Second, since 2016, several new, pangenotypic DAA medicines have been approved by at least one stringent regulatory authority, reducing the need for genotyping to guide treatment decisions. Third, the continued substantial reduction in the price of DAAs has enabled treatment to be rolled out rapidly in a number of low- and middle- income countries.13

WHO recommends the use of pangenotypic DAA regimens for the treatment of persons with chronic HCV infection aged 18 years and above.13 Maviret is a pangenotypic direct acting antiviral regimen indicated for and recommended by WHO for the treatment of adults 18 years of age or older infected with HCV GT 1–6, without or with compensated cirrhosis, including persons co-infected with HIV and persons with renal insufficiency and ESRD. Maviret is contraindicated in persons with decompensated cirrhosis (Child-Pugh Class C).

WHO recommends Maviret for use in adults infected with HCV GT 1–6, without cirrhosis who are TN or TE with pegIFN, RBV, and/or SOF, for 8 weeks, with the exception of persons with GT3 infection who have received interferon and/or ribavirin in the past, who should be treated for 16 weeks. Adults infected with HCV GT 1–6 with compensated cirrhosis should be administered Maviret for 12 weeks, with the exception of persons with GT3 infection who have received interferon and/or ribavirin in the past, who should be treated for 16 weeks.13

Maviret is also approved in multiple countries for retreatment in patients with HCV GT1 infection who have failed treatment with either a PI or an NS5A inhibitor (but not both), which is also acknowledged within the WHO Guidelines.

All patients should be tested for evidence of current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating HCV treatment with MAVIRET.15 Also, in some countries globally, Maviret

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treatment should be initiated and monitored by a physician experienced in the management of patients with HCV infection.57

8.0 Information supporting the public health relevance

8.1 Epidemiological information on disease burden

Chronic HCV is a global health problem, affecting approximately 71 million individuals worldwide.1 It is the leading cause of liver transplantation in the developed world and the most common chronic blood borne infection in both the United States and Europe with approximately 80% of infected individuals becoming chronically infected.2 In these patients, chronic hepatic inflammation and fibrosis persist over several decades. Progression is accelerated in the presence of cofactors including alcohol consumption, diabetes mellitus, older age of acquisition, HIV coinfection, and coinfection with other hepatotropic viruses.2 In addition to liver-related morbidity and mortality, HCV infection is related to extrahepatic complications including type 2 diabetes and cardiovascular complications.2,3

Approximately 15 million persons are chronically infected with HCV throughout Europe16 and HCV infection is recognized as a major public health challenge; in 2013, 31,513 new cases of HCV were reported in 26 EU/EEA Member States.11 HCV is the leading cause of liver cirrhosis, hepatocellular carcinoma (HCC), and liver transplantation. In EU nations, on average, 21% of liver transplants were attributable to HCV, but may be as high as 40% of all liver transplants.17,18,19 Every year, 86,000 Europeans die from HCV-related liver disease and HCC.4

The prevalence of HCV in the general adult population ranges from ≤ 0.5% (Northern European countries) to ≥ 3% (Greece, Italy, and Eastern European countries).16,20,21 Genotype 1 is the most prevalent in Europe accounting for 70% of chronically infected Europeans10 with GT1b subtype predominating over GT1a in most European countries including those with the highest prevalence.22 Genotype 3 is the next most common genotype in Europe, ranging from 24.8% to 30.4% of HCV cases followed by GT2 which ranges from 0.1% to 10.4%. Genotype 5 has only been reported in Western Europe,

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comprising not more than 2% of all HCV genotypes; GT6 comprises less than 1% of HCV genotypes in any of the EU nations.23 HCV GT4 has become increasingly prevalent in Southern European countries where prevalence rates among HCV-infected patients of 10%–24% have been reported.4

In the United States, approximately 3.4 million individuals are chronically infected with HCV24,63,64 and the distribution of HCV genotypes is approximately 76% GT1, 22% GT2 and 3, and 2% GT4-6.66 New HCV infections are on the rise, fueled by the opioid drug use epidemic. In the time period from 2004-2014, a 300% increase in HCV infections has been observed among PWIDs)25, and HCV seroprevalence is approximately 55% among PWIDs25. About 50% of individuals infected with HCV are not aware of the HCV infection and only 1 in 6 patients diagnosed with chronic HCV infection is referred to care and prescribed treatment.26,27,28 Similar to Europe, HCV infection and associated morbidity and mortality in the United States is recognized as a major public health burden.65

8.2 Assessment of current use

Maviret is currently being used in adult patients with CHC.

8.3 Target population(s)

Maviret is indicated for the treatment of chronic HCV infection in adults with GT 1, 2, 3, 4, 5, and 6 without cirrhosis and with compensated cirrhosis.

8.4 Likely impact of treatment on the disease

Meaningful advances have been made in the development of DAAs but current regimens are not equally potent across all HCV GTs and subtypes nor are they equally efficacious across all subpopulations. Whilst Maviret is a convenient, pangenotypic, RBV free regimen, it also addresses key remaining areas of unmet medical need in HCV including: 1) Patients infected with HCV GT2, 3, 5, or 6 who have chronic kidney disease (CKD) Stage 4 or 5 (creatinine clearance of < 30 mL/min) and 2) GT3-infected patients with cirrhosis.

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A recent study in the US projects that 8-week pan-genotypic treatment for non-cirrhotic HCV patients could streamline and accelerate the path to HCV elimination, allow more patients to be treated with a given budget and treater capacity, and ultimately deliver greater health benefits to patients and cost savings to the healthcare system.29 When compared to cumulative mortality in uninfected persons there are substantially higher rates of all-cause mortality, liver cancer, and HCV-associated extrahepatic disease attributed mortality in persons with HCV viremia.29,56 Treatment of chronic HCV infection with all oral DAAs and achievement of sustained virological response is associated with significant mortality benefit.29,56

8.4.1 GT2-, 3-, 5- or 6-infected patients with CKD Stage 4 and 5 (CrCl < 30 mL/min)

Maviret is the only approved pangenotypic, IFN and RBV-free regimen suitable for use in GT2-, GT3-, GT5- and GT6-infected patients with CKD Stage 4 and 5 (creatinine clearance [CrCl] < 30 mL/min).

Persons infected with HCV are at higher risk for various types of kidney disease as a result of extrahepatic manifestations of HCV or as a disease process independent of the HCV infection, such as diabetic neuropathy.30 HCV infection itself is associated with a higher risk of reduced estimated glomerular filtration rate (eGFR) and increased proteinuria (independent of metabolic factors).7,38,39,40 Patients with HCV and CKD have higher comorbidity burden and worse outcomes than those without CKD, i.e., more cardiovascular disease, liver-related diseases, and chronic obstructive pulmonary disease.8,41,42 HCV positivity also lowers graft and patient survival after kidney transplantation.43 Among patients with ESRD, HCV infection correlates with higher all-cause mortality rates, up to 8 deaths per 100 patients per year.9,44 European Association for the Study of the Liver (EASL) treatment guidelines urge consideration of treatment without delay for hemodialysis patients.2

Using published references, the prevalence of CKD Stages 4 and 5 is estimated to be 2.2%.42,45 The approximate number of GT2, 3, 5 and 6-infected patients with CKD Stage

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4 or 5 has been estimated at over 46,000 and broken down by genotype as follows: 12,848 (GT2); 32,912 (GT3); 572 (GT5); and 44 (GT6).24 Due to the severity of this disease, this patient population represents a significant burden on healthcare systems across Europe.

The treatment of these patients is especially challenging because SOF and its main metabolite are renally excreted and their concentrations are substantially higher in patients with CKD Stage 4 and 5 compared with patients with normal renal function (+171% and +451% AUC0 inf).46 The safety of SOF-based regimens has not been established in patients with CrCl < 30 mL/min. Real-world data provide evidence that when a sofosbuvir-based regimen is administered to patients with this degree of renal impairment progressive deterioration of renal function and renal symptoms occur.2 Zepatier, which provides a treatment option for GT1- and 4-infected patients, is not approved for use in patients infected with GT 2, 3, 5 or 6.

In patients with CKD Stage 4 and 5, the reduced clearance of pegIFN and RBV can accentuate treatment-related toxicity. In addition, since patients with kidney disease frequently have baseline anemia, RBV-induced hemolytic anemia can put these patients at greater risk of developing severe treatment-related anemia. PegIFN is poorly tolerated in patients with this degree of renal impairment.

8.4.2 Maviret for treatment of GT2, 3, 5 and 6 infected patients with CKD Stage 4 and 5 (CrCl < 30 mL/min)

● Maviret provides the first DAA regimen for GT 2, 3, 5 and 6 patients with CKD Stage 4 and 5 that can be used without dose adjustment. ● Both GLE and PIB have minimal renal elimination. No significant increase in exposure for either compound has been observed in subjects with CKD Stage 4 and 5 compared to subjects with normal renal function. ● Sustained virologic response (SVR) of 98% (102/104), with no virologic failures achieved in subjects across GTs1-6 with CKD Stage 4 and 5 in ongoing Phase 3 Study M15-462 GLE/PIB, including subjects on hemodialysis without dose adjustment. ● All 29 GT2, 3, 5 and 6-infected subjects achieved SVR.

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● The safety profile of Maviret in these subjects was favorable and the majority of treatment-emergent adverse events (TEAEs) reported in the study were mild. For all parameters except CrCl, which is not unexpected in this population, the numbers of subjects with Grade 3 or 4 laboratory values were low.

In Phase 1 studies (M13-355, M13-356, M13-890 and M13-600), both GLE and PIB have been shown to have minimal renal elimination. Evaluation of pharmacokinetics and safety for 300 mg/120 mg Maviret in subjects with mild, moderate, and severe stable renal impairment, or in subjects with ESRD not yet on dialyses (Study M13-600) suggested that GLE and PIB exposures were not significantly increased in patients with CKD Stage 4 and 5 including patients with ESRD compared to patients with normal renal function. Compared to subjects with normal renal function, GLE and PIB exposures as determined by AUC in subjects with renal impairment were up to 9% (mild), 22% (moderate), 32% (severe) and 39% (ESRD) higher based on CrCl (Figure 1). These changes in exposure are not clinically relevant. The terminal phase elimination half-life values of GLE and PIB were also similar among subjects with renal impairment and normal renal function.

For ESRD on hemodialysis, no significant impact of hemodialysis on GLE and PIB exposures was observed. GLE and PIB exposures were similar (≤ 18% difference) on dialysis days and non-dialysis days. In addition, clearance of GLE and PIB due to dialysis accounted for < 1% of total clearance. Safety results from the study showed no major safety concern of using GLE and PIB in subjects with renal impairment.

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Figure 1. Exposure of GLE and PIB in Subjects with Renal Impairment versus Normal Renal Function (Central Value Ratios and 90% Confidence Intervals) with CrCl as Predictor

Mild 1.03 (0.92 – 1.15) 1.07 (0.98 – 1.17) 1.04 (0.97 – 1.11) 1.09 (1.03 – 1.17)

Moderate 1.06 (0.83 – 0.35) 1.16 (0.95 – 1.42) 1.09 (0.94 – 1.26) 1.22 (1.06 – 1.40)

Severe 1.08 (0.77 – 1.52) 1.24 (0.94 – 1.64) 1.13 (0.92 – 1.38) 1.32 (1.08 – 1.61)

ESRD 1.10 (0.73 – 1.65) 1.29 (0.92 – 1.81) 1.15 (0.90 – 1.47) 1.39 (1.09 – 1.77)

ABT-493 Cmax ABT-493 AUC ABT-530 Cmax ABT-530 AUC

0.0 0.5 1.0 1.5 2.0 2.5 3.0 Central Value and 90% CI

A similar benefit/risk ratio of Maviret was seen in subjects with CKD Stage 4 and 5 compared to that observed in subjects without renal impairment.

The Phase 3 Study M15-462 in patients with CKD Stage 4 and 5 enrolled a total of 104 subjects, including 85 subjects on hemodialysis and 20 subjects with compensated cirrhosis. Subjects received 12 weeks of treatment with Maviret. There were no virologic failures in the study (Table 1). These data are also consistent with preliminary data from registration studies (M15-464, M13-594, M13-583, M14-172, and M14-868 Parts 3 and 4) in subjects with HCV GT2, 3, 5, or 6 without renal impairment (CKD Stages 4 and 5).

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Table 1. SVR12 Results in HCV-Infected Subjects with CKD Stage 4 and 5, (Study M15-462)

Total Subjects on GT2, 3, 5, 6 (all GTs) Hemodialysis (N = 29) (N = 104) (N=85)

SVR12 (ITT), n(%) 102/104 (98%) 29/29 (100%) 83/85 (98%) Breakthrough 0 0 0 Relapse 0 0 0 Other 2a 0 2a ITT = intent-to-treat; SVR12 = sustained virologic response 12 weeks postdosing. a. One GT1 subject discontinued prematurely due to an AE of diarrhea, and one GT1 subject achieved SVR4 and subsequently died due to an unrelated SAE of cerebral hemorrhage.

The majority of TEAEs reported in the study were mild events. The most common (≥ 10% of subjects) TEAEs were pruritus (20.2%), fatigue (14.4%), and nausea (11.5%). One subject died during the Post-Treatment Period due to cerebral hemorrhage; the event was considered by the investigator to have no reasonable possibility of relationship to DAA treatment. No subject experienced a treatment-related serious adverse event (SAE). Two subjects discontinued study drug due to DAA-related TEAEs. The numbers of subjects with Grade 3/4 hematology and chemistry values during the treatment period were low for all parameters evaluated except for creatinine (21.2% [22/104]) and CrCl (13.5% [14/104]) of which were Grade 4 elevations for 19 subjects and 11 subjects, respectively, and is consistent with the CKD population and inherent variability.

Maviret provides a very effective and well tolerated treatment for patients with CKD Stage 4 and 5, including those on hemodialysis that can be used without dose adjustment.

8.4.3 GT3-infected patients with cirrhosis

There has been an urgent need for a regimen that delivers high SVR rates in GT3-infected patients with cirrhosis to minimize the impact of HCV infection. Using published references, it has been estimated the prevalence of cirrhosis in the HCV-infected population in Europe is 15.7%.47,48,49 When extrapolated to the GT3 population,24 it is estimated that 234,872 GT3 patients in Europe have cirrhosis.

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The impact of failure to treat GT3-infected patients with cirrhosis is more significant compared with other genotypes; the disease is more severe, progresses faster and is associated with worse clinical outcomes. Steatosis is more frequent and more severe in GT3-infected patients than in other genotypes.50 GT3 infection is an independent risk factor for hepatic fibrosis progression51 and is associated with increased severity of disease. It is also associated with higher incidence of HCC, especially in the context of advanced liver disease likely leading to higher mortality. 52 Due to this increased morbidity and mortality, failure to clear HCV infection in these patients places a significant burden on healthcare systems.2

Besides Maviret, for GT3-infected patients with cirrhosis, the most effective IFN-free DAA regimens licensed in the EU are SOF/velpatasvir (VEL) ± RBV for 12 weeks 46 (SVR12 of 89% [33/37] TE and 93% [40/43] TN subjects), and SOF + daclatasvir ± RBV for 24 weeks (SVR12 of 69% TE and 58% TN subjects).46 In addition, because GT3 is more difficult-to-treat than other genotypes, and in the absence of data with 12 weeks of therapy SOF/VEL/voxilaprevir for 12 weeks is recommended by 2018 EASL guidelines.53

Although SOF/velpatasvir has provided an increase in SVR for this patient group, most GT3-infected patients with cirrhosis who experienced virologic failure with SOF/VEL ± RBV had NS5A Y93H at the time of failure (8/11 GT3 virologic failure subjects with compensated cirrhosis in the ASTRAL-3 study had Y93H emerge post-treatment and 10/11 had Y93H at failure in total). A similar outcome has been observed in patients failing treatment with SOF + daclatasvir (11/14 GT3 virologic failure subjects in Phase 2 and 3 studies had Y93 substitutions emerge post-treatment).54 As Y93H is known to impact the efficacy of subsequent treatment its presence makes these patients extremely difficult to retreat.

The SVR of SOF/VEL in GT3-infected patients, particularly those with cirrhosis, is significantly impacted by the presence of the NS5A Y93H resistance-associated polymorphism at baseline as seen in the ASTRAL-3 study (Table 2). In that study, Y93H was detected at baseline in 9% of GT3 patients.

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Table 2. SVR12 of Sofosbuvir/Velpatasvir in Patients with or without Baseline Y93H

SVR12 All Subjects Cirrhotic Non-cirrhotic SVR with Y93H 84.0% (21/25) 50% (2/4) 90.5% (19/21) SVR without Y93H 96.4% (242/249) 93.4% (71/76) 98.8% (171/173) Source: Epclusa SmPC.46

The presence of Y93H at baseline also reduces the SVR of SOF + daclatasvir in GT3-infected patients, especially those with cirrhosis: SVR in presence and absence of Y93H was 54% (7/13) and 134/145 (92%), respectively.55 In that Study, Y93H was detected in 8% of GT3-infected subjects at baseline.

Given the severity and rapidity of disease progression associated with HCV GT3 infection particularly in patients with cirrhosis, Maviret is required to provide high SVR rates and overcomes the limitations of other regimens with regards to NS5A resistance-associated substitutions, particularly Y93H.

8.4.4 Use of Maviret in GT3 infected patients with cirrhosis

 Maviret is a highly effective treatment for GT3-infected patients with cirrhosis with SVR rates of ≥ 96% in Phase 2 (Study M14-868 Part 2) and preliminary registration study data (Study M14-868 Part 3).  PIB is highly potent against GT3 and its antiviral activity is maintained against the Y93H polymorphism. PIB provides an advantage over existing NS5A inhibitors for which baseline Y93H has a significant impact on SVR and drug pressure in many cases results in a high degree of enrichment of Y93H variants in subjects who experience virologic failure.  Data from the clinical program do not suggest an impact on outcome of the NS5A Y93H baseline polymorphism in GT3-infected subjects with cirrhosis. Six GT3-infected subjects with cirrhosis in Study M14-868 Part 2 and Part 3 had the NS5A Y93H polymorphism at baseline and all 6 achieved SVR.

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PIB is highly potent against GT3 and its antiviral activity is maintained against the Y93H polymorphism (<3 fold increase in half maximal effective concentration). This denotes a major innovation compared with first-generation NS5A inhibitors VEL and daclatasvir to which Y93H has been reported to confer resistance both in vitro (Table 2) and in clinical practice, particularly in patients with cirrhosis. The high efficacy from Maviret in GT3-infected patients with cirrhosis, including those with NS5A Y93H present at baseline, has been confirmed in Study M14-868 Parts 2 and 3.

8.4.4.1 Study M14-868 Part 2

Study M14-868 Part 2 randomized a total of 55 TN and PR-experienced GT3-infected subjects with compensated cirrhosis 1:1 to receive 300 mg GLE + 120 mg PIB either with or without once-daily 800 mg RBV for 12 weeks. Complete SVR12 data are summarized in Table 3.

Table 3. SVR12 in HCV GT3-Infected Subjects with Compensated Cirrhosis (Study M14-868 Part 2)

Arm O Arm P GLE + PIB GLE + PIB + RBV 12 weeks GT3 Naïve (12 weeks) and PR- GT3 Naïve and PR-experienced experienced (16 weeks) (N = 27) (N = 28)

SVR12, n (%) [ITT] 27/28 (96.4%) 27/27 (100%) Breakthrough 0 0 Relapse 1 0 Other 0 0

SVR12, n (%) [non-virologic 27/28 (96.4%) 27/27 (100%) failures excluded]

Note: Recruitment of HCV GT3 TE subjects with compensated cirrhosis in Arms O and P was halted after receiving FDA feedback recommending first demonstrating efficacy in TN cirrhotic and/or TE non-cirrhotic patients given limited data in these populations. Prior to that, there were 7 GT3 TE subjects with compensated cirrhosis already dosed in Arms O (n=4) and P (n=3). The four GT3 TE cirrhotics in Arm O were assigned a 16 week treatment duration; one of the four subjects relapsed (included in Table 1). All three (100%) of the GT3 TE cirrhotics in Arm

P (included in Table 1) achieved SVR12.

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8.4.4.2 Study M14-868 Part 3

In the registration part of Study M14-868 (Part 3) TN and TE GT3-infected subjects with compensated cirrhosis were randomized to receive Maviret 300 mg/120 mg for 12 weeks in Arm Q or 16 weeks in Arm R. SVR12 data are summarized in Table 4 and are consistent with Part 2.

Table 4. SVR12 in HCV GT3-Infected Subjects with Compensated Cirrhosis (Study M14-868 Part 3)

Arm Qa Arm Rb GLE + PIB GLE + PIB 16 weeks GT3 Naïve (12 weeks) GT3 experienced (N = 40) (N = 47)

SVR12, n (%) [ITT] 39/40 (98%) 45/47 (96%) Breakthrough 0 1 Relapse 0 1 Other 1c 0 a. Arm Q also included 22 GT3 TE subjects without cirrhosis, which are not included in the table. b. Arm R also included 22 GT3 TE subjects without cirrhosis, which are not included in the table. c. One subject is potentially lost to follow up

Maviret is a very effective treatment for GT3-infected patients with cirrhosis. Unlike other NS5A inhibitors, the available clinical data do not suggest an impact on outcome of the NS5A Y93H polymorphism in GT3-infected subjects with cirrhosis. In Parts 2 and 3 of this study, 6 GT3-infected subjects with cirrhosis had the NS5A Y93H polymorphism at baseline and all 6 achieved SVR.

8.4.5 Impact on Public Health

The RBV-free combination of GLE and PIB, 2 DAAs with different mechanisms of action, both of which have potent antiviral activity across all major HCV genotypes, and show limited cross-resistance with earlier generation HCV therapies, represents a major innovation in DAA therapy.

18 Maviret (Glecaprevir/Pibrentasvir) 2019 Application for Inclusion on WHO Model List of Essential Medicines

As well as providing a highly effective and convenient once-daily, pangenotypic, RBV-free regimen, Maviret addresses many key remaining areas of important medical need in HCV:

● The pangenotypic activity of the product combined with minimal renal elimination provides HCV GT 2, 3, 5 and 6-infected patients with a long

awaited, very effective (SVR12 of 98%) and well tolerated DAA-regimen that does not require dose adjustment. ● The high potency of PIB against NS5A Y93H provides a major step forward versus other treatments for GT3-infected patients with cirrhosis. Clinical data do not suggest an impact on outcome of the NS5A Y93H polymorphism and

SVR12 ≥ 96% achieved by Maviret surpasses that of other products. ● Maviret has been shown to be cost-effective in the United States vs other standards of care. Furthermore, 8-week pan-genotypic treatment with Maviret could allow more patients to be treated with a given budget and treater capacity. This would in turn streamline and accelerate the path to HCV elimination and deliver greater health benefits to patients and cost savings to the healthcare system.29,56

9.0 Review of benefits: summary of evidence of comparative effectiveness.

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

The use of Maviret is principally supported by the safety and efficacy of the GLE/PIB regimen demonstrated in treatment-naïve (TN) and/or treatment-experienced (TE) HCV GT1- to GT6-infected subjects without and with compensated cirrhosis, including subjects co-infected with human immunodeficiency virus (HIV) in 8 registrational studies and 3 supportive Phase 2 studies, resulting in regulatory approvals in 58 countries globally to date. The clinical evidence presented in this application represents evidence gathered in AbbVie sponsored clinical trials.

19 Maviret (Glecaprevir/Pibrentasvir) 2019 Application for Inclusion on WHO Model List of Essential Medicines

9.2 Summary of available data (appraisal of quality, outcome measures, summary of results)

The efficacy of the Maviret regimen in HCV TN and/or TE HCV GT1- to GT6-infected subjects with compensated liver disease (with or without cirrhosis), including subjects with severe renal impairment or ESRD (CKD Stages 4 or 5), and subjects coinfected with HIV-1 have been demonstrated in 8 registrational studies and 3 supportive Phase 2 studies. The final overall efficacy conclusions for the Phase 3 registration trials remain consistent with the conclusions made at the time of submission for marketing approval.

The SVR12 rates in the currently ongoing clinical trials utilizing the marketing approved/recommended regimen remain consistent with those seen in the completed Phase 3 clinical trials. Data from post-registrational Phase 3 Studies M13-596 and M14-730 provide support for the benefit of the use of Maviret in HCV/HIV-1 co-infected subjects and in post-primary orthotopic liver or renal transplant subjects.

Real-world data for Maviret is emerging from multiple cohorts with ca. 10,000 patients across a variety of countries, confirming clinical trial efficacy and safety. 30 Data published to date include for example large real-world cohorts from England, Germany, Italy, Spain, and the United States. The English real-world data31 showed an SVR12 rate of 97,7% (627/642 patients), the German real-world cohort32 of 99,5% (592/595 patients, mITT), the Italian Navigatore II cohort30 of 99,3% (680/685 patients, mITT), the Italian Mistral cohort33 of 99,4% (1177 patient included), the Spanish C-HEP cohort34 of 99% (1185 / 1198 patients, mITT), the US VA35 of 92% (1415/1539 patients), the US Trio cohort36 presented an SVR12 rate of 98.4% (1049/1066 patients, mITT). There were no unexpected safety findings reported by these real-world cohorts, which included TN and TE (pegIFN, RBV, and/or SOF [PRS] and DAA) as well as non-cirrhotic and compensated cirrhotic patients across all genotypes reflecting the respective local epidemiology.

The key benefits of treatment with the Maviret regimen are high SVR12 rates across GT1 – GT6 infections and with shorter duration of treatment for TN subjects without cirrhosis, high SVR12 rates in subpopulations, and stable quality of life (QoL).

20 Maviret (Glecaprevir/Pibrentasvir) 2019 Application for Inclusion on WHO Model List of Essential Medicines

9.2.1 High Sustained Virologic Response Rates

There are few pangenotypic regimens such as Maviret that have high SVR12 rates across all genotypes, allowing a prescriber to consider the elimination of genotype testing in some patient populations, e.g., TN patients, as treatment duration is the same regardless of genotype. A high SVR12 rate translates into high clinical cure rates, and subsequently low risk for the development of resistance-associated substitutions. Clinical cure reduces the risk of HCV progression to end-stage liver disease and its complications including decompensated cirrhosis, liver transplantation and HCC. A shorter treatment duration is generally associated with better treatment compliance, lower healthcare resources usages, and thus is an important factor in the development of global HCV elimination strategies.

9.2.2 Pangenotypic Response (GT1 – GT6)

Overall, the Maviret regimen consistently demonstrated high SVR12 rates across all genotypes.

● The SVR12 rate in GT1-infected subjects treated with Maviret for 12 weeks (99.7%; 331/332) was noninferior to the historical control of ombitasvir, paritaprevir, and ritonavir + dasabuvir ± RBV or SOF/ ledipasvir (LDV) (Figure 2).

21 Maviret (Glecaprevir/Pibrentasvir) 2019 Application for Inclusion on WHO Model List of Essential Medicines

Figure 2. Forest Plot for Risk of Maviret in All Treated Subjects (HCV GT1 – GT6, Phase 2 and 3 Analysis Set)

 The SVR12 rate in GT2-infected subjects treated with Maviret for 8 weeks (98.5%; 135/137) or 12 weeks (99.5%; 195/196) was noninferior to the historical control of SOF + RBV (Figure 2).

 The SVR12 rate in GT3-infected subjects treated with Maviret for 12 weeks (95.3%; 222/233) was noninferior to the active control of SOF + daclatasvir (DCV) (Figure 3).

22 Maviret (Glecaprevir/Pibrentasvir) 2019 Application for Inclusion on WHO Model List of Essential Medicines

Figure 3. Forest Plot for Benefit of Maviret in All Treated Subjects (HCV GT1 – GT6, Phase 2 and 3 Analysis Set)

● The Maviret regimen consistently demonstrated high SVR12 rates with the 12-week treatment duration in GT4-infected (99%; 95/96), GT5-infected (100%; 21/21), and GT6-infected (100%; 30/30) subjects (Figure 2). ● Among all GT1 – GT6-infected subjects, regardless of renal function, cirrhosis status, or presence of HIV-1 coinfection, who were TN or regimens containing IFN, pegIFN, RBV, and/or SOF (PRS-TE) and received the recommended 56 durations, 97.5% (1,252/1,284) achieved SVR12 overall.

23 Maviret (Glecaprevir/Pibrentasvir) 2019 Application for Inclusion on WHO Model List of Essential Medicines

○ In GT1 – GT6-infected TN subjects without cirrhosis who received the 56 recommended duration of 8 weeks, 97.5% (749/768) achieved SVR12. ○ In GT1 – GT6-infected PRS-TE subjects without cirrhosis who received the recommended duration (12 weeks for GT1, 2, 4, 5, 6 and 16 weeks for 56 GT3), 98.2% (215/219) achieved SVR12. ○ In GT1 – GT6-infected TN or PRS-TE subjects with compensated cirrhosis who received the recommended duration (12 weeks for GT1, 2, 4, 5, 6 and

16 weeks for GT3), 97.0% (288/297) achieved SVR12 (among which 56 98.0% [192/196] of TN subjects achieved SVR12).

9.2.3 Response with Shorter Duration of Treatment (Naïve, Non- Cirrhotics)

Among all GT1 – GT6-infected TN subjects without cirrhosis, Maviret regimen consistently demonstrated high SVR12 rates with the 8-week treatment duration (97.5%; 749/768).56

 Among GT3-infected TN subjects without cirrhosis, the 8-week regimen (SVR12 rate of 94.9%; 149/157) was noninferior to the 12-week regimen (SVR12 rate of 95.3%; 222/233) (Figure 2).  Among GT1-infected subjects without cirrhosis (TN and pegIFN/RBV-

experienced), the 8-week regimen (SVR12 rate of 99.1%; 332/335) was noninferior

to the 12-week regimen (SVR12 rate of 99.7%; 331/332) (Figure 2).  Among GT2-infected subjects without cirrhosis (TN and pegIFN/RBV-

experienced), the 8-week duration (SVR12 rate of 98.5% 135/137) was noninferior

to the 12-week duration (SVR12 rate of 99.5%; 195/196) in a cross study comparison (Figure 2).

24 Maviret (Glecaprevir/Pibrentasvir) 2019 Application for Inclusion on WHO Model List of Essential Medicines

9.2.4 High SVR12 Rates in Subpopulations

There are several key HCV subpopulations in need of treatment options:

● Patients with CKD Stages 4 or 5 (since these patients are not candidates for DAAs with high renal excretion, such as SOF). ● Post-liver/kidney transplant patients (since HCV infection can affect both patient and graft survival). ● HCV/HIV-1 co-infected patients (since these patients have poorer prognosis than HCV monoinfected patients, with acceleration of liver disease leading to cirrhosis and hepatic decompensation). ● Compensated cirrhosis patients (to help prevent progression of the cirrhosis to decompensated cirrhosis). ● NS5A inhibitor or NS3/4A PI TE patients (since these patients may harbor resistance-associated substitutions that may impact the efficacy of certain treatments).

9.2.4.1 CKD Stages 4 or 5 (With or Without Hemodialysis)

GT1 – GT6-infected subjects with CKD Stages 4 or 5 (including those requiring dialysis), with compensated liver disease, who received 12 weeks of Maviret achieved an SVR12 rate of 98.1% (102/104) (Figure 4).

25 Maviret (Glecaprevir/Pibrentasvir) 2019 Application for Inclusion on WHO Model List of Essential Medicines

Figure 4. Forest Plot of Benefit-Risk of Maviret in Subpopulations of Interest

9.2.4.2 Post-Liver/Renal Transplant

GT1 – GT6-infected noncirrhotic post-liver/renal transplant subjects who received

12 weeks of Maviret at achieved an SVR12 rate of 98.0 % (98/100) (Figure 4).

9.2.4.3 HCV/HIV-1 Coinfection

Among HCV GT1 – GT6/HIV-1 coinfected subjects who received Maviret at the recommended 8 weeks' duration for subjects without cirrhosis and 12 weeks for subjects with compensated cirrhosis (excluding GT3-TE), an SVR12 rate of 98.2% (165/168) was

26 Maviret (Glecaprevir/Pibrentasvir) 2019 Application for Inclusion on WHO Model List of Essential Medicines

achieved (Figure 4). Subjects with HCV/HIV-1 coinfection showed similar rates of

SVR12 as observed in the HCV monoinfected subjects.

9.2.4.4 Compensated Cirrhosis

The Maviret regimen demonstrated an SVR12 rate of 96.4% (297/308) among

GT1 – GT6-infected subjects with compensated cirrhosis (Figure 4).

9.2.4.5 NS5A Inhibitor or NS3/4A PI Treatment-Experience

Treatment with Maviret regimen for 12 weeks demonstrated an SVR12 rate of 100% (27/27) in PI-only experienced (NS5A inhibitor-naïve) subjects, and Maviret treatment for

16 weeks demonstrated an SVR12 rate of 94.4% (17/18) in NS5A inhibitor-only experienced (PI-naïve) subjects and 81.3% (13/16) in NS5A inhibitor-experienced and PI experienced subjects.

9.2.5 Stable Quality of Life

Some earlier HCV therapies (RBV, IFN) negatively impacted QoL for general QoL, as well as for fatigue.58,59 The negative effect on QoL caused by therapy can impact patient adherence to treatment.

Treatment with the Maviret regimen does not negatively impact the patient with regards to fatigue (Fatigue Severity Scale [FSS]), general quality of life (EQ-5D Visual Analog Scale [EQ-5D-3L-VAS] and Health Utility Index [EQ-5D-3L-HUI], and 36-Item Short Form Health Survey Physical Component Score [SF-36v2-PCS] and Mental Component Score [SF-36v2-MCS]), or work productivity (Work Productivity and Activity Impairment [WPAI] – activity impairment and overall scores), when compared to placebo (Figure 5) or SOF + DCV (Figure 3).

27 Maviret (Glecaprevir/Pibrentasvir) 2019 Application for Inclusion on WHO Model List of Essential Medicines

Figure 5. Forest Plot for Benefit-Risk of Maviret vs SOF + DCV (HCV GT3, Study M13-594)

A study on pooled data from 8 phase 3 studies for Maviret has shown that treatment with Maviret has a positive effect on patient's health-related QoL across a broad range of patient-reported outcome measures, including SF-36 (8 domains), EQ-5D (Health Utility Index and VAS scores) and FSS.58

28 Maviret (Glecaprevir/Pibrentasvir) 2019 Application for Inclusion on WHO Model List of Essential Medicines

9.2.6 Summary of available estimates of comparative effectiveness

The comparative effectiveness of Maviret was evaluated in 2 clinical studies. Study M15-828 was performed in Japan and evaluated the safety and efficacy of Maviret compared to SOF/RBV in the treatment of HCV GT2. Study M15-594 was performed in the global program and compared the safety and efficacy of 12 weeks Maviret versus 12 weeks SOF and DCV.

9.2.6.1 Study M15-828

Study Design

Study M15-828 was a Phase 3, randomized, open-label, active-controlled, multicenter study evaluating the efficacy, safety, and pharmacokinetics of Maviret in chronic HCV GT2-infected Japanese adult subjects without cirrhosis. Subjects were TN or IFN TE with or without RBV (i.e., DAA TN). Enrolled subjects were randomized in a 2:1 ratio to Maviret for 8 weeks (Arm A) or SOF + RBV for 12 weeks (Arm B.

The primary efficacy variable was SVR12 (HCV RNA < lower limit of quantitation 12 weeks after the last actual dose of study drug). The primary efficacy endpoint in the study was non-inferiority of the Maviret 8-week regimen (Arm A) to the SOF + RBV 12 week regimen (Arm B) in SVR12 using a non-inferiority margin of 10% in the ITT population.

To show non-inferiority of the SVR12 rate of the Maviret 8-week regimen (Arm A) to the

SOF + RBV 12-week regimen (Arm B), the percentage of subjects achieving SVR12 was calculated for each arm and a 2-sided 95% confidence interval (CI) for the difference in

SVR12 rates (Arm A minus Arm B) was calculated using the normal approximation to the binomial distribution. If the lower bound of the CI for the difference was above the non-inferiority margin of –10%, then the Maviret 8-week regimen would be considered non-inferior to SOF + RBV 12-week regimen.

29 Maviret (Glecaprevir/Pibrentasvir) 2019 Application for Inclusion on WHO Model List of Essential Medicines

Subject Disposition and Demographics

A total of 136 subjects were enrolled in the study and received at least 1 dose of study drug. One hundred thirty-four subjects completed study drugs.

Two subjects, 1 randomized to Arm A (Maviret) and 1 randomized to Arm B (SOF + RBV), prematurely discontinued study drugs. Three subjects, 2 randomized to Arm A and 1 randomized to Arm B, prematurely discontinued from the study. Nine subjects in Arm A completed the study. One hundred twenty-four subjects are ongoing in the study.

Demographic characteristics were comparable between Arms A and B with no statistically significant differences between arms for any variable. As required by the protocol, all subjects in the study were Japanese. The majority of subjects was female and had a body mass index (BMI) of < 25 kg/m2. Approximately one-third of the subjects were ≥ 65 years old.

Baseline characteristics were comparable between Arms A and B. All subjects had HCV GT2 infection.

Efficacy

A 97.8% SVR12 rate was achieved for the Maviret arm (Arm A), and a 93.5% SVR12 rate was achieved for the SOF + RBV arm (Arm B). The difference in SVR12 rates between the Maviret arm and the SOF + RBV arm (Arm A – Arm B) was 4.3% with 95% CI of (-3.5%, 12.1%). The lower bound of the 95% CI for the difference was above the predefined noninferiority margin of –10%. Therefore, the 8-week Maviret regimen was noninferior to the 12-week SOF + RBV regimen.

There were no virologic failures (on treatment or relapse) in the Maviret arm. Two subjects in the Maviret arm did not achieve SVR12 (one subject due to missing data, and one due to premature study drug discontinuation). Two subjects in the SOF + RBV arm failed to achieve SVR12 due to relapse. A third subject in the SOF + RBV arm failed to achieve SVR12 due to premature study drug discontinuation.

30 Maviret (Glecaprevir/Pibrentasvir) 2019 Application for Inclusion on WHO Model List of Essential Medicines

Given only 5 subjects (2 subjects in Arm A and 3 subjects in Arm B) failed to achieve

SVR12, all subgroups achieved high SVR12 rates and there was no heterogeneity of odds ratios of SVR12 rates across subgroups by treatment arm for any of the subgroups tested.

9.2.6.2 Study M15-594

Study M15-594 was an open-label study to evaluate the safety and efficacy of Maviret in the treatment of HCV GT3 treatment naïve non-cirrhotic subjects. The objective of study

M15-594 was to demonstrate noninferiority in the percentage of subjects achieving SVR12 after 12 weeks of treatment with Maviret to 12 weeks of treatment with SOF and DCV and to demonstrate noninferiority in the percentage of subjects achieving SVR12 after 8 weeks of treatment with Maviret. Subjects were randomized 2:1 to Arm A: Maviret 300 mg/120 mg QD for 12 weeks or Arm B: SOF 400 mg + DCV 60 mg QD for 12 weeks. Additionally, following completion of randomization into Arms A and B, subjects were enrolled into Arm C: Maviret 300 mg/120 mg QD for 8 weeks.

The primary efficacy analysis was sequential: 1) Noninferiority in the SVR12 rate of the 12-week Maviret 300 mg/120 mg QD regimen (Arm A) to the active control arm (SOF + DCV; Arm B) was demonstrated if:

 The lower confidence bound (LCB) for the 95% CI for the difference (Arm A minus Arm B) was above the noninferiority margin of –6% and the LCB for the 95% CI for the SVR12 rate within Arm A was greater than 92%, or  The LCB for the 95% CI for the difference was below –6% and the LCB for the 97.5% CI for the SVR12 rate within Arm A was greater than 92%; or  The LCB for the 97.5% CI for the difference was above –6% and the LCB for the 95% CI for the SVR12 rate within Arm A was below 92%.

Arms A, B and C enrolled 233, 115, and 157 subjects, respectively. The arms were well balanced with respect to gender, and median age.

For Study M13-594 (GT3), Maviret for 12 weeks was noninferior to SOF + DCV for

12 weeks, as the LCB for the 95% CI for the difference in SVR12 rates between Arm A

31 Maviret (Glecaprevir/Pibrentasvir) 2019 Application for Inclusion on WHO Model List of Essential Medicines

and Arm B exceeded the noninferiority margin of –6% (Figure 6) and the LCB for the

95% CI for the SVR12 rate in Arm A exceeded the prespecified threshold of 92% (Figure 7). Maviret for 8 weeks was noninferior to Maviret for 12 weeks as the LCB for the 97.5% CI for the difference in SVR12 rates between Arm C and Arm A exceeded the noninferiority margin of –6% (Figure 6), although the LCB for the 95% CI for the SVR12 rate in Arm C was not greater than the historical threshold of 92% (Figure 7).

32 Maviret (Glecaprevir/Pibrentasvir) 2019 Application for Inclusion on WHO Model List of Essential Medicines

Figure 6. Forest Plot of SVR12 Difference Between 8- and 12-Week Treatment Arms and CIs Compared to Protocol Specified Noninferiority Margins (Excluding SOF/R-Experienced Subjects)

33 Maviret (Glecaprevir/Pibrentasvir) 2019 Application for Inclusion on WHO Model List of Essential Medicines

Figure 6. Forest Plot of SVR12 Difference Between 8- and 12-Week Treatment Arms and CIs Compared to Protocol Specified Noninferiority Margins (Excluding SOF/R-Experienced Subjects) (continued)

M13-590 Arm A (GT1): Maviret 300 mg/120 mg QD for 12 weeks M13-590 Arm B (GT1): Maviret 300 mg/120 mg QD for 8 weeks M13-594 Arm A (GT3): Maviret 300 mg/120 mg QD for 12 weeks M13-594 Arm C (GT3): Maviret 300 mg/120 mg QD for 8 weeks M14-868 Arm S (GT2, GT4 – GT6): Maviret 300 mg/120 mg QD for 8 weeks M15-464 Arm A (GT2): Maviret 300 mg/120 mg QD for 12 weeks CI = confidence interval; GLE = glecaprevir; GT = genotype; ITT = intention-to-treat; NIM = noninferiority margin; PIB = pibrentasvir; PP = per protocol; PS = protocol

specified; QD = once daily; SOF/R = regimens containing sofosbuvir and ribavirin; SVR12 = sustained virologic response 12 weeks postdosing a. 95% CI. b. 97.5% CI. Notes: The CI was calculated using the normal approximation to the binomial distribution unless the difference in rates was 0%; otherwise, the Wilson's score method was used instead. Analysis population included ITT-PS-PP and ITT-PS population in Study M13-590, ITT population in Study M13-594, and ITT population excluding SOF/R- experienced subjects in Study M14-868 Arm S GT2 8 weeks and Study M15-464 Arm A.

34 Maviret (Glecaprevir/Pibrentasvir) 2019 Application for Inclusion on WHO Model List of Essential Medicines

Figure 7. Forest Plot of SVR12 Rates and 95% CIs Compared to Historical Noninferiority Thresholds (ITT Population Excluding SOF/R Experienced Subjects)

35 Maviret (Glecaprevir/Pibrentasvir) 2019 Application for Inclusion on WHO Model List of Essential Medicines

Figure 7. Forest Plot of SVR12 Rates and 95% CIs Compared to Historical Noninferiority Thresholds (ITT Population Excluding SOF/R Experienced Subjects) (continued)

M13-590 Arm A (GT1): Maviret 300 mg/120 mg QD for 12 weeks excluding HIV-1-coinfected subjects M15-464 Arm A (GT2): Maviret 300 mg/120 mg QD for 12 weeks M13-594 Arm A (GT3): Maviret 300 mg/120 mg QD for 12 weeks M13-594 Arm C (GT3): Maviret 300 mg/120 mg QD for 8 weeks M14-868 Arm S (GT2, GT4 – GT6): Maviret 300 mg/120 mg QD for 8 weeks CI = confidence interval; GLE = glecaprevir; GT = genotype; HIV-1 = human immunodeficiency virus-1; ITT = intention-to-treat; NIT = noninferiority threshold; PIB = pibrentasvir; QD = once daily; SOF/R = regimens containing sofosbuvir and ribavirin; SVR12 = sustained virologic response 12 weeks postdosing Note: The CI was calculated using the normal approximation to the binomial distribution unless the rate was 100%; otherwise, the Wilson's score method was used instead.

36 Maviret (Glecaprevir/Pibrentasvir) 2019 Application for Inclusion on WHO Model List of Essential Medicines

Among TN subjects infected with GT3 without cirrhosis (Study M13-594), the 8-week regimen achieved noninferiority versus the 12-week regimen; both arms achieved approximately 95% SVR12 rates (Figure 8). The frequency of relapse was similarly low in the 8- and 12-week durations (3% and 1%, respectively; Table 5). In Study M13-594, there were no subgroups identified, including the presence of any baseline NS5A (without

NS3) polymorphisms, with statistically significant differences in SVR12 between the 8- and 12-week arms.

37 Maviret (Glecaprevir/Pibrentasvir) 2019 Application for Inclusion on WHO Model List of Essential Medicines

Figure 8. Forest Plot of SVR12 Rates and 95% CIs of All Treatment Arms (Phase 2 and 3 Analysis Set)

M14-867 Arm I (GT4 – GT6): GLE 300 mg QD + PIB 120 mg QD for 12 weeks M14-867 Arm K (GT1): GLE 300 mg QD + PIB 120 mg QD for 8 weeks M14-868 Arm A (GT2): GLE 300 mg QD + PIB 120 mg QD for 12 weeks M14-868 Arm D (GT3): GLE 300 mg QD + PIB 120 mg QD for 12 weeks

38 Maviret (Glecaprevir/Pibrentasvir) 2019 Application for Inclusion on WHO Model List of Essential Medicines

Figure 8. Forest Plot of SVR12 Rates and 95% CIs of All Treatment Arms (Phase 2 and 3 Analysis Set) (continued)

M14-868 Arm J (GT2): GLE 300 mg QD + PIB 120 mg QD for 8 weeks M14-868 Arm L (GT3): GLE 300 mg QD + PIB 120 mg QD for 8 weeks (TN) or 12 weeks (TE) M14-868 Arm O (GT3): GLE 300 mg QD + PIB 120 mg QD for 12 weeks (TN) or 16 weeks (TE) M14-868 Arm Q (GT3): Maviret 300 mg/120 mg QD for 12 weeks M14-868 Arm R (GT3): Maviret 300 mg/120 mg QD for 16 weeks M14-868 Arm S (GT2, GT4 – GT6): Maviret 300 mg/120 mg QD for 8 weeks M15-410 Arm C (GT1): GLE 300 mg QD + PIB 120 mg QD for 12 weeks M15-410 Arm D (GT1, GT4): Maviret 300 mg/120 mg QD for 12 weeks M15-410 Arm E (GT1, GT4): Maviret 300 mg/120 mg QD for 16 weeks M13-590 Arm A (GT1): Maviret 300 mg/120 mg QD for 12 weeks M13-590 Arm B (GT1): Maviret 300 mg/120 mg QD for 8 weeks M15-464 Arm A (GT2): Maviret 300 mg/120 mg QD for 12 weeks M13-594 Arm A (GT3): Maviret 300 mg/120 mg QD for 12 weeks M13-594 Arm C (GT3): Maviret 300 mg/120 mg QD for 8 weeks M13-583 (GT4 – GT6): Maviret 300 mg/120 mg QD for 12 weeks M15-462 (GT1 – GT6): Maviret 300 mg/120 mg QD for 12 weeks M14-172 (GT1, GT2, GT4 – GT6): Maviret 300 mg/120 mg QD for 12 weeks CI = confidence interval; DCV = daclatasvir; GLE = glecaprevir; GT=genotype; ITT = intention-to-treat; PIB = pibrentasvir; PS = primary subset; SVR12 = sustained virologic response 12 weeks postdosing; QD = once daily; RBV = ribavirin; SOF = sofosbuvir; SOF/R = regimens containing SOF and ribavirin; TE = treatment-experienced; TN = treatment-naïve @ CI = CI calculated using the normal approximation to the binomial distribution. & CI = CI calculated using the Wilson's score method. Notes: ITT population used for all treatment arms except that Study M15-464 Arm A excludes SOF/R-experienced subjects and Study M13-590 Arms A and B are in the ITT PS population. Arm B (SOF 400 mg QD + DCV 60 mg QD for 12 weeks) of Study M13-594 is not included in the Phase 2 and 3 Analysis Set but included in this forest plot.

39 Maviret (Glecaprevir/Pibrentasvir) 2019 Application for Inclusion on WHO Model List of Essential Medicines

Table 5. Number and Percentage of Subjects with On-Treatment Virologic Failure and Relapse12 by Treatment Arm (ITT Population, Phase 2 and 3 Analysis Set)

On-Treatment Study Number Virologic Failure Relapse12 (Treatment Arm – Duration – Genotype) n/N (%) 95% CI n/N (%) 95% CI M13-590 (Arm A – 12 weeks – GT1) 0/332 0.0, 1.1 0/332 0.0, 1.1 M13-590 (Arm B – 8 weeks – GT1) 1/335 (0.3) 0.1, 1.7 0/333 0.0, 1.1 M15-464 (Arm A – 12 weeks – GT2) 0/196 0.0, 1.9 0/195 0.0, 1.9 M13-594 (Arm A – 12 weeks – GT3) 1/233 (0.4) 0.1, 2.4 3/222 (1.4) 0.5, 3.9 M13-594 (Arm C – 8 weeks – GT3) 1/157 (0.6) 0.1, 3.5 5/150 (3.3) 1.4, 7.6 M13-583 (12 weeks – GT4 – GT6) 0/121 0.0, 3.1 0/118 0.0, 3.2 M14-172 (12 weeks – GT1, GT2, GT4 – GT6) 0/146 0.0, 2.6 1/144 (0.7) 0.1, 3.8 M15-462 (12 weeks – GT1 – GT6) 0/104 0.0, 3.6 0/100 0.0, 3.7 M14-868 (Arm Q – 12 weeks – GT3) 0/62 0.0, 5.8 2/61 (3.3) 0.9, 11.2 M14-868 (Arm R – 16 weeks – GT3) 1/69 (1.4) 0.3, 7.8 2/68 (2.9) 0.8, 10.1 M14-868 (Arm S – 8 weeks – GT2, GT4 – GT6) 0/203 0.0, 1.9 2/201 (1.0) 0.3, 3.6 M15-410 (Arm D – 12 weeks – GT1, GT4 – GT6) 1/44 (2.3) 0.4, 11.8 4/43 (9.3) 3.7, 21.6 M15-410 (Arm E – 16 weeks – GT1, GT4 – GT6) 4/47 (8.5) 3.4, 19.9 0/43 0.0, 8.2 M14-867 (Arm I – 12 weeks – GT4 – GT6) 0/32 0.0, 10.7 0/32 0.0, 10.7 M14-867 (Arm K – 8 weeks – GT1) 0/34 0.0, 10.2 0/33 0.0, 10.4 M14-868 (Arm A – 12 weeks – GT2) 0/25 0.0, 13.3 0/24 0.0, 13.8 M14-868 (Arm D – 12 weeks – GT3) 0/30 0.0, 11.4 1/29 (3.4) 0.6, 17.2 M14-868 (Arm J – 8 weeks – GT2) 0/54 0.0, 6.6 0/53 0.0, 6.8 M14-868 (Arm L – 8 weeks [TN] or 12 weeks 1/53 (1.9) 0.3, 9.9 1/51 (2.0) 0.3, 10.3 [TE] – GT3) M14-868 (Arm O – 12 weeks [TN] or 16 weeks 0/28 0.0, 12.1 1/28 (3.6) 0.6, 17.7 [TE] - GT3) M15-410 (Arm C – 12 weeks – GT1) 1/22 (4.5) 0.8, 21.8 0/21 0.0, 15.5

CI = confidence interval; GT = genotype; ITT = intention-to-treat; Relapse12 = relapse before or during the SVR12 window; TE = treatment-experienced; TN = treatment-naïve Note: CI was calculated using the Wilson's score method.

40 Maviret (Glecaprevir/Pibrentasvir) 2019 Application for Inclusion on WHO Model List of Essential Medicines

10.0 Review of harms and toxicity: summary of evidence of safety.

10.1 Patient Exposure to Date

As of 12 November 2018, a total of 3,286 adult HCV-infected patients have received GLE 300 mg QD and PIB 120 mg QD without RBV in the completed Phase 2 and 3/3b studies in the Maviret clinical development program. The Maviret clinical development program has enrolled a broad range of HCV-infected patients across HCV genotypes, treatment durations, and prior treatment experience, including patients with baseline polymorphisms or comorbidities (cirrhosis, renal impairment, HIV-1 coinfection, and renal and liver transplant).

Since its initial marketing authorization (Europe [centralized procedure]) on 26 July 2017 through 31 October 2018, an estimated 206,525 patient treatment courses (PTCs) of Maviret have been distributed worldwide.

10.2 Integrated Safety Data from the Maviret Product Information

The Company Core Data Sheet (CCDS) is an internal reference document considered by AbbVie to be most relevant and helpful in describing the drug's benefits and risks for patients. The DAA class risk of Hepatitis B Virus reactivation is described in the Warnings and Precautions section. The Adverse Reactions section of the CCDS summarizes the safety profile of Maviret in patients with the approved indication. This is presented below:

The safety assessment for Maviret in subjects with compensated liver disease (with or without cirrhosis) were derived from Phase 2 and 3 studies which evaluated approximately 2,300 subjects infected with GT 1, 2, 3, 4, 5, or 6 HCV who received Maviret for 8, 12 or 16 weeks.

The overall proportion of subjects who permanently discontinued treatment due to adverse reactions was 0.1% for subjects who received Maviret.

41 Maviret (Glecaprevir/Pibrentasvir) 2019 Application for Inclusion on WHO Model List of Essential Medicines

Across the Phase 2 and 3 clinical studies, the most common (occurring in at least 10% of subjects) adverse reactions (adverse events assessed as possibly related by the investigator) were headache and fatigue in subjects treated with Maviret for 8, 12 or 16 weeks.

Adverse reactions observed in greater than or equal to 5% of subjects receiving 8, 12, or 16 weeks of treatment with Maviret were headache (13.2%), fatigue (11.4%), and nausea (7.6%). In subjects receiving Maviret who experienced adverse reactions, 80% had an adverse reaction of mild severity (Grade 1).

In the placebo controlled study, these adverse reactions occurred at a similar frequency in subjects treated with placebo compared to subjects treated with Maviret. In the active-controlled study, adverse reactions occurred at a similar frequency in subjects treated with sofosbuvir and daclatasvir compared to subjects treated with Maviret.

There were no differences in the overall safety for subjects receiving Maviret for 8, 12 or 16 weeks. The type and severity of adverse reactions in subjects with cirrhosis were comparable to those seen in subjects without cirrhosis.

10.2.1 Adverse Reactions in Subjects with Severe Renal Impairment Including Subjects on Dialysis

The safety of Maviret in subjects with CKD (Stage 4 or Stage 5 including subjects on dialysis) and GT 1, 2, 3, 4, 5 or 6 chronic HCV infection with compensated liver disease (with or without cirrhosis) was assessed in 104 subjects (EXPEDITION-4). The most common adverse reactions were pruritus and fatigue in subjects treated with Maviret for 12 weeks. Adverse reactions observed in greater than or equal to 5% of subjects receiving 12 weeks of treatment with Maviret were pruritus (17.3%), fatigue (11.5%), nausea (8.7%), asthenia (6.7%), and headache (5.8%). In subjects treated with Maviret who reported an adverse reaction, 55% had adverse reactions of mild severity. No subjects experienced a serious adverse reaction. The proportion of subjects who permanently discontinued treatment due to adverse reactions was 1.9%.

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10.2.2 Adverse Reactions in HCV/HIV-1 Co-infected Subjects

The overall safety profile in HCV/HIV-1 co-infected subjects (ENDURANCE-1 and EXPEDITION-2) was comparable to that observed in HCV mono-infected subjects.

10.2.3 Adverse Reactions in Subjects with Liver or Kidney Transplant

The safety of Maviret was assessed in 100 post-liver or -kidney transplant recipients with GT 1, 2, 3, 4, or 6 chronic HCV infection without cirrhosis (MAGELLAN-2). The overall safety profile in transplant recipients was comparable to that observed in subjects in the Phase 2 and 3 studies. Adverse reactions observed in greater than or equal to 5% of subjects receiving Maviret for 12 weeks were headache (17%), fatigue (16%), nausea (8%), and pruritus (7%). In subjects treated with Maviret who reported an adverse reaction, 81% had adverse reactions of mild severity. Two percent of subjects experienced a serious adverse reaction, and no subjects permanently discontinued treatment due to adverse reactions.

Serum bilirubin elevations

Elevations in total bilirubin of at least 2 × upper limit normal (ULN) were observed in 1% of subjects related to glecaprevir-mediated inhibition of bilirubin transporters and metabolism. Bilirubin elevations were asymptomatic, transient, and typically occurred early during treatment. Bilirubin elevations were predominantly indirect and not associated with alanine aminotransferase (ALT) elevations.

10.3 Integrated Summaries of Safety of Specific Clinical Trials

10.3.1 Placebo-Controlled and Active-Controlled Analysis Sets

10.3.1.1 Placebo-Controlled Trial

In the Placebo-Controlled Analysis Set, the overall frequency and severity of AEs were similar in subjects receiving Maviret and placebo (Table 6). In the Active-Controlled Analysis Set, the overall frequency and severity of AEs were similar in subjects receiving

43 Maviret (Glecaprevir/Pibrentasvir) 2019 Application for Inclusion on WHO Model List of Essential Medicines

Maviret and SOF + DCV (Table 6). No subject experienced an SAE related to study drug in either analysis set.

Table 6. Overview of Adverse Events (Placebo-Controlled and Active Controlled Analysis Sets)

Placebo-Controlled Active-Controlled Analysis Set Analysis Set Treatment Group, n (%) Maviret Maviret 300 mg/120 mg × Placebo × 12 300 mg/120 mg SOF + DCV 12 Weeks Weeksa × 12 Weeks × 12 Weeks (N = 202) (N = 100) (N = 233) (N = 115) Any AE 131 (64.9) 58 (58.0) 177 (76.0) 80 (69.6) Any DAA-related AEb,c 64 (31.7) 33 (33.0) 112 (48.1) 50 (43.5) An AE Grade ≥ 3 5 (2.5) 1 (1.0) 11 (4.7) 2 (1.7) Any DAA-related AE 1 (0.5) 0 1 (0.4) 1 (0.9) Grade ≥ 3b,c Any SAE 3 (1.5) 1 (1.0) 5 (2.1) 2 (1.7) Any DAA-related SAEb,c 0 0 0 0 Discontinuation of study drug due to: Any AE 0 0 3 (1.3) 1 (0.9) Any DAA-related AEb,c 0 0 1 (0.4) 1 (0.9) Any fatal AE 0 0 0 0 All deathsd 0 0 0 1 (0.9) AE = adverse event; DAA = direct-acting antiviral agent; DCV = daclatasvir; GLE = glecaprevir; PIB = pibrentasvir; SAE = serious adverse event; SOF = sofosbuvir a. For the placebo arm, treatment-emergent AEs were defined as any event that began or worsened in severity after the first dose of placebo through 30 days after the last dose of placebo and prior to open-label Day 1. b. DAAs = GLE, PIB, GLE/PIB, DCV, or SOF. c. Investigator assessment. d. Includes nontreatment-emergent deaths.

Adverse events experienced by ≥ 10.0% of subjects in the Maviret or placebo treatment groups were headache and fatigue (Table 7). Overall, the percentage of subjects with any AE was similar in the Maviret and placebo groups.

44 Maviret (Glecaprevir/Pibrentasvir) 2019 Application for Inclusion on WHO Model List of Essential Medicines

Table 7. Adverse Events Reported for ≥ 5.0% of Subjects in Either Treatment Group (Placebo-Controlled Analysis Set)

Treatment Group, n (%) Maviret 300 mg/120 mg × Placebo × 12 Weeks 12 Weeks Risk Difference Preferred Term (N = 202) (N = 100) (%)a Any adverse event 131 (64.9) 58 (58.0) 6.9 Headache 24 (11.9) 12 (12.0) –0.1 Fatigue 23 (11.4) 10 (10.0) 1.4 AE = adverse event; GLE = glecaprevir; MedDRA = Medical Dictionary for Regulatory Activities; PIB = pibrentasvir a. Risk difference was calculated as the percentage of subjects who experienced an AE in the Maviret treatment group minus the percentage of subjects who experienced the same AE (MedDRA preferred term) in the placebo treatment group.

No clinically or statistically significant difference in the incidence of any AE considered related to study drug was observed between the Maviret and placebo treatment groups. There were no AEs considered related to study drug reported for ≥ 10.0% of subjects in the Maviret group (Table 8). Most subjects with AEs experienced events that were a maximum of Grade 1 (mild) in severity.

45 Maviret (Glecaprevir/Pibrentasvir) 2019 Application for Inclusion on WHO Model List of Essential Medicines

Table 8. Adverse Events Considered Related to Study Drug Reported for ≥ 5.0% of Subjects in Either Treatment Group (Placebo Controlled Analysis Set)

Treatment Group, n (%) Maviret 300 mg/120 mg × Placebo × 12 Weeks 12 Weeks Preferred Term (N = 202) (N = 100) Risk Difference (%)a Any adverse event 64 (31.7) 33 (33.0) –1.3 Headache 18 (8.9) 6 (6.0) 2.9 Fatigue 17 (8.4) 8 (8.0) 0.4 Asthenia 14 (6.9) 7 (7.0) –0.1 Nausea 13 (6.4) 2 (2.0) 4.4 MedDRA = Medical Dictionary for Regulatory Activities. a. Risk difference was calculated as the percentage of subjects in the Maviret treatment group minus the percentage of subjects in the placebo treatment group for the same adverse event (MedDRA preferred term). Note: The incidence of diarrhea was 4.95% (10/202) for Maviret and 2.00% (2/100) for placebo.

10.3.1.2 Active-Controlled Analysis Set

Common adverse events (≥ 10.0% of subjects) were the same in the Maviret and SOF + DCV treatment groups: headache, fatigue, and nausea. The frequency of AEs in subjects randomized to Maviret was similar to subjects randomized to SOF + DCV (Table 9). The only statistically significant difference was for the AE of asthenia, reported more frequently in the SOF + DCV treatment group.

46 Maviret (Glecaprevir/Pibrentasvir) 2019 Application for Inclusion on WHO Model List of Essential Medicines

Table 9. Adverse Events Reported for ≥ 5.0% of Subjects in Either Treatment Group (Active-Controlled Analysis Set)

Treatment Group, n (%) Maviret 300 mg/120 mg × SOF + DCV × 12 Weeks 12 Weeks Risk Difference Preferred Term (N = 233) (N = 115) (%)a Any adverse event 177 (76.0) 80 (69.6) 6.4 Headache 60 (25.8) 23 (20.0) 5.8 Fatigue 44 (18.9) 16 (13.9) 5.0 Nausea 32 (13.7) 15 (13.0) 0.7 Diarrhoea 15 (6.4) 4 (3.5) 3.0 Upper respiratory tract infection 15 (6.4) 4 (3.5) 3.0 Nasopharyngitis 12 (5.2) 7 (6.1) –0.9 AE = adverse event; DCV = daclatasvir; MedDRA = Medical Dictionary for Regulatory Activities; SOF = sofosbuvir a. Risk difference was calculated as the percentage of subjects who experienced an AE in the Maviret treatment group minus the percentage of subjects who experienced the same AE (MedDRA preferred term) in the SOF + DCV treatment group.

No clinically relevant differences in the incidences of AEs considered related to DAAs were observed between the Maviret and SOF + DCV treatment groups (Table 10). The majority of subjects with AEs in the Maviret (65.5%, 116/177) and SOF + DCV (68.7%, 55/80) 12-week arms experienced AEs with a maximum severity of Grade 1 (mild).

47 Maviret (Glecaprevir/Pibrentasvir) 2019 Application for Inclusion on WHO Model List of Essential Medicines

Table 10. Adverse Events Considered Related to Study Drug Reported for ≥ 5.0% of Subjects in Either Treatment Group (Active-Controlled Analysis Set)

Treatment Group, n (%) Maviret 300 mg/120 mg SOF + DCV × 12 Weeks × 12 Weeks Preferred Term (N = 233) (N = 115) Risk Difference (%)a Any adverse event 112 (48.1) 50 (43.5) 4.6 Headache 39 (16.7) 17 (14.8) 2.0 Fatigue 33 (14.2) 14 (12.2) 2.0 Nausea 27 (11.6) 14 (12.2) –0.6 AE = adverse event; DCV = daclatasvir; MedDRA = Medical Dictionary for Regulatory Activities; SOF = sofosbuvir a. Risk difference was calculated as the percentage of subjects who experienced an AE in the Maviret treatment group minus the percentage of subjects who experienced the same AE (MedDRA preferred term) in the SOF + DCV treatment group. Note: Order is by decreasing incidence in the Maviret treatment group.

10.3.2 Phase 2 and 3 Analysis Set

Adverse events experienced by ≥ 10.0% of subjects were headache and fatigue (Table 11). Similar to the Placebo- and Active-Controlled Analysis Sets, headache and fatigue were the most common study drug-related AEs.

48 Maviret (Glecaprevir/Pibrentasvir) 2019 Application for Inclusion on WHO Model List of Essential Medicines

Table 11. Adverse Events Reported for ≥ 5.0% of Subjects (Phase 2 and 3 Analysis Set)

Phase 2 and 3 Analysis Seta (N = 2,265) n (%) Preferred Term All Adverse Events Study Drug-Related Adverse Eventsb Any adverse event 1,529 (67.5) 929 (41.0) Headache 410 (18.1) 298 (13.2) Fatigue 330 (14.6) 259 (11.4) Nausea 208 (9.2) 172 (7.6) Diarrhoea 146 (6.4) 86 (3.8) a. Excluding Study M15-462. b. Investigator assessment.

Seven deaths were reported in the Phase 2 and 3 Analysis set (N = 2369). None of the deaths were considered related to study drug and the majority occurred several months after the last dose of study drug. Adverse events that led to death included cerebral hemorrhage (2 subjects), hepatic cancer metastatic, pneumonia, accidental overdose, and adenocarcinoma. One subject died due to unknown cause (preferred term death).

10.3.2.1 Events of Interest

Events of interest were identified based on the safety profiles of other DAAs and were monitored in the Maviret clinical development program. These events included potential cases of hepatotoxicity and hepatic decompensation/hepatic failure events.

Potential Cases of Hepatotoxicity

Potential cases of hepatotoxicity were defined as 1 of the following:

● Confirmed ALT value > 5 × ULN (regardless of grade change) and ≥ 2 × baseline ● Post-nadir increase in ALT grade to Grade 2 (ALT value > 3 × ULN) and a concurrent total bilirubin ≥ 2 × ULN with direct bilirubin:total bilirubin ratio > 0.4

49 Maviret (Glecaprevir/Pibrentasvir) 2019 Application for Inclusion on WHO Model List of Essential Medicines

In the Phase 2 and 3 Analysis Set, there were no cases consistent with drug-induced liver injury identified.

Hepatic Decompensation/Hepatic Failure Events

Hepatic decompensation/hepatic failure events were defined as ascites, hepatic encephalopathy, esophageal variceal bleeding, or spontaneous bacterial peritonitis. Potential events were identified using the AbbVie Product Medical Dictionary for Regulatory Activities (MedDRA) Query (PMQ) for hepatic decompensation/hepatic failure.

In the Phase 2 and 3 Analysis Set, only 1 subject met the above criteria for hepatic decompensation/hepatic failure events. The subject was a 64-year-old white male with cirrhosis, a baseline Child-Pugh score of 6, and known esophageal varices, who experienced an event of esophageal varices hemorrhage on Day 22. There were no clinical signs of hepatic failure and no concurrent change in ALT, total bilirubin (direct and indirect), platelets, albumin, or international normalized ratio. The subject continued treatment and achieved SVR12. The esophageal varices hemorrhage was not considered related to study drug.

10.3.2.2 Overall Analysis for Intrinsic Risk Factors

Overall, in the Phase 2 and 3 Analysis Set and Study M15-462, there were no apparent differences in AE profiles by sex, race, ethnicity, or baseline BMI. Adverse events and their incidences reported in male and female subjects, black and non-black subjects, Hispanic/Latino and not Hispanic/Latino subjects or subjects with a baseline BMI < 30 kg/m2 and subjects with a baseline BMI ≥ 30 kg/m2 were generally similar.

Age

No difference in the percentage of subjects who reported any AE was observed by age (Table 12). The Phase 2 and 3 Analysis Set included 328 (13.8%) subjects who were ≥ 65 years of age and included subjects as old as 88 years. Numerically greater

50 Maviret (Glecaprevir/Pibrentasvir) 2019 Application for Inclusion on WHO Model List of Essential Medicines

percentages of subjects ≥ 65 years of age experienced any SAE and any AE of Grade ≥ 3 (Table 12). Study M15-462 had a higher percentage of subjects ≥ 65 years of age compared with other studies in the Phase 2 and 3 Analysis Set. Therefore, the percentages of subjects who experienced events such as SAEs or AEs of Grade ≥ 3 were higher among older versus younger subjects due to the higher rate of comorbidities in subjects in Study M15-462 compared to the population in the other studies. Adverse events and their incidences reported in subjects < 65 years of age and in those ≥ 65 years old were otherwise similar.

Table 12. Overview of Adverse Events by Age (Phase 2 and 3 Analysis Set)

Phase 2 and 3 Analysis Seta n (%) Age < 65 Years ≥ 65 Years (N = 2,041) (N = 328) Any AE 1,392 (68.2) 211 (64.3) Any DAA-related AEb,c 857 (42.0) 123 (37.5) Any AE Grade ≥ 3 66 (3.2) 24 (7.3) Any DAA-related AE Grade ≥ 3b,c 7 (0.3) 2 (0.6) Any SAE 49 (2.4) 24 (7.3) Any DAA-related SAEb,c 1 (< 0.1) 0 Discontinuation of study drug due to: Any AE 8 (0.4) 4 (1.2) Any DAA-related AEb,c 4 (0.2) 1 (0.3) Any fatal AE 2 (< 0.1) 1 (0.3) All deathsd 5 (0.2) 2 (0.6) AE = adverse event; DAA = direct-acting antiviral agent; GLE = glecaprevir; PIB = pibrentasvir; SAE = serious adverse event a. Including Study M15-462. b. DAAs = GLE, PIB, or GLE/PIB. c. Investigator assessment. d. Includes nontreatment-emergent deaths.

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Overall, the safety profile of Maviret in the elderly population (≥ 65 years old) was comparable to the safety profile of Maviret in the non-elderly population.

Cirrhosis

Among the 288 (12.7%) subjects in the Phase 2 and 3 Analysis Set (excluding Study M15-462) with cirrhosis, there were no SAEs or Grade ≥ 3 AEs related to study drug (Table 13). No subject with cirrhosis prematurely discontinued study drug due to an AE or had a DAA-related SAE. Overall, there were no apparent differences in AE profiles by cirrhosis status.

Table 13. Overview of Adverse Events by Cirrhosis Status (Phase 2 and 3 Analysis Set)

Phase 2 and 3 Analysis Seta n (%) With Cirrhosis Without Cirrhosis Total (N = 288) (N = 1,977) (N = 2,265) Any AE 213 (74.0) 1,316 (66.6) 1,529 (67.5) Any DAA-related AEb,c 132 (45.8) 797 (40.3) 929 (41.0) An AE Grade ≥ 3 20 (6.9) 45 (2.3) 65 (2.9) Any DAA-related AE Grade ≥ 3b,c 0 4 (0.2) 4 (0.2) Any SAE 17 (5.9) 31 (1.6) 48 (2.1) Any DAA-related SAEb,c 0 1 (< 0.1) 1 (< 0.1) Discontinuation of study drug due to: Any AE 0 8 (0.4) 8 (0.4) Any DAA-related AEb,c 0 3 (0.2) 3 (0.1) Any fatal AE 0 2 (0.1) 2 (< 0.1) All deathsd 1 (0.3) 5 (0.3) 6 (0.3) AE = adverse event; DAA = direct-acting antiviral agent; GLE = glecaprevir; PIB = pibrentasvir; SAE = serious adverse event a. Excluding Study M15-462. b. DAAs = GLE, PIB, or GLE/PIB. c. Investigator assessment. d. Includes nontreatment-emergent deaths.

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Among the 288 subjects (excluding Study M15-462) with cirrhosis, the type and severity of AEs and AEs considered related to study drug were comparable to those observed in the 1,977 subjects (excluding Study M15-462) without cirrhosis (Table 14).

Table 14. Adverse Events by Cirrhosis Status Reported for ≥ 5.0% of Subjects Overall (Phase 2 and 3 Analysis Set)

Phase 2 and 3 Analysis Seta n (%) With Cirrhosis Without Cirrhosis Total Preferred Term (N = 288) (N = 1,977) (N = 2,265) Headache 47 (16.3) 363 (18.4) 410 (18.1) Fatigue 58 (20.1) 272 (13.8) 330 (14.6) Nausea 27 (9.4) 181 (9.2) 208 (9.2) Diarrhoea 24 (8.3) 122 (6.2) 146 (6.4) a. Excluding Study M15-462.

10.3.3 Severe Renal Impairment (Expedition 4: Study M15-462) (Patients with severe renal impairment including subjects on dialysis [CKD Stages 4 and 5])

In Study M15-462, 104 subjects with Stage 4 or 5 CKD were enrolled and received Maviret treatment for 12 weeks. The frequency of SAEs and Grade ≥ 3 AEs was higher in subjects in Study M15-462 with severe renal disease and on dialysis compared to those without CKD Stages 4 and 5, although none of the SAEs and only a fraction of Grade ≥ 3 AEs were considered DAA related. The safety profile in subjects in Study M15-462 was consistent with underlying ESRD and its associated comorbidities (Table 15). When study drug-related AEs are considered, no Maviret safety concerns specific to subjects with ESRD could be identified. Pruritus was the most common AE among subjects in this study. This was not an unexpected finding, as pruritus is commonly observed in patients with severe renal impairment, ranging in prevalence from 26% in CKD Stage 4 patients to 58% in CKD Stage 5 patients on hemodialysis.61,62

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Table 15. Summary of Adverse Events in Study M15-462 Study M15-462

Study M15-462 (N = 104) n (%) DAA-Related Adverse All Adverse Events Eventsa Any AE 74 (71.2) 51 (49.0) An AE Grade ≥ 3 25 (24.0) 5 (4.8) Any SAE 25 (24.0) 0 Discontinuation of study drug due to any AE 4 (3.8) 2 (1.9) All deathsb 1 (1.0) 0 Preferred Termc Pruritus 21 (20.2) 18 (17.3) Fatigue 15 (14.4) 12 (11.5) Nausea 12 (11.5) 9 (8.7) Asthenia 10 (9.6) 7 (6.7) Headache 9 (8.7) 6 (5.8) AE = adverse event; DAA = direct-acting antiviral agent; GLE = glecaprevir; PIB = pibrentasvir; SAE = serious adverse event a. DAAs = GLE, PIB, or GLE/PIB. b. Includes nontreatment-emergent deaths. c. DAA-related AEs reported for ≥ 5.0% of subjects

The safety profile of Maviret was similar among subjects in the Phase 2 and 3 Analysis Set including Study M15-462 with baseline creatinine clearance ≥ 30 to < 60 mL/min, ≥ 60 to < 90 mL/min, and ≥ 90 mL/min.

One subject in Study M15-462 (Subject 101602) died 17 days after the last dose of study drug due to an SAE of cerebral hemorrhage on Day 99, 14 days after the last dose of study drug. The event was considered to be not related to study drug; the investigator provided an alternative etiology of uncontrolled hypertension.

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Adverse events leading to premature discontinuation of study drug considered related to study drug occurred in 2 subjects: Subject 303603 (non-serious diarrhea) and Subject 504604 (non-serious pruritus).

10.3.4 HCV/HIV-1 Coinfection (Study M14-730)

Study M14-730 was a dedicated study in subjects with HCV/HIV-1 coinfection; 153 subjects were enrolled. The study consisted of 2 treatment arms: Arm A (noncirrhotic subjects treated with Maviret (300 mg/120 mg QD) for 8 weeks) and Arm B (subjects with compensated cirrhosis treated with Maviret (300 mg/120 mg QD) for 12 weeks).

Sixty-one percent of subjects experienced at least 1 TEAE (Table 16). Most subjects (55/94) with AEs had events with a maximum severity of Grade 1 (mild), with the most common overall being fatigue. Thirty-five of 94 subjects had TEAEs with a maximum severity of Grade 2. No subject experienced a study drug-related Grade ≥ 3 AE, study drug-related SAE, or died during the study. Four subjects reported 5 Grade ≥ 3 AEs (calculus urinary, cerebral haemorrhage and cerebrovascular accident, peripheral arterial occlusive disease, and upper gastrointestinal haemorrhage); all were SAEs and none was assessed as related to study drug. One subject prematurely discontinued study drug on Day 25 due to non-study drug-related SAEs of cerebrovascular accident and cerebral hemorrhage.

No clinically meaningful observations were noted for hematology, clinical chemistry, urinalysis, vital signs, or 12-lead electrocardiogram (ECG) assessments. Overall, 2 subjects met 1 of the criteria for hepatic laboratory abnormalities of special interest, 1 with an elevated ALT > 5 × ULN that was present at baseline and trended towards normalization within the first week of treatment, and the other with asymptomatic direct hyperbilirubinemia that resolved without study drug interruption or discontinuation. Neither of these cases is consistent with drug-induced liver injury. No subjects experienced an event of hepatic decompensation/hepatic failure. No case of failure to

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maintain HIV-1 virologic suppression was identified in subjects compliant with their antiretroviral treatment.

Table 16. Overview of Treatment-Emergent Adverse Events in HCV/HIV-1 Coinfected Subjects (Study M14-730)

Arm A Arm B Total (n = 137) (n = 16) (n = 153) n (%) n (%) N (%) Subjects with: Any AE 86 (62.8) 8 (50.0) 94 (61.4) Any AE with a reasonable possibility of being related to 50 (36.5) 3 (18.8) 53 (34.6) DAAs (GLE/PIB)a Any AE with a Grade 3 or higher 3 (2.2) 1 (6.3) 4 (2.6) Any serious AE 3 (2.2) 1 (6.3) 4 (2.6) Any DAA related serious AE 0 0 0 Any AE leading to discontinuation of study drug 0 1 (6.3) 1 (0.7) Any DAA related AE leading to discontinuation of study 0 0 0 drug Any DAA related AE with a Grade 3 or higher 0 0 0 Any serious AE leading to discontinuation of study drug 0 1 (6.3) 1 (0.7) Any AE leading to interruption of study drug 0 0 0 Any fatal AE 0 0 0 Deathsb 0 0 0 AE = adverse event; DAA = direct-acting antiviral agent; QD = once daily a. As assessed by investigator. b. Includes non-treatment-emergent deaths.

Efficacy and safety results of the Maviret 300 mg/120 mg QD combination regimen in this current study in subjects with HCV/HIV-1 coinfection are consistent and expand on the results of the AbbVie's Phase 3 studies in subjects with HCV monoinfection and HCV GT1/HIV-1 coinfection.

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10.3.5 Renal and Liver Transplant (Study M13-596)

Study M13-596 was a dedicated study in chronic HCV GT1 – 6 infected, post-primary orthotopic liver or renal transplant subjects without cirrhosis; 100 subjects were enrolled to receive 12 weeks of Maviret 300 mg/120 mg QD.

The majority of subjects experienced at least 1 AE during the Treatment Period (Table 17). Most subjects experienced AEs with a maximum severity of Grade 1 (mild), with the most common overall being fatigue, headache, nausea, pruritus, and diarrhea. Three subjects, all liver transplant recipients, experienced Grade ≥ 3 AEs (Grade 3 hepatic enzyme increased, sinusitis, hepatic function abnormal in 1 subject each) assessed as related to study drug; the events of sinusitis and hepatic function abnormal were serious. There were no study drug-related SAEs in the renal transplant population. One subject experienced an SAE of cerebrovascular accident on Day 50, which led to premature discontinuation of study drug (last dose of study drug was on Day 49); the event was considered not related to study drug.

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Table 17. Overview of Treatment-Emergent Adverse Events in Chronic HCV GT1 – 6 infected, Post-Primary Orthotopic Liver or Renal Transplant Subjects (Study M13-596)

Maviret Renal Transplant Maviret Only (N = 100) (N = 20) n (%) n (%) Subjects with: Any AE 85 (85.0) 18 (90.0) Any AE with a reasonable possibility of being related to 48 (48.0) 7 (35.0) DAAs (GLE/PIB)a Any AE with a Grade 3 or higher 12 (12.0) 5 (25.0) Any serious AE 8 (8.0) 3 (15.0) Any DAA related serious AE 2 (2.0) 0 Any AE leading to discontinuation of study drug 1 (1.0) 0 Any DAA related AE leading to discontinuation of 0 0 study drug Any DAA related AE with a Grade 3 or higher 3 (3.0) 0 Any serious AE leading to discontinuation of study drug 1 (1.0) 0 Any AE leading to interruption of study drug 1 (1.0) 1 (5.0) Any fatal AE 0 0 Deathsb 0 0 GLE/PIB 300 mg/120 mg QD for 12 weeks AE = adverse event; DAA = direct-acting antiviral agent; QD = once daily a. As assessed by investigator. b. Includes nontreatment-emergent deaths.

Few subjects had Grade 3/4 hematology or chemistry values that worsened compared with baseline during the Treatment Period. The majority of subjects with Grade 3/4 hematology or chemistry values had isolated values that were not clinically significant. No cases of drug-induced liver injury or hepatic decompensation/failure were identified. One case of mild liver transplant rejection occurred while the subject was taking Maviret,

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which was managed with titration of immunosuppression regimen, without changes in Maviret dosing.

No clinically meaningful observations were noted for urinalysis, vital signs, or 12-lead ECG assessments.

The fixed-dose combination of Maviret 300 mg/120 mg QD for 12 weeks was well tolerated and demonstrated a favorable safety profile in patients with renal and liver transplant.

10.4 Overall Conclusion on the Safety and Tolerability of Maviret

Maviret demonstrated a favorable safety profile that was similar to placebo and SOF + DCV, and that was similar across durations of 8, 12, and 16 weeks. Maviret was well tolerated across a broad and diverse population of subjects, including subjects with cirrhosis, HIV coinfection, renal and liver transplant, and CKD Stage 4 or 5.

Common study drug-related AEs (ADRs) occurring in ≥ 5% of subjects were headache, fatigue, and nausea. Adverse drug reactions were mostly Grade 1 (mild) in severity. Serious ADRs and ADRs leading to premature study drug discontinuation were rare (≤ 0.1%).

There were no hematological or blood chemistry findings of concern or considered likely related to treatment. Unlike other PIs, no liver-related toxicities and no cases consistent with drug-induced liver injury were identified.

The safety profile in subjects with cirrhosis was similar to those in subjects without cirrhosis. The safety of Maviret was not affected by coinfection with HIV-1, sex, older age (≥ 65 years), race, ethnicity, obesity, or geographic location. In addition, Maviret 300 mg/120 mg QD demonstrated a favorable safety profile in subjects with any degree of renal insufficiency, including subjects on dialysis.

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Real-world data for Maviret emerging from multiple cohorts with approximately 10,000 patients across a variety of countries, also confirm the safety demonstrated with the clinical trials.30 There were no unexpected safety findings reported by these real-world cohorts which included treatment naïve and treatment experienced (PRS and DAA) as well as non-cirrhotic and compensated cirrhotic patients across all genotypes reflecting the respective local epidemiology.

11.0 Summary of available data on comparative cost and cost-effectiveness of the medicine.

In a 2017 cost-effectiveness analysis set in the United States, Maviret was shown to be a dominant pan-genotypic treatment option compared to current standard practices providing most favorable health outcomes at lowest cost (Figure 9).56 Health outcomes included quality-adjusted life years (QALYs) and number needed to treat (NNT) to achieve a QALY, SVR or avoid an adverse liver event (Figure 10). In this analysis, Maviret was compared to two treatment strategies: (i) SOF/LDV for GTs 1 and 4, and SOF/VEL for GTs 2, 3, 5 and 6; and (ii) grazoprevir/elbasvir for GTs 1 and 4, and SOF/VEL for GTs 2, 3, 5 and 6. A 12-week regimen course of Maviret was assumed to cost $27,929 USD per 2017 wholesale acquisition drug costs. In summary, this study suggests that Maviret is associated with improvement in QoL and reduced hepatic risks. In the United States, Maviret is not only cost-effective but also cost-saving compared to other standards of care. Cost-effectiveness results in other countries may vary based on the different pricing of Maviret and competitors.

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Figure 9. Lifetime Costs and QALYs with Maviret Compared to Strategies 1 and 2

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Figure 10. NNT to achieve/avoid health outcomes with Maviret Compared to Strategies 1 and 2

Regulatory information

12.0 Summary of regulatory status and market availability of the medicine.

Maviret is approved, and commercially available for market, for the treatment of TN and TE HCV GT1- to GT6-infected patients with compensated liver disease (with or without cirrhosis), including patients with severe renal impairment or ESRD (CKD Stages 4 or 5), and patients coinfected with HIV in 58 countries globally to date. In the United States, Canada, Australia, Taiwan, South Korea, Brazil, and Belarus, Maviret is also indicated for the treatment of adult patients with HCV GT1 infection who previously have been treated either with a regimen containing an HCV NS5A inhibitor or an NS3/4A PI, but not both. Furthermore, in Turkey, New Zealand, and Japan, Maviret is also indicated for the

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treatment of adult patients with HCV GT1 to GT6 infection who previously have been treated with a regimen containing an HCV NS5A inhibitor, an NS3/4A PI, or both. The worldwide marketing authorization status for Maviret is detailed in Table 18.

Table 18. Worldwide Marketing Authorization Status – Glecaprevir/Pibrentasvir Tablets (100 mg/40 mg)

Country Submission Date Approval Date United States 14-Dec-2016 03-Aug-2017 Austria 20-Dec-2016 26-Jul-2017 Belgium 20-Dec-2016 26-Jul-2017 Bulgaria 20-Dec-2016 26-Jul-2017 Croatia 20-Dec-2016 26-Jul-2017 Cyprus 20-Dec-2016 26-Jul-2017 Czech Republic 20-Dec-2016 26-Jul-2017 Denmark 20-Dec-2016 26-Jul-2017 Estonia 20-Dec-2016 26-Jul-2017 Finland 20-Dec-2016 26-Jul-2017 France 20-Dec-2016 26-Jul-2017 Germany 20-Dec-2016 26-Jul-2017 Greece 20-Dec-2016 26-Jul-2017 Hungary 20-Dec-2016 26-Jul-2017 Ireland 20-Dec-2016 26-Jul-2017 Italy 20-Dec-2016 26-Jul-2017 Latvia 20-Dec-2016 26-Jul-2017 Lithuania 20-Dec-2016 26-Jul-2017 Luxembourg 20-Dec-2016 26-Jul-2017 Malta 20-Dec-2016 26-Jul-2017 Netherlands 20-Dec-2016 26-Jul-2017 Poland 20-Dec-2016 26-Jul-2017 Portugal 20-Dec-2016 26-Jul-2017 Romania 20-Dec-2016 26-Jul-2017

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Table 18. Worldwide Marketing Authorization Status – Glecaprevir/Pibrentasvir Tablets (100 mg/40 mg) (continued)

Country Submission Date Approval Date Slovakia 20-Dec-2016 26-Jul-2017 Slovenia 20-Dec-2016 26-Jul-2017 Spain 20-Dec-2016 26-Jul-2017 Sweden 20-Dec-2016 26-Jul-2017 United Kingdom 20-Dec-2016 26-Jul-2017 Iceland 20-Dec-2016 26-Jul-2017 Liechtenstein 20-Dec-2016 26-Jul-2017 Norway 20-Dec-2016 26-Jul-2017 Switzerland 12-Jan-2017 22-Sep-2017 Canada 24-Jan-2017 16-Aug-2017 Australia 25-Jan-2017 21-Dec-2017 Japan 14-Feb-2017 27-Sep-2017 Turkey 01-Mar-2017 12-Feb-2018 New Zealand 21-Mar-2017 21-Jun-2018 Taiwan 27-Mar-2017 02-Feb-2018 South Korea 26-Apr-2017 12-Jan-2018 Russia 30-Jun-2017 13-Apr-2018 Israel 03-Jul-2017 15-Feb-2018 Puerto Rico 03-Aug-2017 04-Aug-2017 Argentina 04-Aug-2017 24-Jan-2018 Hong Kong 10-Aug-2017 19-Mar-2018 Brazil 15-Aug-2017 16-Apr-2018 Uruguay 22-Aug-2017 02-Oct-2017 United Arab Emirates 24-Aug-2017 21-Jan-2018 Peru 27-Sep-2017 16-May-2018 Lebanon 19-Oct-2017 26-Jun-2018 Kazakhstan 03-Nov-2017 10-Sep-2018 Montenegro 08-Nov-2017 10-Sep-2018 Mexico 15-Nov-2017 20-Dec-2017

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Table 18. Worldwide Marketing Authorization Status – Glecaprevir/Pibrentasvir Tablets (100 mg/40 mg) (continued)

Country Submission Date Approval Date Bosnia and Herzegovina 16-Nov-2017 31-Jan-2018 Saudi Arabia 22-Nov-2017 30-Sep-2018 Belarus 12-Dec-2017 29 Oct-2018 Albania 16-Feb-2018 16-May-2018 Macau 29-Mar-2018 21-May-2018

AbbVie and the Medicines Patent Pool (MPP) have entered into a new, royalty-free licensing agreement to accelerate access to Maviret in 99 low- and middle-income countries and territories at affordable prices, enabling access to and treatment scale-up with Maviret. Through this agreement, AbbVie will grant WHO prequalified generic manufacturers to license, manufacture and supply generic versions of Maviret, while maintaining the highest quality and production standards. AbbVie is also considering the inclusion of Maviret on the WHO List of Prequalified Medicinal Products.

AbbVie has a long history of working together with the community to ensure broad and long-term access to care for our virology medicines worldwide and this agreement with MPP is one way AbbVie is partnering to find sustainable solutions to help achieve HCV elimination.

13.0 Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia, European Pharmacopeia).

Maviret is a proprietary drug regimen that does not have an existing published pharmacopeia quality standard to confirm its strength, quality or purity. AbbVie has established the standards for Maviret; these have been approved as part of the marketing authorization in 58 countries globally to date.

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