application for inclusion of ledipasvir/sofosbuvir (harvoni ) tablets … · diamond-shaped,...

Application for inclusion of Harvoni® tablets in the WHO Model List

of Essential Medicines. November 28, 2014

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Application for inclusion of ledipasvir/sofosbuvir (Harvoni®) tablets on the WHO Model List

of Essential Medicines

Submitted by

Gilead Sciences Inc.

November 28, 2014

Gilead Sciences Inc.

333 Lakeside Drive

Foster City

California 94404

USA

Gilead Submission Reference number:



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Contents

1. Summary statement of the proposal for inclusion .................................................... 5

2. Name of the focal point in WHO submitting or supporting the application .................. 8

3. Name of the organization(s) consulted and/or supporting the application .................. 8

4. International Nonproprietary Name (INN, generic name) of the medicine .................. 8

5. Formulation proposed for inclusion ........................................................................ 8

6. International availability ...................................................................................... 10

7. Listing type requested ........................................................................................ 12

8. Information supporting the public health relevance ................................................ 12

8.1 Epidemiological information on disease burden ........................................... 12

8.2 Assessment of current use ........................................................................ 15

8.3 Target population ..................................................................................... 18

9. Treatment details ............................................................................................... 18

9.1 Indications and usage ............................................................................... 18

9.2 Dosage and administration ........................................................................ 18

9.2.1 Special populations ............................................................................ 19

9.3 Duration .................................................................................................. 20

9.4 Reference to existing WHO and other clinical guidelines .............................. 20

9.5 Special requirements ................................................................................ 21

10. Summary of comparative effectiveness in a variety of clinical settings ............. 22

10.1 Identification of clinical evidence ................................................................ 22

10.2 Summary of available data on comparative effectiveness of Harvoni® ........... 22

10.2.1 Summary of the Phase 2 clinical trial program for Harvoni® .................... 23

10.2.2 Background and design of the Phase 3 studies of Harvoni®

in HCV GT 1 ...................................................................................... 29



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10.2.3 Results of the Phase 3 registration studies of Harvoni® in mono-infected

patients with HCV GT 1 ...................................................................... 31

10.2.4 Virologic failure and resistance analysis in the clinical studies ................ 40

10.2.5 Results of the Phase 3 studies of Harvoni® in patients with traditionally

hard-to-treat baseline characteristics ................................................... 46

10.2.6 Results of the studies of Harvoni® in patients with genotypes

other than GT 1 ................................................................................. 50

10.2.7 Impact of Harvoni® on patient health-related quality of life ...................... 51

10.2.8 Effect of Harvoni® therapy on long-term patient outcomes ..................... 52

10.3 Summary of available estimates of comparative effectiveness ...................... 53

11. Summary of comparative evidence on safety ................................................. 55

11.1 Estimate of total patient exposure to Harvoni® ............................................... 56

11.2 Description of adverse effects/reactions ..................................................... 57

11.2.1 Treatment-emergent adverse events in patients with HCV GT 1 ............. 57

11.2.2 Safety of Harvoni® in patients with HCV GT 1 and cirrhosis ................... 63

11.2.3 Safety of Harvoni® in patients with HIV/HCV co-infection ....................... 64

11.2.4 Safety of Harvoni® in patients with HCV GT 2, 3, 4, 5 and 6 infection ...... 65

11.2.5 Drug interactions ............................................................................... 66

11.3 Summary of comparative safety ................................................................... 70

12. Summary of available data on comparative cost and cost-effectiveness

within the pharmacologic class or therapeutic group ...................................... 72

12.1 Range of costs of the proposed medicine ................................................... 72

12.1.1 USA ................................................................................................. 72

12.1.2 Developing countries .......................................................................... 72

12.2 Cost-effectiveness of medicines for HCV ...................................................... 73

13. Summary of regulatory status of the medicine ................................................ 76



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14. Availability of pharmacopoeial standards ....................................................... 76

14.1 Specifications of Harvoni® tablets............................................................... 76

15. Proposed (new/adapted) text for the WHO Model Formulary ........................... 78

15.1 Other antivirals ......................................................................................... 78

16. References ................................................................................................. 79

Appendix 1. Harvoni® Access PI ............................................................................. 88



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1. Summary statement of the proposal for inclusion

Harvoni® (ledipasvir/sofosbuvir 90 mg/400 mg) is a once-daily, fixed-dose combination

tablet for oral administration for the treatment of hepatitis C virus (HCV). Harvoni®

contains ledipasvir (LDV), an HCV NS5A inhibitor, and sofosbuvir (SOF), a nucleotide

analog inhibitor of HCV NS5B polymerase. It is proposed for inclusion in the WHO Model

List of Essential Medicines as a treatment for chronic HCV infection in adult patients

(≥18 years).

The use of Harvoni® is based primarily on efficacy and safety data from three published

open-label Phase 3 studies, ION-1, ION-2 and ION-3. The ION studies evaluated

Harvoni® in 1952 patients with HCV genotype (GT) 1 and compensated liver disease,

and comprised one study in non-cirrhotic, treatment-naïve patients (ION-3), one study in

cirrhotic and non-cirrhotic treatment-naïve patients (ION-1), and one study in cirrhotic

and non-cirrhotic patients who had failed prior therapy with an interferon (IFN)-based

regimen, including regimens containing an HCV protease inhibitor (PI; ION-2). In

addition, a Phase 3 Japanese study evaluated Harvoni®, with or without ribavirin (RBV),

in 341 treatment-naïve and treatment-experienced patients with HCV GT 1.

The principal reasons for requesting inclusion in the World Health Organization (WHO)

Model List of Essential Medicines are as follows:

• Infection with HCV imposes a significant global burden, with wide-ranging personal,

societal and economic effects [WGO Guidelines, 2013]

o Up to 85% of patients infected with HCV develop chronic infection, placing

them at risk of serious sequelae, including liver fibrosis, cirrhosis,

hepatocellular carcinoma (HCC) and death [Chen and Morgan, 2006]

o Chronic HCV infection is associated with increased morbidity and mortality

from extrahepatic manifestations, including circulatory diseases, renal

diseases, autoimmune disorders, cutaneous manifestations and non-liver

cancers [Himoto et al, 2012; Lee et al, 2012]

o Chronic HCV infection significantly affects patients’ quality of life (QoL) and

ability to work, and confers high medical costs, which rise with increasing

disease severity [Vietri et al, 2013]



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o Whilst the incidence of new HCV infections has fallen in many countries

following the introduction of blood product screening [CDC, 2011; EASL,

2014a], the substantial burden of chronic HCV infection is growing, as

individuals who contracted HCV in the past begin to develop long-term

complications [Davis et al, 2010; Razavi et al, 2013]

• Until recently, the standard of care for patients with chronic HCV infection consisted

of long-duration treatment regimens based on pegylated interferon (PEG-IFN) plus

RBV, with the addition of a direct-acting antiviral agent (DAA) of the PI class in

patients with HCV GT 1 [EASL, 2014a]. Such regimens are limited by the inability or

unwillingness of patients to tolerate long-duration IFN-based regimens (up to

48 weeks); medical ineligibilities to PEG-IFN + RBV (e.g. psychiatric disorders,

co-morbidities, substance use disorders); and other barriers to IFN-based treatment

(e.g. intolerance, fear of known side effects, needle phobia and contraindications due

to drug–drug interactions with other medications) [North et al, 2013]

• The recent approval of SOF (Sovaldi®; Sovaldi US PI, 2014), and its

recommendation as the backbone of the new standard of care for HCV infection

[EASL, 2014b], has improved treatment options for patients with chronic HCV

infection and offers a number of potential benefits [Jacobson et al, 2013; Lawitz et al,

2013; Afdhal et al, 2014a; WHO Guidelines, 2014; Zeuzem et al, 2014; Data on file –

Gilead Sciences EAME – (HCV1300034); Data on file – Gilead Sciences EAME –

(HCV1300042); Data on file – Gilead Sciences EAME – (HCV1300053)]:

o High rates of sustained virologic response (SVR) in treatment-naïve and

treatment-experienced patients

o Pangenotypic activity with efficacy across HCV GT 1–6

o Efficacy in patients unwilling or unable to tolerate IFN-based therapy

o Shorter duration of treatment where combination therapy including IFN is

required for optimum efficacy (e.g. those with GT 1)

o Efficacy in difficult-to-treat patients, including those with cirrhosis, human

immunodeficiency virus (HIV) co-infection and HCC awaiting liver

transplantation

o Favorable safety and tolerability profiles across all genotypes in patients with

and without cirrhosis



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o High barrier to resistance

• As part of its ongoing clinical development program, SOF has been investigated in

combination with LDV, with or without RBV, to address the need for an all-oral

treatment option with a short and simple regimen that would eliminate the toxicity,

tolerability issues and contraindications associated with the use of IFN- or

RBV-based regimens. LDV and SOF (LDV/SOF) have been co-formulated as the

once-daily, oral fixed-dose single tablet regimen (STR), Harvoni®.

• A series of clinical trials have established the efficacy, tolerability and safety of

Harvoni® in treatment-naïve and treatment-experienced HCV GT 1 patients with

8–12 weeks of therapy. Exclusion of RBV from the regimen maintained efficacy and

substantially reduced the incidences of adverse events (AEs) and laboratory

abnormalities experienced by patients. In patients with compensated cirrhosis,

Harvoni® for 24 weeks or Harvoni® + RBV for 12 weeks also resulted in high rates of

response, with the shorter-duration regimen being a considerable treatment advance

in this group of patients. It is noteworthy that Harvoni® has been associated with a

low incidence of drug–drug interactions (DDIs), compared with other DAAs, and has

been studied in patients receiving a number of immunosuppressant drugs or

antiretroviral therapy (ART), supporting its use in traditionally hard-to-treat patient

populations, including those receiving concomitant therapies for complex comorbid

conditions, such as HIV. Finally, data have shown that Harvoni® is effective in

patients with resistance-associated variants (RAVs), with a high proportion of

patients with baseline RAVs and PI-resistant mutations achieving SVR [Lawitz et al,

2014; Afdhal et al. 2014b and 2014c; Kowdley et al, 2014; Data on file – Gilead

Sciences EAME – (HCV1300044); Data on file – Gilead Sciences EAME –

(HCV1300045); Data on file – Gilead Sciences EAME – (HCV1300046); Data on file

– Gilead Sciences EAME – (HCV1300047); Data on file – Gilead Sciences EAME –

(HCV1300049); Data on file – Gilead Sciences EAME – (HCV1300050); Data on file


(HCV13000103); Data on file – Gilead Sciences EAME – (HCV1300074); Data on

file – Gilead Sciences EAME – (HCV13000119)].

• Harvoni® builds on the proven efficacy of SOF to offer a high chance of cure to a

wide range of patients, including those with traditionally difficult-to-treat disease, with

a short-duration, mostly IFN- and RBV-free regimen.



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2. Name of the focal point in WHO submitting or supporting the application

Stefan Wiktor, 20 Avenue Appia, 1211 Geneva, 27-Switzerland.

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

World Health Alliance.

4. International Nonproprietary Name (INN, generic name) of the medicine

Ledipasvir and sofosbuvir.

5. Formulation proposed for inclusion

Harvoni® is a two-drug fixed-dose combination medication that contains 90 mg of LDV

and 400 mg of SOF in a single tablet. The recommended dosage of Harvoni® is one

tablet taken orally once daily with or without food. It is available as an orange,

diamond-shaped, film-coated tablet of dimensions 19 mm x 10 mm, debossed with ‘GSI’

on one side and ‘7985’ on the other side [Harvoni® US PI, 2014; Harvoni® SmPC, 2014].

An alternative white, film-coated tablet presentation is also available, which differs only

from the aforementioned tablet formulation in the color of the film coat applied.

The tablets are packaged in 100 mL, white, high-density polyethylene bottles containing

one gram of silica gel desiccant and a polyester fiber coil. Each bottle contains

28 tablets and is capped using a white, continuous thread, child-resistant polypropylene

screw cap with an induction-sealed, aluminum-faced liner [Harvoni® US PI, 2014].

The qualitative and quantitative composition of Harvoni® tablets is provided in Table 1.



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Table 1. Qualitative composition of Harvoni® (LDV/SOF) tablets

Tablet core

Colloidal silicon dioxide (E551)

Copovidone (E1201)

Croscarmellose sodium (E468)

Lactose monohydrate

Magnesium stearate (E470b)

Microcrystalline cellulose (E460[i])

Film coating (orange film coat)

FD&C yellow 6/sunset yellow FCF aluminium lake (E110)

Polyethylene glycol (E1521)

Polyvinyl alcohol (E1203)

Talc (E553b)

Titanium dioxide (E171)

Film coating (white film coat)

Polyethylene glycol (E1521)

Polyvinyl alcohol (E1203)

Talc (E553b)

Titanium dioxide (E171)

Harvoni® is indicated for use in adult patients (≥18 years). Harvoni® is not presently

recommended for patients aged <18 years because its safety and efficacy in children

and adolescents have not yet been established [Harvoni® US PI, 2014]. Thus, no

pediatric formulation is proposed for inclusion and its potential for use in this patient

population will not be discussed further in this application.



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6. International availability

Harvoni® is a registered trademark of Gilead Sciences, Inc, or its related companies in

the USA and other countries.

Harvoni® tablets are currently manufactured, packaged, labeled and tested for Gilead

Sciences, Inc. at the facilities listed in Table 2. All of the sites are currently approved and

listed in the US New Drug Application (NDA). The manufacturing steps conducted at all

facilities are in compliance with European Union (EU) and US Food and Drug

Administration (FDA) Good Manufacturing Practice (GMP) guidelines.



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Table 2. Manufacturing, packaging, labeling and testing facilities for Harvoni® tablets

Manufacturing site Function(s)

Patheon, Inc.

2100 Syntex Court

Mississauga, Ontario

Canada L5N 7K9

Manufacturing, packaging, labeling and

release testing

Patheon, Inc.

977 Century Drive

Burlington, Ontario

Canada L7L 5J8

Release testing

Gilead Sciences, Inc.

650 Cliffside Drive

San Dimas, California 91773

USA

Packaging, labeling and batch release

Gilead Sciences Limited

IDA Business and Technology Park

Carrigtohill

County Cork

Ireland

Manufacturing, packaging, labeling,

release testing and batch release

PPD Development, LLC

8551 Research Way, Suite 90

Middleton, Wisconsin 53562-4663

USA

Release testing


333 Lakeside Drive

Foster City, California 94404

USA

Batch release

Gilead’s mission is to transform care for life-threatening diseases, including chronic HCV

infection. To achieve this, Gilead believes it is important to apply innovation not just to

drug discovery but also to finding new ways to get affordable medicines to people in



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need as quickly as possible. Gilead’s model for Harvoni® is based on its HIV treatment

provision in developing countries, which has evolved over time, in response to lessons

learned, stakeholder feedback and evidence of program effectiveness. Gilead learned

early about the importance of partnership and collaboration for increasing drug access.

Today, Gilead works with more than 70 manufacturers, regional and local distributors,

and generic licensees to expand access to marketed medicines and to plan for future

access to pipeline products (see Section 12).

7. Listing type requested

Listing is requested on the Model List of Essential Medicines as an example of the

therapeutic class of DAAs for HCV infection.

8. Information supporting the public health relevance

8.1 Epidemiological information on disease burden

Following its isolation and identification in 1989, HCV infection has been recognized

as a major cause of chronic liver disease worldwide. Estimates suggest that more than

185 million people (approximately 3% of the global population) are infected with HCV,

the majority of whom live in resource-limited settings [Mohd Hanafiah et al, 2013].

Egypt is believed to have the highest prevalence rate in the world with more than 15% of

the population infected [Sievert et al, 2011], while Africa has the highest WHO estimated

regional HCV prevalence at 5.3% [Karoney and Siika, 2013]. Each year, 3–4 million

more people become infected with HCV and more than 350,000 die from liver-related

diseases such as liver cirrhosis and HCC [WHO Fact Sheet, July 2013].

HCV is a blood-borne infection; the majority of HCV transmission in the developing world

is associated with unsafe injection practices and poor infection control. In many

resource-limited countries, the reuse of syringes and use of contaminated medical

equipment without proper sterilization are common and known risk factors for HCV

transmission [WGO Guidelines, 2013], together with the widespread use of unscreened

blood for transfusions [Hauri et al, 2004]. Lack of access to sterile injection equipment



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continues to fuel the HCV epidemic in many countries, notably Pakistan, where

transmission is also influenced by community-related activities, such as traditional

healers, unqualified medical providers, tattoo parlors and barber shops [Qureshi et al,

2010; Sievert et al, 2011]. While people who inject drugs (PWID) remain the primary

route by which HCV infection is transmitted in developed countries, injection drug use is

also becoming an increasingly important risk factor for HCV transmission in developing

countries [Nelson et al, 2011]. Globally, China has the highest estimated number of

HCV-infected PWID but prevalence is also high in Mexico, Pakistan and Thailand where

more than 80% of PWID are HCV antibody-positive [Nelson et al, 2011].

A small proportion of newly infected patients will clear the virus spontaneously and do

not require treatment; however, up to 85% of acute cases become chronic and, if left

untreated, about 60–70% go on to develop chronic liver disease: approximately 5–20%

develop cirrhosis and 1–5% die from cirrhosis or HCC. HCV infection is the underlying

cause of liver cancer in approximately 25% of patients [WHO Fact Sheet, July 2013]

and, as more than 80% of HCC cases occur in sub-Saharan Africa and the Far East,

notably China [Villar et al, 2012], infection with HCV is an important driver of morbidity

and mortality in many medium- to low-resource settings.

As HIV and HCV share common routes of parenteral transmission, HIV/HCV co-infection

is relatively common, with estimates suggesting that, of the 34 million persons infected

with HIV worldwide, up to 30% are concurrently infected with HCV [UNAIDS, 2012;

Price and Thio, 2010].

Prevalence is highest in sub-Saharan Africa, where more than two-thirds of all those

infected with HIV live today [WHO Fact Sheet, June 2013]. Co-infection with HIV is

associated with persistent HCV viremia and higher HCV viral load, leading to

accelerated progression of liver disease and increased mortality among HCV-infected

patients [Mohsen et al, 2002; Operskalski and Kovacs, 2011]. HIV may also increase the

risk of mother-to-child transmission of HCV [Gibb et al, 2000]. The early use of ART

among HIV/HCV co-infected individuals has been shown to slow the progression of liver

disease and improve health outcomes [Averhoff et al, 2012].



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In contrast to HIV, for which infected patients require lifelong therapy, HCV is a curable

viral infection. However, because acute HCV infection is generally asymptomatic, most

individuals living with HCV infection are unaware that they are infected and, as a result,

do not receive appropriate drug therapy early in the course of infection. Such patients

are at risk of HCV-associated complications, including cirrhosis and HCC [Averhoff et al,

2012]. In addition, HCV-infected persons can serve as a reservoir for ongoing HCV

transmission within the community; therefore, antiviral treatment is a vital measure in

disease prevention to reduce the number of infected individuals.

Significant barriers exist in many low-resource countries that inhibit the widening of

access to screening and treatment for HCV infection. However, awareness is growing in

many parts of the developing world relating to the importance of managing HCV and

chronic HCV infection. In 2010, the World Health Assembly urged its Member States

“to support or enable an integrated and cost-effective approach to the prevention, control

and management of viral hepatitis considering the linkages with associated co-infection

such as HIV, as well as to collaborate with other organizations in the United Nations

system, partners, international organizations and other relevant stakeholders in

enhancing access to affordable treatments in developing countries” [World Health

Assembly, 2010].

These sentiments coincide with the advent of DAAs for the treatment of HCV. These

agents have the potential to revolutionize the management of HCV, addressing concerns

that treatment success rates with PEG-IFN/RBV are too low and that treatment is too

complex and produces troublesome side effects [Cooper et al, 2009], while outcomes in

patients with HIV/HCV co-infection are poor [Operskalski and Kovacs, 2011]. A 2012

systematic review and meta-analysis of treatment outcomes in a large number of

HCV-infected patients in low- and middle-income countries showed that rates of

treatment success with PEG-IFN/RBV were similar to those reported in high-income

countries. The meta-analysis also suggested that the availability of new DAAs “will be

particularly useful in resource-limited settings where the disease burden is greatest”

[Ford et al, 2012].



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Evidence that HCV-infected persons in resource-limited settings have treatment success

rates similar to those in developed countries provides a solid foundation for increasing

efforts to improve access to HCV treatment in low- and middle-income countries, as well

as providing a rationale for the inclusion of Harvoni® on the WHO Model List of Essential

Medicines.

8.2 Assessment of current use

In the USA, Harvoni® is indicated for use as a treatment for chronic HCV GT 1 infection

in adult patients (≥18 years), as illustrated in Table 3; Harvoni® is not presently

recommended for patients aged <18 years because its safety and efficacy in children

and adolescents (<18 years) have not yet been established [Harvoni® US PI, 2014].

In Europe, Harvoni® is also indicated for the treatment of chronic HCV GT 4 infection

and some GT 3 adult patients (Table 4) [Harvoni® SmPC, 2014; Gilead Press Release,

2014]. Countries in which Harvoni® is currently licensed for use are detailed in

Section 13.

Table 3. Recommended treatment duration for Harvoni® in patients with chronic HCV GT 1 infection [Harvoni® US PI, 2014]

Patient population Duration

Treatment-naïve patients with or without cirrhosis 12 weeks*

Treatment-experienced patients** without cirrhosis 12 weeks

Treatment-experienced patients** with cirrhosis 24 weeks *Harvoni® for 8 weeks can be considered in treatment-naïve patients without cirrhosis who have

pre-treatment HCV RNA of <6 million IU/mL

**Treatment-experienced patients who have failed treatment with either PEG-IFN and RBV

or an HCV PI + PEG-IFN + RBV



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Table 4. Recommended treatment duration for Harvoni® and the recommended use of co-administered ribavirin in patients with chronic HCV infection [Harvoni® SmPC, 2014]

Patient population* Treatment Duration

Patients with HCV GT 1 or GT 4

Patients without cirrhosis Harvoni® 12 weeks

– 8 weeks may be considered

in previously untreated GT 1-

infected patients

– 24 weeks should be considered

for previously treated patients

with uncertain subsequent

retreatment options

Patients with compensated

cirrhosis

Harvoni® 24 weeks

– 12 weeks may be considered

for patients deemed at low risk

for clinical disease progression

and who have subsequent

retreatment options

Patients with

decompensated cirrhosis or

who are pre-/post-liver

transplant

Harvoni® +

ribavirin

24 weeks

Patients with HCV GT 3

Patients with cirrhosis

and/or prior treatment failure

Harvoni® +

ribavirin

24 weeks

*Includes patients co-infected with HIV

Harvoni® was approved on October 10, 2014 by the US Food and Drug Administration

(FDA) for the treatment of chronic HCV GT 1 in adult patients [FDA News Release,

2014], and international treatment guidelines have not yet been updated to reflect this

addition to the treatment armamentarium. Harvoni® represents the first oral,



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short-duration combination therapy to be approved for the treatment of HCV GT 1

infection and the first approved regimen that does not require administration with either

PEG-IFN or RBV [FDA News Release, 2014]. As such, it may help to shorten and

simplify treatment regimens; reduce the incidences of AEs and drug–drug interactions;

decrease monitoring requirements; and widen patient eligibility for treatment. Edward

Cox, Director of the Office of Antimicrobial Products in the FDA’s Center for Drug

Evaluation and Research has stated, “We are changing the treatment paradigm…

Until last year, the only available treatments for hepatitis C virus required administration

with interferon and ribavirin. Now, patients and healthcare professionals have multiple

treatment options, including a combination pill to help simplify treatment regimens”

[FDA News Release, 2014]. Approval for the use of Harvoni® in Europe followed on

November 18, 2014, after the European Commission granted marketing authorization

for Harvoni® to treat the majority of chronic HCV G1 and GT 4 infections in adults

[Gilead Press Release, 2014]. As Harvoni®, like SOF, was reviewed under the FDA’s

and European Medicine Agency’s priority review programs and received breakthrough

therapy designation, it seems likely that international treatment guidelines will be revised

rapidly to reflect its availability, as they were with SOF.

Guidelines issued by a number of international associations continue to recommend

PEG-IFN/RBV as standard of care, with the addition of boceprevir or telaprevir as part of

a triple-therapy regimen, for patients with HCV GT 1. However, further revisions in line

with those from the American Association for the Study of Liver Diseases (AASLD), the

European Association for the Study of Liver Diseases (EASL) and the World Health

Organization (WHO), and following the US approval of Harvoni®, are anticipated. As the

new generation of DAAs gain wider international approval, updates can be expected

from the Asian Pacific Association for the Study of the Liver (APASL; guidance last

updated 2012) and the World Gastroenterology Organisation (WGO; guidance last

updated 2013), both of which focus on the needs of patients living in developing

countries.



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8.3 Target population

Harvoni® is suitable for the treatment of chronic HCV GT 1 infection in a wide range of

patient subgroups, regardless of race or gender, including geriatric patients; patients

with mild or moderate renal impairment; and post-liver transplant patients. Harvoni® has

also been approved for use in GT 4 patients and some GT 3 patients in Europe

[Harvoni® SmPC, 2014; Gilead Press Release, 2014]. The safety and efficacy of

Harvoni® have not been established in children and adolescents, pregnant women or

nursing mothers [Harvoni® US PI, 2014].

9. Treatment details

9.1 Indications and usage

Harvoni® is indicated for the treatment of chronic HCV GT 1 infection in adult patients

(aged ≥18 years) (Table 3) [Harvoni® US PI, 2014]. In Europe, Harvoni® is also indicated

for the treatment of adult patients with chronic HCV GT 4 infection and some GT 3

patients (Table 4) [Harvoni® SmPC, 2014; Gilead Press Release, 2014].

9.2 Dosage and administration

The recommended dose of Harvoni® in adult US patients with HCV GT 1 is one tablet

(90 mg of LDV and 400 mg of SOF) taken orally, once daily with or without food for the

duration shown in Table 3, depending on patient characteristics [Harvoni® US PI, 2014].

In Europe, once-daily Harvoni® is recommended as a monotherapy for the treatment of

patients with HCV GT 1 or GT 4 infection with compensated cirrhosis or without

cirrhosis; HCV GT 4 patients with decompensated cirrhosis or who are pre-/post-liver

transplant and HCV GT 3 patients with cirrhosis and/or prior treatment failure should

receive Harvoni® in combination with ribavirin (Table 4) [Harvoni® SmPC, 2014].

As Harvoni® contains LDV and SOF, any interactions that have been identified with

these agents individually may occur with Harvoni®. The concomitant use of Harvoni® and

P-glycoprotein (P-gp) inducers, such as rifampin or St John’s wort, may significantly

decrease plasma concentrations of LDV and SOF, thus potentially reducing the

therapeutic effect of Harvoni®; therefore, the use of Harvoni® is not recommended in



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combination with P-gp inducers. The use of Harvoni® in combination with other products

containing SOF is also not recommended. It is noteworthy that Harvoni® does not

demonstrate significant drug interactions with immunosuppressant drugs or ART,

other than tenofovir disoproxil fumarate, and thus offers an additional treatment choice

for patient populations for whom therapeutic options have always been limited [Harvoni®

US PI, 2014]. The reader is referred to Section 11.2.5 ‘Drug interactions’ and Table 17

for more detailed information on potential drug interactions associated with Harvoni®.

No specific antidote is available for overdose with Harvoni®. If overdose occurs, the

patient must be monitored for evidence of toxicity. Treatment for overdose consists of

general supportive measures, including monitoring of vital signs and observation of the

patient’s clinical status. Hemodialysis can remove the predominant circulating metabolite

of SOF (GS-331007) with an extraction ratio of 53% but is unlikely to result in significant

removal of LDV as LDV is highly bound to plasma protein [Harvoni® US PI, 2014].

9.2.1 Special populations

Pregnancy Category B: Harvoni® should be used during pregnancy only if the potential

benefit justifies the potential risk to the fetus [Harvoni® US PI, 2014].

Nursing mothers: It is not known whether Harvoni® and its metabolites are present in

human breast milk. The health benefits of breastfeeding should be considered alongside

the mother’s clinical need for Harvoni® and any potential adverse effects on the child

from the drug or the mother’s condition [Harvoni® US PI, 2014].

Pediatric use: The safety and efficacy of Harvoni® have not been established in children

and adolescents [Harvoni® US PI, 2014].

Geriatric use: No dose adjustment is warranted for elderly patients [Harvoni® US PI,

2014].



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Renal impairment: No dose adjustment of Harvoni® is required for patients with mild or

moderate renal impairment. The safety and efficacy of Harvoni® have not been

established in patients with severe renal impairment (estimated glomerular filtration rate

[eGFR] <30 mL/min/1.73 m2) or end-stage renal disease (ESRD) requiring hemodialysis.

Therefore, no dose recommendation can be given for these patient populations

[Harvoni® US PI, 2014].

Hepatic impairment: No dose adjustment of Harvoni® is required for patients with mild,

moderate or severe hepatic impairment (Child–Pugh–Turcotte [CPT] class A, B or C).

The safety and efficacy of Harvoni® have not been established in patients with

decompensated cirrhosis [Harvoni® US PI, 2014].

9.3 Duration

Harvoni® should be administered once daily for a duration of 12 or 24 weeks, according

to the presence or absence of cirrhosis and the patient’s treatment experience.

Administration of Harvoni® for 8 weeks can be considered in treatment-naïve patients

without cirrhosis who have pre-treatment HCV RNA of <6 million IU/mL (Table 3)

[Harvoni® US PI, 2014].

9.4 Reference to existing WHO and other clinical guidelines

The WHO issued its first set of guidelines on the treatment of HCV infection in April

2014, with the recommendation that all adults and children with chronic HCV infection,

including persons who inject drugs (PWID), should be assessed for HCV therapy [WHO

Guidelines, 2014]. With respect to the choice of treatment, the WHO recommendations

are as follows:

• PEG-IFN/RBV is recommended for the treatment of chronic HCV, rather than

non-pegylated IFN/RBV (strong recommendation, moderate quality of evidence)

• PI-based (boceprevir or telaprevir) triple therapy is suggested for chronic HCV

GT 1, rather than PEG-IFN/RBV alone (conditional recommendation, moderate

quality of evidence)



21

• SOF, in combination with RBV, with or without PEG-IFN depending on genotype,

is recommended for HCV GT 1, GT 2, GT 3 and GT 4, rather than PEG-IFN/RBV

alone or no treatment in those who are intolerant to IFN (strong recommendation,

high quality evidence)

• Simeprevir, in combination with PEG-IFN/RBV, is recommended for patients with

HCV GT 1b infection and for those with HCV GT 1a without the Q80K

polymorphism, rather than PEG-IFN/RBV alone (strong recommendation, high

quality evidence).

Evidence-based guidelines have also been issued by a number of internationally

recognized bodies, including the AASLD, the Infectious Diseases Society of America

(IDSA) and the International Antiviral Society-USA (IAS-USA) [AASLD Guidelines, 2014],

as well as EASL [EASL Guidelines, 2014a] and WGO [WGO Guidelines, 2013].

While both US and European guidelines include next-generation DAAs, such as SOF,

in line with WHO recommendations, the APASL and WGO currently recommend

PEG-IFN/RBV as standard therapy for chronic HCV, with the addition of boceprevir or

telaprevir as part of a triple-therapy regimen for patients with HCV GT 1 [WGO

Guidelines, 2013]. Additionally, the WGO suggests how therapy might be modified for

specific regions and in countries where resources are very limited.

As Harvoni® has only been approved recently by the US FDA and EMA, it is not currently

included in international management guidelines for HCV. However, it seems likely that

the guidelines will be updated rapidly to include Harvoni®, reflecting its breakthrough

therapy designation by the FDA. Section 8.2, ‘Assessment of current use’, provides

further information about international guidelines for the management of HCV.

9.5 Special requirements

Treatment with Harvoni® should be initiated and monitored by a physician experienced in

the management of patients with chronic hepatitis C.



22

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

10.1 Identification of clinical evidence

In compiling evidence for this submission, a search of the Medline® database was

performed using the search criteria: ledipasvir [AND] sofosbuvir. A search of abstracts

from relevant congresses over the past 2 years was also performed using the same

search criteria. In addition, review articles on new DAAs, including Harvoni®, were

identified and the reference lists of these examined for any further articles of relevance.

The use of Harvoni® is supported principally by data from three Phase 3 studies (ION-1,

ION-2 and ION-3) [Afdhal et al, 2014b and 2014c; Kowdley et al, 2014], following

successful completion of a Phase 2 clinical program that comprised several studies in

HCV treatment-naïve and treatment-experienced patients (see Table 5) [Data on file –

Gilead Sciences EAME – (HCV13000050); Lawitz et al, 2014; Data on file – Gilead


(HCV1300045); Data on file – Gilead Sciences EAME – (HCV1300044)]. The Phase 2

program continues to be reinforced by additional studies and analyses in traditionally

difficult-to-treat patient populations, including SIRIUS (PI failures), SOLAR-1

(decompensated cirrhosis and post-liver transplantation) and the LDV/SOF in

Compensated Cirrhosis post-hoc analysis (Table 5) [Data on file – Gilead Sciences

EAME – (HCV13000113); Data on file – Gilead Sciences EAME – (HCV13000101); Data

on file – Gilead Sciences EAME – (HCV13000116); Data on file – Gilead Sciences

EAME – (HCV13000100)]. Some of the analyses from the Phase 2 studies and most

results from the Phase 3 clinical program have been published in international, peer-

reviewed journals.

10.2 Summary of available data on comparative effectiveness of Harvoni®

This section will focus primarily on the outcomes of the Phase 3 clinical trials that have

formed the basis of the regulatory submissions for Harvoni®. The extensive Phase 2

clinical program that has also been undertaken for Harvoni® is overviewed in Table 5.



23

10.2.1 Summary of the Phase 2 clinical trial program for Harvoni®

The Phase 2 clinical trial program for Harvoni® has evaluated this regimen in patients

with HCV GT 1, GT 3, GT 4 and GT 6 infection, and is ongoing.

The Phase 2 studies in GT 1 patients (LONESTAR, ELECTRON, ELECTRON-2,

SIRIUS, ERADICATE, LDV/SOF in SOF failures) demonstrated that administration of

LDV/SOF for 8, 12 or 24 weeks, with or without RBV, resulted in high rates of SVR12 in

a diverse range of patients, including those with difficult-to-treat characteristics, for

example, with HCV recurrence following liver transplantation [Lawitz et al, 2014; Data on

file – Gilead Sciences EAME – (HCV1300047); Data on file – Gilead Sciences EAME –

(HCV13000050); Data on file – Gilead Sciences EAME – (HCV1300045); Data on file –


(HCV13000103); Data on file – Gilead Sciences EAME – (HCV1300097)]. Of note,

patients who had relapsed following treatment with SOF-based regimens were

successfully retreated with LDV/SOF [Data on file – Gilead Sciences EAME –

(HCV1300031)].

Several Phase 2 studies have investigated the efficacy and tolerability of LDV/SOF in

patients with non-GT 1 HCV infections, and a number of these studies are ongoing.

ELECTRON-2 evaluated LDV/SOF in treatment-naïve and treatment-experienced GT 3

patients and GT 6 patients [Data on file – Gilead Sciences EAME – (HCV1300045); Data

on file – Gilead Sciences EAME – (HCV13000114], whilst patients with HCV GT 4

infection have been enrolled in the ongoing SYNERGY and SOLAR-1 studies [Data on


(HCV13000101)]. Results of the Phase 2 studies of LDV/SOF in patients with genotypes

other than GT 1 are discussed in Section 10.2.6.

Resistance monitoring was performed for all patients in the LONESTAR study in order to

detect treatment-emergent RAVs [Lawitz et al, 2014]. Virologic failure and resistance

analysis, including findings from the Phase 2 LONESTAR study, are discussed more

fully in Section 10.2.4 of this document.

The results from some of the studies in the extensive Phase 2 clinical program guided

the development of the Phase 3 studies described in the next section, and provide



24

preliminary evidence for the efficacy of Harvoni® in patients with HCV genotypes other

than GT 1.



25

Table 5. Overview and key efficacy results for the Phase 2 studies of Harvoni® in HCV [Data on file – Gilead Sciences EAME – (HCV13000050); Lawitz et al, 2014; Data on file – Gilead Sciences EAME – (HCV1300046); Data on file – Gilead Sciences EAME – (HCV1300045); Data on file – Gilead Sciences EAME – (HCV13000114); Data on file – Gilead Sciences EAME – (HCV1300097); Data on file – Gilead Sciences EAME – (HCV13000100); Data on file – Gilead Sciences EAME – (HCV13000113); Data on file – Gilead Sciences EAME – (HCV13000116); Data on file – Gilead Sciences EAME – (HCV13000103)]

Study Treatment and

duration Population Key findings

HCV mono-infection

ELECTRON: Multiple-arm trial that represented

proof-of-concept study for safety and

efficacy of Harvoni® in non-cirrhotic,

treatment-naïve patients with HCV GT 1

LDV/SOF + RBV,

12 weeks

GT 1 treatment-naïve, non-cirrhotic • SVR12 in 100% of patients

1 previous null responder, non-cirrhotic • SVR12 in 100% of patients

LONESTAR: Initial Phase 2 study of safety and

efficacy of Harvoni® in non-cirrhotic,

treatment-naïve and -experienced

patients with HCV GT 1

.

LDV/SOF,

8 weeks


LDV/SOF + RBV,

8 weeks


LDV/SOF,

12 weeks


GT 1 treatment-experienced

(PI failures) • SVR12 in 95% of patients; 91% in

cirrhotic and 100% in non-cirrhotic



26

patients

LDV/SOF + RBV,

12 weeks

GT 1 treatment-experienced

(PI failures) • SVR12 in 100% of patients,

including both cirrhotic and non-

cirrhotic patients

SYNERGY*: Investigator-initiated study conducted by

NIH NIAID/CC. Included predominantly

African-American GT 1 patients with

non-CC IL28B genotype

LDV/SOF,

12 weeks

GT 1 prior SOF + RBV relapsers • SVR12 in 100% of patients

GT 4 treatment-naïve or -experienced • SVR12* in 95% of patients

ELECTRON-2: Studied safety and efficacy of Harvoni®

in difficult-to-treat populations:

1) GT 1 patients who had not achieved

an SVR with prior SOF + RBV in

ELECTRON

2) GT 1 patients with decompensated

cirrhosis

3) Treatment-naïve and

-experienced GT 3 patients with or

without cirrhosis

4) Treatment-naïve and

-experienced GT 6 patients

LDV/SOF,

12 weeks

GT 1 decompensated cirrhosis (CTP B) • SVR12 in 65% of patients

GT 3 treatment-naïve • SVR12 in 64% of patients

GT 6 treatment-naïve or -experienced • SVR12 in 96% of patients

LDV/SOF + RBV,

12 weeks

GT 1 prior SOF exposure • SVR12 in 100% of patients

GT 3 treatment-naïve • SVR12 in 100% of patients

GT 3 treatment-experienced • SVR12 in 82% of patients; 73% in

cirrhotic and 89% in non-cirrhotic

patients



27

LDV/SOF in SOF failures: Studied use of Harvoni®-based regimens

in patients with prior SOF treatment

failure

LDV/SOF + RBV,

12 weeks

GT 1 prior SOF exposure • SVR12 in 98% of patients

LDV/SOF in compensated cirrhosis: Retrospective analysis of study data for

Harvoni® in treatment-naïve and -

experienced patients with compensated

cirrhosis

LDV/SOF + RBV,

8 weeks

GT 1 treatment-naïve/treatment-

experienced • SVR12 in 89% of patients

SIRIUS: Assessed Harvoni® in patients with

compensated cirrhosis who had failed

prior PI therapy

LDV/SOF + RBV,

12 weeks

GT 1 treatment-experienced (prior PEG-

IFN/RBV and PI treatment failures) with

compensated cirrhosis

• SVR12 in 96% of patients

LDV/SOF + RBV,

24 weeks

GT 1 treatment-experienced (prior PEG-

IFN/RBV and PI treatment failures) with

compensated cirrhosis

• SVR12 in 97% of patients

SOLAR-1*: Evaluated Harvoni® in patients with

decompensated cirrhosis

LDV/SOF + RBV,

12 weeks

GT 1 or GT 4 treatment-naïve/treatment-

experienced with decompensated

cirrhosis

• SVR12 in 87% of patients;

87% in CTP B and 86% in CTP C

patients

LDV/SOF + RBV,

24 weeks

GT 1 or GT 4 treatment-naïve/treatment-

experienced with decompensated

cirrhosis

• SVR12 in 89% of patients; 89% in

CTP B and 90% in CTP C patients



28

HIV/HCV co-infection

ERADICATE:

Investigator-initiated study conducted by

NIAID/CC that investigated Harvoni® in

HIV/HCV co-infected patients and

included ARV treatment-naïve and

-experienced patients

LDV/SOF,

12 weeks

GT 1 HIV/HCV ARV-untreated • SVR12 in 100% of patients

GT 1 HIV/HCV ARV-treated • SVR12 in 97% of patients

Special populations

SOLAR-1*: Evaluated Harvoni® in patients with

recurrent HCV infection post-liver

transplantation

LDV/SOF + RBV,

12 weeks

GT 1 or GT 4 patients, post-liver

transplant, non-cirrhotic (F0–F3) • SVR12 in 96% of patients


transplant, cirrhotic (CTP A, B or C) • SVR12 in 96% in CTP A, 85% in


LDV/SOF + RBV,

24 weeks


transplant, non-cirrhotic (F0–F3) • SVR12 in 98% of patients


transplant, cirrhotic (CTP A, B or C) • SVR12 in 96% in CTP A, 83% in


ART, antiretroviral therapy; CTP, Child–Turcotte–Pugh; GT, genotype; HCV, hepatitis C virus; HIV, human immunodeficiency virus; LDV, ledipasvir;

LLOQ, lower limit of quantification; NIAID, National Institute of Allergy and Infectious Diseases; NIH, National Institutes of Health; PEG-IFN, pegylated interferon;

PI, protease inhibitor; RBV, ribavirin; SOF, sofosbuvir; SVR, sustained virologic response

*Study ongoing



29

10.2.2 Background and design of the Phase 3 studies of Harvoni® in HCV GT 1

The efficacy of Harvoni® was evaluated in four Phase 3 studies (ION-1, ION-2, ION-3,

Japanese study) in a total of 2293 patients with HCV GT 1 infection [Afdhal et al, 2014b

and 2014c; Kowdley et al, 2014; Data on file – Gilead Sciences EAME – (HCV1300057);

Data on file – Gilead Sciences EAME – (HCV13000104)].

ION-1, ION-2 and ION-3 were randomized, open-label, multicenter studies that

evaluated Harvoni®, with or without RBV, for 8, 12 or 24 weeks in patients with HCV

GT 1 infection. The Japanese study was a randomized, multicenter, Phase 3 study of

12 weeks of Harvoni®, with or without RBV, in 341 treatment-naïve and treatment-

experienced Japanese patients with HCV GT 1 infection.

The primary efficacy endpoint in all four studies was SVR12 (HCV RNA below the lower

limit of quantification [25 IU/mL] 12 weeks after the end of treatment); in ION-1, ION-3

and the Japanese study, data were compared with a prespecified historical SVR rate.

All four studies investigated safety and tolerability, virologic failure and viral resistance

associated with Harvoni® therapy. The designs of the four studies are shown in Figure 1.



30

Figure 1. Designs of the Phase 3 studies of Harvoni® in treatment-naïve and treatment-experienced patients with HCV GT 1 [Afdhal et al, 2014b and 2014c; Kowdley et al, 2014; Data on file – Gilead Sciences EAME – (HCV1300057)]

GT, genotype; HCV, hepatitis C virus; LDV, ledipasvir; RBV, ribavirin; SOF, sofosbuvir;

SVR, sustained virologic response

Specific and general inclusion and exclusion criteria for the ION studies are shown in

Table 6. As the table shows, the ION-1 and ION-2 studies enrolled a high proportion of

patients with cirrhosis, thus providing a strong evidence base for the use of Harvoni® in

this important patient population.



31

Table 6. Key inclusion and exclusion criteria in the Phase 3 ION studies of Harvoni® [Afdhal et al, 2014b and 2014c; Kowdley et al, 2014]

ION-1 ION-2 ION-3

Specific inclusion criteria

Treatment-naïve:

no prior treatment

with RBV or IFN

Prior treatment

failure with

IFN-based therapy

(including

PI failures)

Treatment-naïve:

no prior treatment

with RBV or IFN

Cirrhosis permitted?

Up to 20% 20% Not permitted

General inclusion criteria

≥18 years of age; confirmation of chronic hepatitis C by positive

anti-HCV, positive HCV RNA or positive HCV genotyping

≥6 months prior to baseline or liver biopsy with evidence of

chronic hepatitis C; serum HCV RNA ≥104 IU/mL during

screening; BMI ≥18 kg/m2 (no upper limit to age or BMI)

Exclusion criteria Co-infection with HBV or HIV; any other clinically significant

chronic liver disease; clinical hepatic decompensation; history of

major organ transplant; clinically relevant drug or alcohol abuse

Women who were pregnant or breastfeeding or men whose

partners were pregnant

BMI, body mass index; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus;

IFN, interferon; PI, protease inhibitor; RBV, ribavirin

10.2.3 Results of the Phase 3 registration studies of Harvoni® in mono-infected

patients with HCV GT 1

Efficacy in treatment-naïve patients: ION-1 (ClinicalTrials.gov: NCT01701401)

Of the patients enrolled in ION-1, approximately two-thirds (67%) were infected with

HCV GT 1a. The mean age of patients across the treatment arms was 52 years;

59% were male, the majority (85%) were white, and mean body mass index (BMI) was

27 kg/m2. The study included a high proportion of patients with traditional negative



32

predictors of response to IFN-based therapy: 77‒80% had a high baseline viral load

(HCV RNA ≥800,000 IU/mL); and 16% had cirrhosis. In addition, more than 70% of

patients had a non-CC IL28B genotype. Overall, 8% of patients were considered by the

investigators to be ineligible for IFN-based therapy [Afdhal et al, 2014b].

Treatment with Harvoni®, with or without RBV, resulted in a rapid decline in HCV RNA

levels. Overall, ≥99% of patients achieved a rapid virologic response (RVR) and a

response at Week 12 of treatment. SVR12 was achieved by 97‒99% of patients across

all treatment arms (Table 7), which was significantly superior to the historical control rate

in all groups (P<0.001 for all comparisons) [Afdhal et al, 2014b].

Table 7. Summary of SVR12 rates with Harvoni® treatment in the ION-1 study [Afdhal et al, 2014b]

Treatment Efficacy endpoint: SVR12

Overall* Cirrhosis*

Harvoni®, 12 weeks 99% GT 1a 99%¥

GT 1b 100%

97%¥

Harvoni® + RBV, 12 weeks 97% GT 1a 100%¥

GT 1b 100%¥

100%

Harvoni®, 24 weeks 98% GT 1a 100%¥

GT 1b 97%¥

97%

Harvoni® + RBV, 24 weeks 99% GT 1a 100%¥

GT 1b 100%

100%

GT, genotype; RBV, ribavirin; SVR, sustained virologic response

*Subgroup results do not include patients who withdrew consent (n=3) or were lost to follow-up (n=10),

whilst these data are included in the overall results; hence, the subgroup results are, in some cases, higher

than those for the populations overall. ¥Numbers shown in blue indicate where data from the ION-1 publication differ from those in the US



33

Prescribing Information. These discrepancies have arisen as a result of patient reclassification, a lack of

available data at the appropriate time point or incorrectly captured genotype in the interim data.

Of the 16 patients who failed to achieve an SVR12 in ION-1, 13 were lost to follow-up

or withdrew consent. One patient who received 24 weeks of Harvoni® had virologic

breakthrough during treatment, which was suspected to be due to non-adherence to

therapy (documented by means of serum assays for drug levels). Only two patients

(<1%) relapsed post-treatment (one each in the Harvoni®12-week and 24-week arms);

both had NS5A resistance variants at baseline [Afdhal et al, 2014b].

Very high response rates were seen in all patient subgroups in ION-1, including patients

with characteristics historically associated with a poor response to treatment; these

patients demonstrated response rates similar to those among patients without these

characteristics (Figure 2) [Afdhal et al, 2014b].



34

Figure 2. SVR12 rates in the ION-1 study of Harvoni® according to prespecified subgroups [Afdhal et al, 2014b]

ALT, alanine aminotransferase; BMI, body mass index; GT, genotype; HCV, hepatitis C virus;

LDV, ledipasvir; RBV, ribavirin; SOF, sofosbuvir; SVR, sustained virologic response;

ULN, upper limit of normal

Thus, ION-1 demonstrated high response rates in treatment-naïve patients with cirrhosis

after 12 weeks of treatment with Harvoni®, including patients with difficult-to-treat

characteristics and those with negative predictors of response to IFN-based therapy.

The addition of RBV to the treatment regimen or extending the duration of treatment to

24 weeks did not increase SVR12.



35

Efficacy in treatment-naïve patients without cirrhosis: ION-3

(ClinicalTrials.gov: NCT01851330)

In the ION-3 study, 80% of enrolled patients had HCV GT 1a infection, 19% were Black,

and 6% were Hispanic, reflecting the population of patients with HCV infection in the

USA. Approximately three-quarters of the patients had a non-CC IL28B genotype and an

estimated 6% were considered to be IFN-ineligible by the study investigators [Kowdley

et al, 2014].


levels, with all but two patients (both in the Harvoni® + RBV arm) achieving an RVR;

≥93% of patients achieved an SVR12 (Table 8) [Kowdley et al, 2014]. Of note, a

non-inferiority analysis demonstrated that the response rate in patients treated with

Harvoni® for 8 weeks was non-inferior to that in patients treated for a longer duration in

the other two groups, supporting the feasibility of a shorter treatment regimen.

Table 8. Summary of SVR12 rates with Harvoni® treatment in the ION-3 study [Kowdley et al, 2014]


Harvoni®, 8 weeks 94% GT 1a 93%

GT 1b 98%

Harvoni®+ RBV, 8 weeks 93% GT 1a 92%

GT 1b 96%¥

Harvoni®, 12 weeks 95%¥ GT 1a 95%¥

GT 1b 98% GT, genotype; RBV, ribavirin; SVR, sustained virologic response ¥Numbers shown in blue indicate where data from the ION-3 publication differ from those in the US

Prescribing Information. These discrepancies have arisen as a result of patient reclassification, a lack of

available data at the appropriate time point or incorrectly captured genotype in the interim data.



36

None of the 647 patients treated in ION-3 experienced virologic breakthrough whilst on

therapy. Overall, 23 patients (4%) had a virologic relapse after the end of therapy:

11 patients (5%) who received Harvoni® for 8 weeks, nine (4%) who received Harvoni® +

RBV for 8 weeks, and three (1%) in the 12-week group. In general, similarly high SVR

rates were observed in all prespecified patient subgroups as in the overall population in

ION-3 (Figure 3) [Kowdley et al, 2014].

Figure 3. Rates of SVR12 with Harvoni® in ION-3 according to patient subgroup [Kowdley et al, 2014]

ALT, alanine aminotransferase; BMI, body mass index; GT, genotype; HCV, hepatitis C virus;

IFN, interferon; LDV, ledipasvir; RBV, ribavirin; SOF, sofosbuvir; SVR, sustained virologic response;

ULN, upper limit of normal



37

Patients with characteristics historically associated with a poor response to IFN-based

treatment (e.g. non-CC IL28B genotype, high viral load at baseline, Black race, HCV

GT 1a infection) demonstrated SVR12 rates that were similar to those among patients

without these characteristics. For example, in the patient cohort receiving 8 weeks of

Harvoni® without RBV, response rates in all subgroups ranged from 89% to 100%,

irrespective of NS5A mutations or HCV RNA levels at baseline. Patients with baseline

HCV RNA <800,000 IU/mL achieved SVR12 rates of 95.5–97.1%, depending on

treatment regimen, with corresponding rates in patients with high baseline HCV RNA

of 92.4–95.3% [Kowdley et al, 2014].

Thus, in ION-3, Harvoni® therapy was associated with a high SVR12 rate in

treatment-naïve patents without cirrhosis, including those with typically hard-to-treat

characteristics. As in ION-1, the co-administration of RBV or the extension of treatment

did not substantially increase SVR12, supporting a short, simplified treatment regimen.

Efficacy in treatment-experienced patients: ION-2 (ClinicalTrials.gov: NCT01768286)

The majority of patients (79%) in the ION-2 study had HCV GT 1a infection. The mean

age of patients across the treatment arms was 55‒57 years; 65% were male; the

majority (81%) were White; and mean BMI was 28 kg/m2. As expected in a population of

patients who had not responded to prior IFN-based therapy, most patients (88%) had the

non-CC IL28B genotype. A total of 20% of patients in each of the four treatment groups

had cirrhosis. Across the treatment arms, 41‒46% were prior non-responders to

PEG-IFN/RBV therapy, with or without PIs. Overall, 52% of the enrolled patients had

failed prior treatment with a PI-based regimen [Afdhal et al, 2014c].


levels, with ≥99% of patients in all groups in ION-2 achieving an RVR and end of

treatment response and ≥94% of patients achieving SVR12 (Table 9). Response rates

were similar between cirrhotic and non-cirrhotic patients treated for 24 weeks with

Harvoni®, with or without RBV. In general, SVR12 rates were lower in cirrhotic patients

treated for 12 weeks than those treated for 24 weeks (P=0.007). However, ION-2 was

not powered for intergroup comparisons, and no baseline or on-treatment indicators



38

could be identified that might predict which cirrhotic patients were most likely to benefit

from 24 weeks and which 12 weeks of treatment [Afdhal et al, 2014c].

Table 9. Summary of SVR12 rates with Harvoni® therapy in the ION-2 study

[Afdhal et al, 2014c]


Overall Cirrhosis


GT 1b 87%

86%

Harvoni® + RBV, 12 weeks 96% GT 1a 96%

GT 1b 100%

82%


GT 1b 100%

100%

Harvoni® + RBV, 24 weeks 99% GT 1a 99%

GT 1b 100%

100%

GT, genotype; RBV, ribavirin; SVR, sustained virologic response.

Only one patient in ION-2 (in the 24-week Harvoni® + RBV group) experienced

on-treatment virologic breakthrough; however, this patient was thought not to have

adhered to the study treatment, as indicated by plasma concentrations of LDV and

GS-221007 (the predominant circulating metabolite of SOF) that were below or near the

lower level of quantification at Weeks 2, 4 and 6 during treatment. Overall, 11 patients

(2%) relapsed post-treatment, seven (6%) in the 12-week Harvoni® group and four (4%)

in the 12-week Harvoni® + RBV group [Afdhal et al, 2014c].

In all treatment arms, response rates were similar among patients with HCV GT 1a

infection and those with HCV GT 1b infection, among patients who had previously



39

received PEG-IFN + RBV and those who had previously received a PI-based regimen,

and among patients with no response to prior treatment and those with prior virologic

breakthrough or relapse (Figure 4). RBV had no effect on response rates, regardless of

treatment duration, and nor did baseline NS5A mutations; 14% of patients had NS5A

RAVs at baseline and 89% of these patients achieved SVR12 [Afdhal et al, 2014c].

Figure 4. Rates of SVR12 with Harvoni® therapy, according to subgroup, in the ION-2 study [Afdhal et al, 2014c]

GT, genotype; HCV, hepatitis C virus; LDV, ledipasvir; PI, protease inhibitor; PEG-IFN, pegylated interferon;

RBV, ribavirin; SOF, sofosbuvir; SVR, sustained virologic response



40

The ION-2 study demonstrated similarly high response rates with Harvoni® therapy

across a wide range of treatment-experienced patient subgroups, including those with

difficult-to-treat characteristics, reflecting the broad applicability of Harvoni® also

demonstrated in the ION-1 and ION-3 studies.

Efficacy in Japanese patients: Japanese Phase 3 study

(ClinicalTrials.gov: NCT01975675)

In the Japanese Phase 3 study, the mean age of treated patients was 59 years and

42% were male; all patients were infected with HCV GT 1 (97% GT 1b) and 22% were

cirrhotic [Data on file – Gilead Sciences EAME – (HCV1300057); Data on file – Gilead

Sciences EAME – (HCV13000104)].

Overall, Harvoni®, with or without RBV, resulted in an SVR12 rate of 98% in GT 1

treatment-naïve patients; SVR12 rates of 96% and 100% were demonstrated with

Harvoni®, with and without RBV, respectively. All treatment-experienced patients

achieved SVR12, irrespective of the inclusion of RBV in the treatment regimen or prior

therapy. The study met its primary endpoint of superiority compared with a predefined

historical SVR rate; only one cirrhotic patient did not achieve SVR12. Of note, 99% of

patients (75/76) with RAVs at baseline achieved SVR12, including a small number of

patients with multiple RAVs [Data on file – Gilead Sciences EAME – (HCV1300057);

Data on file – Gilead Sciences EAME – (HCV13000104)]. Thus, the study demonstrated

that Harvoni® therapy was associated with very high response rates in Japanese

patients with HCV GT 1 infection, including those with cirrhosis, prior treatment failure

and RAVs. These results are noteworthy because the high cure rates were achieved

without the need for IFN or RBV, and thus without the substantial side effects associated

with those therapies.

10.2.4 Virologic failure and resistance analysis in the clinical studies

The potential for the development of viral mutations that are resistant to treatment with

DAAs is an important consideration in patients receiving antiviral therapy for HCV

infection, and has been a limiting factor associated with the use of other drugs in this



41

class. Importantly, studies have shown that SOF has a high genetic barrier to resistance

[Data on file – Gilead Sciences EAME – (HCV1300023)], whilst NS5A mutations that are

resistant to LDV remain susceptible to SOF, thus indicating a lack of cross-resistance

between the two agents [Wong et al, 2013]. The non-overlapping resistance profiles of

SOF and LDV support their combined use in the treatment of HCV.

Resistance monitoring was performed for all patients in the Phase 2 LONESTAR study

in order to detect treatment-emergent RAVs [Lawitz et al, 2014]. At baseline, NS3 PI

RAVs were detected by deep sequencing in 33/100 patients and NS5A RAVs were

detected in 9/100 patients. All of the patients with NS3 RAVs and 7/9 patients with NS5A

RAVs achieved SVR12 with Harvoni®, with or without RBV; only two patients, one

treatment-naïve and one treatment-experienced, experienced post-treatment virologic

relapse. The high rate of SVR12 in patients with baseline RAVs suggested that the

presence of variants did not preclude the possibility to achieve SVR12 or predict

virologic failure [Lawitz et al, 2014].

Resistance monitoring in the Phase 3 studies

Population and/or deep sequencing of the NS5A and NS5B regions of HCV RNA were

performed for all patients at baseline in the ION studies. For those patients who

experienced virologic failure, sequences obtained at the time of failure were compared

with baseline samples and references in order to detect any treatment-emergent RAVs

[Afdhal et al, 2014b and 2014c; Kowdley et al, 2014].

Results of resistance monitoring in treatment-naïve patients

A pooled analysis of data from the ION studies demonstrated that 16% of patients had

baseline NS5A RAVs, irrespective of subtype (Table 10) [Afdhal et al, 2014b and 2014c;

Kowdley et al, 2014].

Of the treatment-naïve patients with baseline NS5A-resistant mutants in ION-1

and ION-3, 96% and 90% achieved SVR12, respectively [Afdhal et al, 2014b;

Kowdley et al, 2014]. The presence of any given NS5A RAV at baseline was not

associated with relapse.



42

In ION-1, virologic failure was rare, occurring in only 3/865 patients [Afdhal et al, 2014b].

One patient had virologic breakthrough during treatment, which was associated with

non-adherence to therapy; this patient did not have baseline NS5A RAVs. Of the two

patients who relapsed post-treatment, both had NS5A-resistant variants at baseline.

All three patients had NS5A-resistant variants at the time of virologic failure (L31M in

the GT 1a patient and Y93H in the two GT 1b patients).

In ION-3, no patient experienced on-treatment virologic breakthrough. Of the 23 patients

who relapsed post-treatment, 15 had NS5A RAVs at the time of relapse and eight did

not. Of the 15 patients with NS5A RAVs at relapse, nine had the variants at baseline and

six did not [Kowdley et al, 2014].

The NS5B S282T variant, which is associated with reduced susceptibility to SOF,

was not detected by means of deep sequencing in any patient at baseline or at the time

of virologic failure in either ION-1 or ION-3, reflecting the high genetic barrier to

resistance that has been observed in clinical trials of SOF [Afdhal et al, 2014b;

Kowdley et al, 2014].

Results of resistance monitoring in treatment-experienced patients

In ION-2, 14% of patients with available data had variants associated with resistance to

NS5A inhibitors at baseline; of these, 89% achieved SVR12 (Table 10) [Afdhal et al,

2014c]. In addition, variants associated with resistance to NS3/4A PIs were detected at

baseline in 71% of patients who had received prior PI-based treatment; of these 98%

achieved SVR12 [Afdhal et al, 2014c].

No patient in ION-2 experienced on-treatment virologic breakthrough whilst remaining

adherent to treatment. Of the 11 patients who relapsed after treatment, six had

NS5A-resistant variants at baseline, and all had detectable NS5A-resistant variants at

the time of virologic failure (Table 10). Early reductions in HCV RNA levels were similar

in patients with and without RAVs at baseline, including those who had relapsed. The

NS5B S282T variant was not observed in ION-2 [Afdhal et al, 2014c].

Resistance analyses have been performed using pooled data from a large number of

treatment-naïve and -experienced GT 1 patients receiving Harvoni®, with or without



43

RBV, in the Phase 2 LONESTAR and ELECTRON studies and the Phase 3 ION studies.

The analysis evaluated the effects of baseline RAVs on treatment outcomes and

characterized NS5A and NS5B RAVs in patients with virologic failure [Data on file –

Gilead Sciences EAME – (HCV13000119)]. It was notable that pre-existing NS5A RAVs

had poor predictive value for virologic failure, while baseline NS5B NI and NS3 PI RAVs

had no effect on SVR12 rate. Furthermore, whilst virologic failure was associated with

NS5A RAVs in the majority of patients, the prevalence of virologic failure was low, at

2.4% (51/2144 patients) across the studies. Thus, SOF-containing regimens continue to

demonstrate a high barrier to SOF resistance and the efficacy of Harvoni® remains high

despite the presence of RAVs.



44

Table 10. NS5A resistance in the Phase 3 ION studies [Afdhal et al, 2014b and 2014c; Kowdley et al, 2014]

Study

Overall NS5A mutations at

baseline, n/N* (%)

SVR in patients with baseline

mutations, n/N (%)

Post-treatment relapse, n/N (%)

NS5A-resistant mutations in patients with post-treatment

relapses

At relapse, n/N

At relapse and baseline, n/N

Treatment-naïve

ION-1 140/861 (16) 135/140 (96) 2/865 (0.2) 2/2 2/2

ION-3 116/647 (18) 104/116 (90) 23/647 (3.5) 15/23 9/15

Treatment-experienced

ION-2 62/439 (14) 55/62 (89) 11/440 (2.5) 11/11 6/11

SVR, sustained virologic response

*Patients with available data.



45

Summary of resistance analyses

Resistance monitoring in the Phase 2 and 3 studies of Harvoni® demonstrated that a

high proportion (92%) of patients who exhibited baseline NS5A RAVs achieved SVR12

[Data on file – Gilead Sciences EAME – (HCV1300119)]. No specific baseline NS5A

mutation was associated with relapse, although patients who experienced relapse were

more likely to have baseline NS5A mutations. No patients receiving Harvoni®

experienced virologic breakthrough other than one non-adherent patient; post-treatment

relapse was also rare, occurring in only 1.8% of patients [Afdhal et al, 2014b and 2014c;

Kowdley et al, 2014]. Response to Harvoni® therapy was not affected substantially by

the presence of either baseline NS5A mutations or, in treatment-experienced patients,

PI-resistant mutations. This latter finding is particularly important as studies of telaprevir

and boceprevir within triple-therapy regimens have detected RAVs in 50‒75% of

treatment-naïve patients not achieving SVR [Wyles et al, 2012]; patients who have failed

therapy with current PI-based therapies represent a growing population with limited

treatment options. Resistance analyses using pooled Phase 2 and 3 data endorse these

results, supporting the efficacy of Harvoni® in patients in whom prior therapies have

proven ineffective [Data on file – Gilead Sciences EAME – (HCV1300119)].

The NS5B S282T variant, which reduces susceptibility to SOF, was detected in only

one patient in the pooled resistance analysis (1/2144), confirming the high genetic

barrier to resistance observed in previous studies of SOF-based therapy; this patient

achieved SVR12 following re-treatment with Harvoni + RBV [Data on file – Gilead

Sciences EAME – (HCV1300119)]. LDV was fully active against S282T, while all

LDV RAVs were fully susceptible to SOF. Both SOF and LDV were fully active against

substitutions associated with resistance to other types of DAAs with different

mechanisms of action (i.e. NS5B non-nucleoside inhibitors and NS3 PIs). This lack

of cross-resistance between LDV, SOF and other DAAs offers an advantage over other

available treatment regimens.



46

10.2.5 Results of the Phase 3 studies of Harvoni® in patients with traditionally hard-to-treat baseline characteristics

Patients with low albumin and platelet levels

Patients with albumin <3.5 g/dL and platelets <90,000/mm3 have been shown to have a

poor prognosis when treated with first-generation PIs [Afdhal et al, 2014b] and,

therefore, were included in subgroup analyses in the ION-1 and ION-2 studies. In ION-1,

the SVR12 rate in the seven patients with these characteristics was 86%, with the only

patient not responding having stopped treatment after a single dose [Afdhal et al,

2014b]. In ION-2, the SVR12 rate was 92% [Data on file – Gilead Sciences EAME –

(HCV1300059)]. These data support the efficacy of Harvoni® in this traditionally

hard-to-treat patient population.

Patients with HIV/HCV co-infection

Patients with HIV/HCV co-infection who require the co-administration of ART have

traditionally presented a treatment challenge to clinicians due to the potential for

drug–drug interactions between anti-HCV and anti-HIV therapies. The Phase 2

ERADICATE study evaluated the efficacy and safety of Harvoni® for 12 weeks in

patients with HIV/HCV GT 1 co-infection and demonstrated that Harvoni® can be

administered with acceptable tolerability in combination with several ART regimens, with

a low rate of AEs, no substantial changes in CD4 T-cell count or HIV RNA levels, no

renal toxicity and no patient withdrawals from treatment due to AEs; SVR12 was 97%

in those patients who received concomitant ART [Data on file – Gilead Sciences EAME –

(HCV13000103)]. These findings are significant given the previously limited treatment

options available for treating this complex patient population. Phase 3 data from ION-4

in 335 GT 1 and GT 4 patients with HIV-1 co-infection that had been virologically

suppressed for more than 6 months with emtricitabine and tenofovir disoproxil fumarate

plus efavirenz or rilpivirine or raltegravir are expected in early 2015.



47

Patients with fibrosis or compensated cirrhosis

A considerable proportion of patients in the ION studies had fibrotic liver disease;

therefore, a post-hoc analysis investigated the impact of fibrosis stage on treatment

response [Data on file – Gilead Sciences EAME – (HCV13000105)]. Importantly,

Harvoni®-based regimens were effective in GT 1 patients, irrespective of the degree of

fibrosis or the method of determining fibrosis severity.

To date, a total of 513 patients with HCV GT 1 infection and compensated cirrhosis have

received Harvoni®, with or without RBV, as part of the Phase 2 and Phase 3 clinical trial

programs. These patients were included in a pooled analysis to determine treatment

efficacy in this patient population [Data on file – Gilead Sciences EAME –

(HCV13000100)]. The majority of patients (69%) were treatment-experienced and, of

these, 68% had received prior PI-based therapy. The overall SVR12 rate in this analysis

was 96%; 95% in patients receiving 12 weeks of therapy and 98% with 24 weeks of

therapy. High SVR rates were observed across all patient subgroups and were

increased with the addition of RBV therapy [Data on file – Gilead Sciences EAME –

(HCV13000100)]. These data support the efficacy of Harvoni® in patients with fibrotic

liver disease or cirrhosis.

Patients with negative predictors of response to IFN-based therapy

The ION study program was designed to allow the enrolment of patients with baseline

characteristics typically associated with a poor response to IFN-based therapy. A total of

308 Black patients were included in a retrospective analysis that evaluated the efficacy

of Harvoni®-based regimens in such patients [Data on file – Gilead Sciences EAME –

(HCV13000117)]. Overall, 95% of Black patients achieved an SVR12, while non-Black

patients achieved a rate of 97%, demonstrating that the all-oral regimen was highly

effective in Black patients. A further retrospective analysis investigated the impact of

age, obesity, IL28B TT genotype, uncontrolled diabetes, high viral load, opiate

replacement therapy and prior treatment failures on treatment response [Data on file –

Gilead Sciences EAME – (HCV13000106)]. This analysis demonstrated that traditional

negative predictors of response for IFN-based therapy do not predict response to



48

Harvoni® (Table 11). Thus, Harvoni®-based regimens achieve high response rates in

patients with negative predictors of response to IFN.



49

Table 11. SVR12 rates in patients with traditional negative predictors of response to IFN-based therapy in the ION studies [Data on file – Gilead Sciences EAME – (HCV13000106)]

Predictor Harvoni® Harvoni® + RBV

8 weeks 12 weeks 24 weeks 8 weeks 12 weeks 24 weeks

Age ≥65 years 90% 100% 97% 92% 97% 100%

IL28B TT 92% 97% 96% 86% 98% 100%

Black 91% 99% 92% 89% 98% 100%

HCV RNA >6 million IU/mL 90% 96% – 87% – –

Opiate replacement therapy 100% 94% 91% 100% 91% 100%

HCV, hepatitis C virus; RBV, ribavirin



50

Summary

These study data support the efficacy of Harvoni® in a number of traditionally challenging

patient populations, including those with low albumin and platelet levels, HIV/HCV

co-infection, compensated cirrhosis and negative predictors for response to IFN therapy.

Historically, these patient populations have had limited treatment options available to

them and low cure rates. The high rates of SVR12 demonstrated with Harvoni® support

the efficacy of this therapy in these patient cohorts and the potential associated

cost-efficacy benefits to healthcare providers. The reader is referred to Section 12 for a

discussion of the cost-effectiveness of Harvoni®.

10.2.6 Results of the studies of Harvoni® in patients with genotypes other than GT 1

Data from small patient populations in the Phase 2 trials have suggested that Harvoni®

therapy is associated with high cure rates in patients with HCV GT 3, GT 4 and GT 6

infection [Data on file – Gilead Sciences EAME – (HCV1300045), Data on file – Gilead

Sciences EAME – (HCV13000114; Data on file – Gilead Sciences EAME –

(HCV1300098); Data on file – Gilead Sciences EAME – (HCV13000114)].

The Phase 2 ELECTRON-2 study evaluated Harvoni® in treatment-naïve and treatment-

experienced patients with GT 3 infection, with and without cirrhosis. All of the treatment-

naïve patients who received Harvoni® plus RBV achieved SVR12 (26/26) [Data on file –

Gilead Sciences EAME – (HCV1300045)]. Data also showed that 82% (41/50) of the

treatment-experienced patients administered Harvoni® + RBV achieved SVR12,

including 73% of cirrhotic and 89% of non-cirrhotic patients [Data on file – Gilead

Sciences EAME – (HCV13000114].

Patients with HCV GT 4 infection were enrolled in the ongoing Phase 2 SYNERGY and

SOLAR-1 studies [Data on file – Gilead Sciences EAME – (HCV1300098); Data on file –

Gilead Sciences EAME – (HCV13000101)]. Of the 20 GT 4 patients who received

Harvoni® in SYNERGY, 95% achieved SVR12 (19/20; one patient had not reached the

12-week time point at the time of analysis) [Data on file – Gilead Sciences EAME –

(HCV1300098)]. These findings are borne out by early Phase 3 trial data. Two

treatment-naïve patients with HCV GT 4 infection were enrolled in the Phase 3 ION-1



51

study, one of whom received Harvoni® for 12 weeks and the other Harvoni® + RBV for

24 weeks; both patients achieved SVR12 [Afdhal et al, 2014b].

There is currently no approved all-oral treatment regimen for patients with HCV GT 6.

One arm of the ELECTRON-2 study evaluated whether Harvoni® would be effective in

treatment-naïve and treatment-experienced GT 6 patients, and a high rate (96%) of

SVR12 was demonstrated in this population [Data on file – Gilead Sciences EAME –

(HCV13000114)]; currently, no data are available in patients with HCV GT 5 infection.

Further data on the efficacy of Harvoni® in non-GT 1 genotypes in the ION and other

Phase 3 trials are awaited with interest.

10.2.7 Impact of Harvoni® on patient health-related quality of life

Patients with chronic HCV infection have reduced health-related quality of life (HRQoL)

compared with the general population, and treatment with PEG-IFN-based regimens

diminishes this further, largely as a result of side effects [Bezemer et al, 2012]. Patients

in the ION study program were asked to complete several questionnaires (Chronic Liver

Disease Questionnaire-HCV, Short Form-36, Functional Assessment of Chronic Illness

Therapy-Fatigue, and Work Productivity and Activity Index: Specific Health Problem) in

order to establish the effect of Harvoni®, with and without RBV, on patient-reported

outcomes (PRO) [Data on file – Gilead Sciences EAME – (HCV13000108)]. During

treatment with RBV-containing regimens, PRO scores decreased compared with

baseline and remained below baseline levels until the end of therapy. In contrast,

PRO improved in the RBV-free treatment arms throughout the treatment period and were

significantly superior to those in the Harvoni® + RBV arms. Patients who achieved

SVR12 (irrespective of treatment regimen) showed a significant improvement in

PRO compared with baseline.

A similar analysis was conducted and stratified according to fibrosis stage [Data on file –

Gilead Sciences EAME – (HCV13000109)]. At baseline, patients with advanced fibrosis

had greater PRO impairment than those in the early stages of disease. However,

significant improvements in PRO were observed in patients who achieved SVR12,

irrespective of fibrosis stage, with those with early-stage liver disease obtaining similar



52

benefits to those with more advanced disease. Thus, Harvoni® therapy is associated with

significant improvements in patient HRQoL regardless of disease stage.

10.2.8 Effect of Harvoni® therapy on long-term patient outcomes

Currently, only short-term data are available from the Phase 3 studies of Harvoni® in

patients with HCV and therefore any conclusions about potential long-term outcomes,

such as the development of decompensated cirrhosis or HCC or the need for liver

transplantation, can only be derived from models. In one such analysis, using SVR12

rates from Phase 3 studies, modeled cohorts of GT 1 patients initiated treatment at

different stages of fibrosis (F0–F1, F2, F3–F4) and received either Harvoni® for 8 or

12 weeks; SOF-, PI- or PEG-IFN-based regimens; or no treatment [Data on file – Gilead

Sciences EAME – (HCV13000110)]. In the analysis, initiating Harvoni® treatment at

F0–F1 or F2 versus F3–F4 resulted in a significant decrease in liver disease progression

and related sequelae.

An additional model evaluated health outcomes associated with 12 weeks of

Harvoni® therapy in GT 1 cirrhotic patients compared with other treatment options (SOF

+

PEG-IFN + RBV for 12 weeks, or simeprevir + PEG-IFN + RBV for 12 weeks, or no

treatment) [Data on file – Gilead Sciences EAME – (HCV13000111)]. Compared with

SOF + PEG-IFN, Harvoni® conferred an anticipated 50% reduction in HCV sequelae and

increased quality-adjusted life years (QALYs). The model also evaluated the benefits of

SOF-based regimens in other genotypes, and demonstrated that they were associated

with a decrease in the incidence of liver disease complications compared with

non-SOF-based treatment options.

These models suggest that Harvoni®, in GT 1 patients, and other SOF-based regimens

in GT 2, GT 3 and GT 4 patients, are likely to yield better health outcomes than other

HCV treatment options in both cirrhotic and non-cirrhotic patients. The reader is referred

to Section 12 for further discussion on modeling of patient outcomes with Harvoni®.



53

10.3 Summary of available estimates of comparative effectiveness

In the Phase 3 clinical trial program, 8–12 weeks of Harvoni® therapy, with or without

RBV, provided high levels of cure in treatment-naïve and treatment-experienced patients

with HCV GT 1, including those with compensated cirrhosis [Afdhal et al, 2014b and

2014c; Kowdley et al, 2014; Data on file – Gilead Sciences EAME –

(HCV13000104)].The ION studies and the Japanese Phase 3 study clearly

demonstrated that exclusion of RBV from the regimen maintained efficacy, with

subsequent analyses showing that patient HRQoL also improved with the omission of

RBV from the regimen [Data on file – Gilead Sciences EAME – (HCV13000108)]. Thus,

the studies supported the feasibility of shorter, simplified, all-oral, Harvoni®-based

regimens for HCV GT 1 patients.

Data from the Phase 2 trials have suggested that Harvoni® therapy is associated with

high rates of cure in patients with HCV GT 3, GT 4 and GT 6 infection [Data on file –

Gilead Sciences EAME – (HCV1300045), Data on file – Gilead Sciences EAME –


Gilead Sciences EAME – (HCV13000114)].

The extensive Phase 2 clinical trial program demonstrated that administration of

Harvoni® for 8, 12 or 24 weeks, with or without RBV, achieved high rates of SVR12 in a

diverse range of HCV GT 1 patients, including those with difficult-to-treat characteristics,

such as HIV/HCV co-infection, recurrent HCV infection following liver transplantation and

previous non-response to PI- and SOF-based therapies [Lawitz et al, 2014; Data on file



Gilead Sciences EAME – (HCV1300097)]. Again, these results are endorsed by findings

from the Phase 3 studies, which showed high cure rates with Harvoni® in patients with

low albumin and platelet levels, and compensated cirrhosis, and in those with baseline

characteristics typically associated with a poor response to IFN-based therapy (i.e. Black

ethnicity, obesity, older age, IL28B TT genotype, uncontrolled diabetes, high viral load,

opiate replacement therapy and prior treatment failure) [Data on file – Gilead Sciences

EAME – (HCV1300059); Data on file – Gilead Sciences EAME – (HCV13000100); Data

on file – Gilead Sciences EAME – (HCV13000105); Data on file – Gilead Sciences

EAME – (HCV13000106); Data on file – Gilead Sciences EAME – (HCV13000117)].



54

Resistance monitoring in the ION studies demonstrated that a high proportion (92%) of

patients who exhibited baseline NS5A RAVs achieved SVR12 [Data on file – Gilead

Sciences EAME – (HCV1300119)]. No specific baseline NS5A mutation was associated

with relapse, and post-treatment relapse was rare. In addition, no patients receiving

Harvoni® experienced virologic breakthrough, other than one non-adherent patient

[Afdhal et al, 2014b and 2014c; Kowdley et al, 2014]. Importantly, response to Harvoni®

therapy was not affected substantially by the presence of baseline NS5A mutations or

PI-resistant mutations. Furthermore, the studies confirmed the high genetic barrier to

resistance observed previously with SOF-based therapy and demonstrated a lack of

cross-resistance between LDV, SOF and other DAAs. These findings are borne out by

pooled data for a large number of treatment-naïve and -experienced patients in Phase 2

and 3 trials of Harvoni®, which demonstrated that the presence of NS5A RAVs prior to

commencing treatment were poor predictors for the risk of virologic failure, while

baseline NS5B or NS3 PI RAVs had no impact on SVR12 rate [Data on file – Gilead

Sciences EAME – (HCV1300119)].

Notably, the high cure rates achieved with Harvoni® in the Phase 3 trials were

associated with significant improvements in PRO and patient HRQoL compared with

baseline assessments [Data on file – Gilead Sciences EAME – (HCV13000108); Data on

file – Gilead Sciences EAME – (HCV13000109], which, together with the simple, all-oral

treatment regimen, may promote improved patient adherence to treatment. Furthermore,

modeling of data from the Phase 3 trials suggested that Harvoni® is likely to confer

substantial reductions in HCV sequelae and increases in QALYs in the long term, in both

cirrhotic and non-cirrhotic patients across the genotypes, compared with other available

HCV treatment options [Data on file – Gilead Sciences EAME – (HCV13000110); Data

on file – Gilead Sciences EAME – (HCV13000111)]. Such findings indicate potential

cost-efficacy benefits for healthcare providers, which may be particularly pertinent to

resource-limited regions, such as developing countries (See Section 12).

The Harvoni® STR builds on the proven efficacy of SOF to offer a wide range of patients,

including those with traditionally difficult-to-treat disease, a high chance of cure with a

short, all-oral, IFN- and, in most cases, RBV-free treatment regimen.

Overall, data from the clinical studies suggest that Harvoni®, with or without RBV, has

the potential to offer HCV patients, including those with historically difficult-to-treat



55

disease, significant efficacy advances over current standards of care. This is reflected in

its designation by the US FDA in October 2014 as a breakthrough therapy for HCV

[FDA News Release, 2014]. Moreover, as the next section will demonstrate, Harvoni® is

well tolerated and – as a once-daily, oral medication – a simple drug to prescribe.

11. Summary of comparative evidence on safety

The safety and tolerability of Harvoni® have been assessed in a diverse range of patients

with chronic HCV GT 1 infection. Data from these studies have demonstrated an

excellent safety and tolerability profile for Harvoni® in this patient population, with a low

rate of treatment discontinuations [Afdhal et al, 2014b and 2014c; Kowdley et al, 2014;

Lawitz et al, 2014; Data on file – Gilead Sciences EAME – (HCV13000045); Data on file






(HCV13000116)].

Reported incidences of anemia, headache, fatigue, rash, pruritus and insomnia were

higher among patients receiving concomitant RBV, consistent with the well-known side

effects of this therapy [Lawitz et al, 2014; Data on file – Gilead Sciences EAME –



(HCV13000103); Data on file – Gilead Sciences EAME – (HCV13000113)]. However,

data from the ION studies indicated that the co-administration of RBV increased toxicity

without providing substantial additional efficacy benefits, supporting the use of RBV-free

regimens, and their potential for reduced patient monitoring, fewer transfusions and

improved treatment adherence [Kowdley et al, 2014].

It is noteworthy that the favorable safety profile of Harvoni® included GT 1 patients with

HIV/HCV co-infection, regardless of ART status, a population for whom treatment is

traditionally limited by the high rate of AEs and the potential for drug–drug interactions



56

[Data on file – Gilead Sciences EAME – (HCV1300069); Data on file – Gilead Sciences

EAME – (HCV1300103)].

Preliminary data on the safety and tolerability of Harvoni® in patients with HCV GT 3,

GT 4 and GT 6 infection suggest that the safety profile of this agent is similar to that

observed in HCV GT 1 patients [Data on file – Gilead Sciences EAME – (HCV1300045);

[Data on file – Gilead Sciences EAME – (HCV1300098); Data on file – Gilead Sciences

EAME – (HCV13000114)]. Studies are ongoing in these patient populations.

11.1 Estimate of total patient exposure to Harvoni®

More than 800 patients have participated in completed and ongoing Phase 2 trials of

Harvoni®, while over 2000 patients have been treated in the Phase 3 clinical trial

program. These studies have enrolled a broad range of chronic HCV patients, including

patients with HIV/HCV co-infection, patients with bleeding disorders, and patients from a

range of ethnicities, including Japanese patients [Data on file – Gilead Sciences EAME –



(HCV13000104)].

Cumulative patient exposure to Harvoni® in the period following drug approval is

presented in Table 12.

Table 12. Estimated cumulative post-marketing exposure to Harvoni® in Europe and North America

Product Time period Cumulative post-marketing exposure

Harvoni® October 10 – October 31, 2014* 19,000 units

*Harvoni® was approved in Canada on October 16, 2014. Patients in the UK were treated on an

early access program.



57

11.2 Description of adverse effects/reactions

11.2.1 Treatment-emergent adverse events in patients with HCV GT 1

Treatment-emergent adverse events in the Phase 2 studies

Harvoni® demonstrated a favorable safety profile in GT 1 patients in the Phase 2 studies.

The most commonly reported AEs in patients treated with Harvoni®, with or without RBV,

across all studies were headache (≤26%), fatigue (≤32%) and rash (≤21%) [Lawitz et al,

2014; Data on file – Gilead Sciences EAME – (HCV1300045); Data on file – Gilead




(HCV13000113)]. Anemia, known to be associated with RBV, was more common in

patients treated with Harvoni® + RBV compared with Harvoni® alone [Data on file –

Gilead Sciences EAME – (HCV1300045)]. Overall, there was a low rate of Grade 3–4

AEs and serious AEs (SAEs), with few patients across all studies withdrawing from

treatment due to AEs [Lawitz et al, 2014; Data on file – Gilead Sciences EAME –



(HCV13000103); Data on file – Gilead Sciences EAME – (HCV13000113)].

In the Phase 2 SIRIUS study in patients (N=155) with compensated cirrhosis who had

failed prior therapy (PEG-IFN/RBV or PI/PEG-IFN/RBV), treatment was well tolerated

and Harvoni® demonstrated a similar AE profile when administered for 12 weeks with

RBV and when administered for 24 weeks alone; one patient withdrew from the study

during the placebo phase due to an SAE and was excluded from the analysis [Data on


(HCV13000113)]. Reductions in hemoglobin levels, consistent with RBV-associated

anemia, were observed during treatment, while alanine aminotransferase and aspartate

aminotransferase elevations were noted during the placebo phase, consistent with the

natural history of untreated HCV infection. These safety findings are encouraging as

patients with cirrhosis are at high risk of disease progression.



58

TEAEs in the Phase 3 trials

The favorable safety profile of Harvoni® demonstrated in the Phase 2 studies was

confirmed in the Phase 3 analyses (Tables 13, 14 and 15). Whilst the majority of patients

in the ION-1, -2 and -3 studies (67‒92%), including those with and without cirrhosis,

exhibited at least one AE, most events were of grade 1 severity; the most commonly

reported AEs were fatigue, headache, insomnia and nausea (Table 13) [Afdhal et al,

2014b and 2014c; Kowdley et al, 2014]. Patients receiving RBV demonstrated higher

incidences of fatigue, insomnia, rash, cough, pruritus and anemia – AEs known to be

associated with RBV – than those receiving Harvoni® alone.

Serious AEs were reported by ≤8% of patients with HCV GT 1 across all arms of the

three ION studies (Table 14). Overall, SAEs were reported more commonly in patients

who received Harvoni® for 24 weeks than in those receiving treatment for 8 or 12 weeks

[Afdhal et al, 2014b and 2014c; Kowdley et al, 2014].

Harvoni® was generally well tolerated, with a low rate of treatment discontinuations

across the trials (≤2% for Harvoni® alone and ≤3% for Harvoni® + RBV) (Table 14).

No patients receiving Harvoni® for 8 or 12 weeks withdrew from treatment due to AEs.

In a Phase 3 study in treatment-naïve (n=166) and treatment-experienced (n=175)

GT 1 patients in Japan, the safety profile of Harvoni® was similar to that in the pivotal

ION studies [Data on file – Gilead Sciences (HCV 1300070)]. Data from the Phase 3

Japanese study are presented in Tables 13, 14 and 15. These data demonstrate

consistency in safety findings across patients of different racial origins.



59

Table 13. AEs reported in patients with HCV GT 1 receiving Harvoni®, with or without RBV, in the Phase 3 ION and Japanese studies [Afdhal et al, 2014b and 2014c; Kowdley et al, 2014; Data on file – Gilead Sciences (HCV 1300070)]*

NA, not available; RBV, ribavirin; URTI, upper respiratory tract infection

*Reported by at least 10% (ION-1 and ION-2) or 5% (ION-3) of patients in any treatment arm



60

Table 14. Overall safety profile and treatment discontinuations reported in patients receiving Harvoni®, with or without RBV, in the Phase 3 ION and Japanese studies [Afdhal et al, 2014b and 2014c; Kowdley et al, 2014; Data on file – Gilead Sciences (HCV 1300070)]

AEs, adverse events; RBV, ribavirin; SAEs, serious adverse events



61

Treatment-emergent laboratory test abnormalities in the Phase 3 clinical trials

Hematologic abnormalities are a well-known side effect of RBV therapy and a common

reason for dose reductions [Fried, 2002]. Anemia was reported in 8‒12% of patients

treated with Harvoni® + RBV versus 0‒1% of patients treated with Harvoni® alone in the

ION studies; all but one case of reduced hemoglobin levels (<10 mg/mL) were observed

with RBV treatment (Table 15) [Kowdley et al, 2014].

Bilirubin, creatine kinase and lipase elevations

Total bilirubin elevations of more than 1.5× the upper limit of normal (ULN) were

observed in 3%, <1% and 2% of patients treated with Harvoni® for 8, 12 and 24 weeks,

respectively, in the ION trials [Harvoni® US PI, 2014].

Creatine kinase (CK) levels were not assessed in the Phase 3 ION trials of

Harvoni® [Harvoni® US PI, 2014]. However, isolated, asymptomatic CK elevations of

greater than or equal to 10×ULN have been reported previously in ≤2% of patients

receiving SOF + RBV, with or without PEG-IFN, for 12 or 24 weeks in the FISSION and

NEUTRINO trials [Sovaldi US PI, 2014].

Transient, asymptomatic lipase elevations of more than 3×ULN were observed in

<1%, 2% and 3% of patients treated with Harvoni® for 8, 12 and 24 weeks, respectively,

in the Phase 3 studies [Harvoni® US PI, 2014], reflecting similar findings to those

reported with SOF + RBV, with or without PEG-IFN, in FISSION and NEUTRINO

[Sovaldi® US PI, 2014].

No clinical significance has been reported in association with these findings in

HCV patients receiving Harvoni® to date.



62

Table 15. Hematologic abnormalities reported in patients receiving Harvoni®, with or without RBV, in the Phase 3 ION and Japanese studies [Afdhal et al, 2014b and 2014c; Kowdley et al, 2014; Data on file – Gilead Sciences (HCV 1300070)]

ANC, absolute neutrophil count; Hb, hemoglobin; NA, available; RBV, ribavirin



63

11.2.2 Safety of Harvoni® in patients with HCV GT 1 and cirrhosis

Patients with cirrhosis tend to be older and to have a lower tolerance to AEs than

patients with less advanced disease; such patients also tend to experience a greater

number of potentially treatment-limiting hematologic AEs [EASL Guidelines, 2014a].

A pooled analysis of safety and tolerability data from the three Phase 3 ION trials

demonstrated similar safety data for GT 1 patients with and without cirrhosis, although a

higher proportion of cirrhotic patients in the Harvoni® + RBV arms experienced AEs

leading to study drug modification or interruption (Table 16). Overall, no patients with

cirrhosis withdrew from treatment due to AEs [Afdhal et al, 2014b and 2014c; Kowdley et

al, 2014].

Phase 2 trial data have demonstrated that Harvoni® was well tolerated in HCV GT 1

patients with decompensated cirrhosis, with a safety profile similar to that in non-cirrhotic

patients [Data on file – Gilead Sciences EAME – (HCV1300045); Data on file – Gilead

Sciences EAME – (HCV13000116]. This is a particularly important finding as such

patients are excluded from treatment with IFN-based regimens due to AEs and,

therefore, have limited treatment options available to them.

Data have also suggested that Harvoni® + RBV is generally well tolerated in patients with

recurrent HCV infection post-transplant, with low rates of treatment discontinuation due

to AEs [Data on file – Gilead Sciences EAME – (HCV13000101)]. No drug–drug

interactions have been reported between Harvoni® and the immunosuppressants that

are critical for the management of post-liver transplant patients [Harvoni® US PI, 2014],

therefore Harvoni® may represent a valuable addition to the treatment options available

for these patients The reader is referred to Section 11.2.5 for further discussion on

potential drug interactions associated with Harvoni® therapy.



64

Table 16. Safety profile according to cirrhosis status in the Phase 3 ION studies [Afdhal et al, 2014b and 2014c; Kowdley et al, 2014]

n (%) Harvoni® Harvoni® + RBV

No cirrhosis (n=969)

Cirrhosis (n=111)

No cirrhosis (n=759)

Cirrhosis (n=113)

AE 715 (73.7) 85 (76.6) 646 (85.1) 99 (87.6)

Treatment-related AE

438 (45.2) 46 (41.4) 528 (69.6) 89 (78.8)

Grade ≥3 AE 39 (4.0) 7 (6.3) 35 (4.6) 10 (8.8)

SAE 29 (3.0) 5 (4.5) 14 (1.8) 3 (2.7)

Treatment-related SAE

3 (0.3) 1 (0.9) 0 1 (0.9)

AEs leading to study drug modification/ interruption

5 (0.5) 1 (0.9) 95 (12.5) 23 (20.4)

Treatment discontinuation due to AE

6 (0.6) 0 11 (1.5) 0

Death 0 0 0 0

AE, adverse event; RBV, ribavirin; SAE, serious adverse event

11.2.3 Safety of Harvoni® in patients with HIV/HCV co-infection

Traditionally, the treatment of patients with HIV/HCV co-infection has been limited due

to the high rate of AEs observed with PEG-IFN- and RBV-based regimens, and the

potential for drug–drug interactions between anti-HCV and anti-HIV therapies. While

efficacy has improved with the advent of PIs, AE profiles did not improve until the advent



65

of SOF; both telaprevir and boceprevir are associated with increased rates of anemia,

rash, pruritus and dysgeusia [Naggie and Sulkowski, 2012].

The Phase 2 ERADICATE study evaluated the efficacy and safety of Harvoni® for

12 weeks in patients with HCV GT 1 and HIV co-infection. Harvoni® was administered in

combination with several ART regimens, with a low rate of AEs, no significant changes in

CD4 T-cell count or HIV RNA levels, no renal toxicity and no patient withdrawals from

treatment due to AEs [Data on file – Gilead Sciences EAME – (HCV13000103)]. The

lack of significant interactions with several ART regimens suggests that Harvoni® may be

administered with acceptable safety and tolerability to some HIV co-infected patients, for

whom current treatment options are limited.

11.2.4 Safety of Harvoni® in patients with HCV GT 2, 3, 4, 5 and 6 infection

Preliminary data on the safety and tolerability of Harvoni® in HCV genotypes other

than GT 1 are available for a small group of patients.

The Phase 2 ELECTRON-2 trial [Data on file – Gilead Sciences EAME –

(HCV1300045); Data on file – Gilead Sciences EAME – (HCV13000114)] evaluated

Harvoni® for 12 weeks in patients with GT 3 infection (n=50). Results from the study

were encouraging, demonstrating a similar safety profile with Harvoni®, with or without

RBV, to that in the Phase 3 studies in GT 1 patients. Preliminary data from the trial

(n=25) also suggest that Harvoni® is well tolerated in patients with GT 6 infections

[Data on file – Gilead Sciences EAME – (HCV13000114)], representing the first

indication of a potentially safe and effective all-oral regimen in this patient population.

Two patients infected with HCV GT 4 were enrolled in the Phase 3 ION-1 study; one

patient received Harvoni® for 12 weeks and the other Harvoni® + RBV for 24 weeks

[Afdhal et al, 2014b]. To date, no specific details of the safety analysis in these two

patients have been published. Thus, studies in patients with GT 4 infection are ongoing,

while the use of Harvoni® is also under investigation in patients with HCV GT 2 and

GT 5.



66

11.2.5 Drug interactions

As Harvoni® contains LDV and SOF, any drug interactions that have been identified with

these agents individually may occur with Harvoni®. Both LDV and SOF are substrates of

the drug transporters P-gp and breast cancer resistance protein (BCRP). Ledipasvir is

an inhibitor of both P-gp and BCRP, and may increase intestinal absorption of

co-administered substrates for these transporters. Medicinal products that are potent

P-gp inducers, such as rifampin or St John’s wort, may decrease plasma concentrations

of LDV and SOF, leading to a potential reduction in the therapeutic efficacy of Harvoni®.

Thus, co-administration of Harvoni® with potent P-gp inducers is not recommended

[Harvoni® US PI, 2014; Data on file – Gilead Sciences EAME – (HCV13000118)].

Table 17 provides a listing of established or potentially clinically significant drug

interactions with Harvoni®, based on predicted drug interactions and studies conducted

with Harvoni® or its individual components. It should be noted that this list is not

all-inclusive.



67

Table 17. Potentially significant drug interactions in patients receiving Harvoni®a [Harvoni® US PI, 2014]

Concomitant drug class and drug name

Effect on concentrationb

Clinical comment

Acid-reducing agents ↓ LDV

LDV solubility decreases as pH increases. Drugs that increase gastric

pH are expected to decrease concentration of LDV

Antacids (e.g. aluminium and

magnesium hydroxide)

It is recommended to separate antacid and Harvoni® administration by

4 hours

H2-receptor antagonistsc

(e.g. famotidine)

H2-receptor antagonists may be administered simultaneously with or

12 hours apart from Harvoni® at a dose that does not exceed doses

comparable to famotidine

40 mg twice daily

Proton-pump inhibitorsc

(PPI; e.g. omeprazole)

PPI doses comparable to omeprazole 20 mg or lower can be

administered simultaneously with Harvoni® under fasted conditions

Antiarrhythmics

Digoxin

↑ digoxin Co-administration of Harvoni® with digoxin may increase the

concentration of digoxin. Therapeutic concentration monitoring of

digoxin is recommended when

co-administered with Harvoni®

Anticonvulsants Carbamazepine

Phenytoin

Phenobarbital

Oxcarbazepine

↓ LDV

↓ SOF

↓GS-331007

Co-administration of Harvoni® with carbamazepine, phenytoin,

phenobarbital or oxcarbazepine is expected to decrease the

concentrations of LDV and SOF, which may lead to reduced

therapeutic efficacy of Harvoni®. Co-administration is not

recommended



68

Antimycobacterials Rifabutin

Rifampin

Rifapentine

↓ LDV

↓ SOF

↓GS-331007

Co-administration of Harvoni® with rifabutin or rifapentine is expected

to decrease the concentrations of LDV and SOF, leading to reduced

therapeutic effect of Harvoni®. Co-administration of Harvoni® with

rifampin, a potent P-gp inducer, is not recommended

HIV antiretrovirals

Efavirenz, emtricitabine,

tenofovir DF

↑ tenofovir Monitor for tenofovir-associated adverse reactions in patients

receiving Harvoni® concomitantly with the combination of efavirenz,

emtricitabine and tenofovir DF. Refer to Viread®, Truvada® or Atripla®

Prescribing Information for recommendations on renal monitoring

Regimens containing tenofovir DF

and an HIV PI/ritonavir

• atazanavir/ritonavir +

emtricitabine/tenofovir DFc

• darunavir/ritonavir +


• lopinavir/ritonavir +

emtricitabine/tenofovir DF

↑ tenofovir The safety of increased tenofovir concentrations in the setting of

Harvoni® and an HIV PI/ritonavir has not been established.

Consider alternative HCV or ART to avoid increases in tenofovir

exposures. If

co-administration is necessary, monitor for tenofovir-associated

adverse reactions. Refer to Viread® or Truvada® Prescribing

Information for recommendations on renal monitoring

Elvitegravir, cobicistat,

emtricitabine, tenofovir DF

↑ tenofovir The safety of increased tenofovir concentrations in the setting of

Harvoni® and the combination of elvitegravir, cobicistat, emtricitabine

and tenofovir DF has not been established. Co-administration is not

recommended



69

Tipranavir/ritonavir ↓ LDV

↓ SOF

↓GS-331007

Co-administration of Harvoni® with tipranavir/ritonavir is expected to

decrease the concentrations of LDV and SOF, leading to reduced

therapeutic effect of Harvoni®.

Co-administration is not recommended

HCV products Simeprevir

↑ LDV

↑ simeprevir

Concentrations of LDV and simeprevir are increased when simeprevir

is

co-administered with LDV. Co-administration of Harvoni® with

simeprevir is not recommended

Herbal supplements St. John’s wort

(Hypericum perforatum)

↓ LDV

↓ SOF

↓GS-331007

Co-administration of Harvoni® with St. John’s wort, a potent P-gp

inducer,

is not recommended

HMG-CoA reductase inhibitors

Rosuvastatin

↑ rosuvastatin Co-administration of Harvoni® with rosuvastatin may significantly

increase the concentration of rosuvastatin, which is associated with an

increased risk of myopathy, including rhabdomyolysis. Co-

administration of Harvoni® with rosuvastatin is not recommended ART, antiretroviral therapy; H2 receptor, histamine receptor; HCV, hepatitis C virus;

HIV, human immunodeficiency virus; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; LDV, ledipasvir;

P-gp, P-glycoprotein; PI, protease inhibitor; PPI, proton-pump inhibitor; SOF, sofosbuvir;

tenofovir DF, tenofovir disoproxil fumarate

a. This table is not all-inclusive

b. ↓ = decrease; ↑ = increase

c. These interactions have been studied in healthy adults

11.3 Summary of comparative safety

Phase 2 and 3 studies conducted to date have demonstrated that Harvoni® is

well tolerated with an excellent safety profile in a diverse range of patients with chronic

HCV GT 1 infection [Afdhal et al, 2014b and 2014c; Kowdley et al, 2014; Lawitz et al,

2014; Data on file – Gilead Sciences EAME – (HCV13000045); Data on file – Gilead






(HCV13000116)].

The advent of the PIs, boceprevir and telaprevir, significantly increased SVR rates in

patients with HCV GT 1 infections receiving PEG-IFN and RBV, including in patients who

had previously failed to respond to treatment [Naggie and Sulkowski, 2012]. However,

triple therapy has been associated with significant additional side effects and drug–drug

interactions, together with stringent dosing requirements and a high pill burden [Butt and

Kanwal, 2012]. The introduction of SOF provided an alternative treatment option

associated with high cure rates and a well-tolerated safety profile, although the

tolerability of SOF has been limited by the requirement for the co-administration of

PEG-IFN. It is noteworthy that very few patients treated with Harvoni® in the Phase 3

ION studies withdrew from treatment due to AEs, and most of those that did were in the

treatment arms receiving 24 weeks of treatment or concomitant RBV [Afdhal et al, 2014b

and 2014c; Kowdley et al, 2014]. The higher rates of AEs, such as anemia, headache,

fatigue, rash, pruritus and insomnia, observed in patients who were co-administered

RBV are consistent with the well-known side effects of RBV therapy. ION study data

suggest that the administration of RBV, in addition to Harvoni®, increases toxicity without

providing substantial additional efficacy benefits. Thus, by administering Harvoni®

without RBV, clinicians may decrease the risk of RBV-related toxicities, reduce the need

for hemoglobin monitoring during treatment, diminish requirements for colony-stimulating

factors and transfusions, and contribute to improved treatment adherence [Kowdley et al,

2014].

Patients with cirrhosis tend to be older, have a lower tolerance to AEs, and experience

more treatment-limiting hematological AEs than those with less advanced disease



71

[EASL, 2014b]. Treatment-related toxicities associated with boceprevir and telaprevir are

particularly challenging in cirrhotic patients, resulting in high discontinuation rates

(approximately 12% and 15%, respectively) in patients with HCV GT 1 [Manns and

Cornberg, 2013; Bourliere et al, 2012]. Data from Phase 2 and 3 studies in patients

receiving Harvoni® have demonstrated a low rate of treatment withdrawal due to AEs in

patients with cirrhosis [Afdhal et al, 2014b and 2014c; Kowdley et al, 2014] and a similar

safety profile in patients with decompensated cirrhosis as those without cirrhosis [Data

on file – Gilead Sciences EAME – (HCV1300045)]. Similarly, the treatment of patients

with HIV/HCV co-infection has been limited by the high rate of AEs experienced with

combination therapies and the potential for drug–drug interactions between anti-HCV

and anti-HIV therapies; telaprevir and boceprevir are associated with increased rates of

anemia, rash, pruritus and dysgeusia in this patient population [Naggie and Sulkowski,

2012]. Phase 2 trial data have shown a very low incidence of AEs with Harvoni® in

HIV/HCV co-infected GT 1 patients, regardless of ART status [Data on file – Gilead

Sciences EAME – (HCV13000103)]. These data support the use of Harvoni® in

traditionally hard-to-treat patient populations, including those receiving concomitant

therapies for complex comorbid conditions.

For patients with HCV non-GT 1 infections, safety data for Harvoni® are available for

a small number of patients. Phase 2 study findings in patients with GT 3 infection and

GT 6 infection have been encouraging, suggesting a similarly favorable safety profile to

that in GT 1 patients [Data on file – Gilead Sciences EAME – (HCV1300045); Data on

file – Gilead Sciences EAME – (HCV13000114)].



72

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

12.1 Range of costs of the proposed medicine

12.1.1 USA

The US FDA approved Harvoni® in October 2014 for the treatment of chronic HCV GT 1

infection in adult patients (aged ≥18 years) [Harvoni US PI, 2014].

The monthly treatment cost of Harvoni® tablets varies among payers in the USA.

Table 18 details the wholesale acquisition cost in the USA.

Table 18. Wholesale acquisition costs of Harvoni® in the USA

Dosage form and product strength

Package size Wholesale acquisition cost (US$)

Tablet containing:

90 mg LDV

400 mg SOF

28 tablets

$31,500

LDV, ledipasvir; SOF, sofosbuvir

12.1.2 Developing countries

Gilead’s mission is to transform care for life-threatening diseases, including chronic

HCV, throughout the world. For Harvoni®, which the FDA has designated a breakthrough

therapy for HCV, Gilead is utilizing mechanisms based on the principle that underpinned

its approach to treatment expansion in developing countries, ie, tiered pricing and

voluntary generic licensing. As a result of this approach, 6.7 million people living with

HIV in developing countries are currently receiving a Gilead-based HIV medicine. In

relation to Harvoni®, Gilead has developed a system of tiered pricing based on a

country’s ability to pay. Countries are categorized within bands according to gross



73

national income per capita and HCV prevalence and final prices are determined on a

country-by-country needs basis.

In addition, Gilead signed an agreement with seven Indian drug manufacturers in

September 2014 to provide generic versions of Harvoni® for distribution in 91 developing

countries, including India, Egypt, Pakistan and Nigeria, which are home to more than

100 million individuals living with chronic HCV.

Lowering prices, however, is just one aspect of successfully scaling up HCV treatments,

such as Harvoni®. Also critical are in-country activities that support drug availability and

use, including product registration, medical education, demand forecasting and

collaborative research. All of these are elements of Gilead’s treatment access initiatives,

the aim of which is to introduce new medicines quickly.

12.2 Cost-effectiveness of medicines for HCV

Chronic HCV currently affects approximately 3.2 million individuals in the USA, with

17,000 new cases arising each year [CDC, 2014]. With such substantial prevalence,

chronic HCV places a considerable burden on US healthcare resources.

The economic burden of HCV is lower in treated patients compared with untreated

patients [McCombs et al, 2011]. In addition, both direct and indirect healthcare costs

increase in a stepwise fashion with disease progression, with the majority of costs

resulting from end-stage liver diseases [Galbraith et al, 2014; McAdam-Marx et al, 2011;

Gordon et al, 2012]. Treatments for HCV aim to cure patients of their infection and, in so

doing, remove the risk of long-term HCV-related complications and the associated

burden and cost to healthcare providers. The endpoint of HCV treatment is SVR12,

which correlates strongly with permanent clearance of the virus and reduced healthcare

costs. Indeed, extrapolation of modeled data over a 5-year post-treatment period in one

study showed that, among patients with chronic HCV, failure to achieve SVR was

associated with a 13-fold increase in costs and a 56-fold increase in costs in patients

who required retreatment [Backx et al, 2014]. In addition, initiation of HCV therapy at an

earlier stage (i.e. in patients without cirrhosis) yields substantially fewer cases of

HCV-related complications and an estimated reduction in total costs of approximately



74

39–46% [Younossi et al, 2014]. Indeed, modeling data for long-term health and

economic outcomes have demonstrated that initiation of Harvoni® therapy at earlier

stages of fibrosis (F0–F1 or F2 versus F3–F4) is associated with estimated absolute

reductions in liver disease progression and related sequelae of 82.2% and 66.1%,

respectively [Data on file – Gilead Sciences EAME – (HCV13000118)].

Until recently, the standard of care for HCV infection was PEG-IFN/RBV, with PI-based

triple therapy for patients with GT 1. However, such regimens have been limited by

variable efficacy, poor tolerability and the unsuitability or unwillingness of many patients

to receive these treatments. With the advent of the next-generation DAAs, including

Sovaldi® and Harvoni®, the potential exists to bridge current treatment gaps and,

importantly, to ®make treatment available to a wider population of chronic HCV patients,

including those who are unable or unwilling to receive IFN. This development is reflected

in recent updates to international treatment guidelines, which recommend Sovaldi® as

the new standard of care for all HCV genotypes and advise against the use of

PEG-IFN/RBV or the first-generation DAAs due to their side-effect profiles and risk of

drug–drug interactions [AASLD Guidelines, 2014].

Cost-effectiveness analyses have demonstrated that the costs of cure with

Harvoni®- and Sovaldi®-based regimens are economically efficient in the short-term

and cost-effective in the longer term compared with other available treatment options.

Harvoni®-based regimens are associated with more favorable health outcomes across

a broad spectrum of patients than comparator therapies, with 25.8–70.0% lower costs

per SVR amongst treatment-naïve patients and substantially lower costs for

treatment-experienced patients (6.5–55.4% and 8.1–48.5% lower, respectively, per

successfully treated patient amongst those who had previously received PEG-IFN/RBV

or PI + PEG-IFN/RBV) [Data on file – Gilead Sciences EAME – (HCV13000120)].

Amongst treatment-naïve patients alone, data suggest that earlier initiation of Harvoni®

therapy (i.e. fibrosis stage F0–F1 or F2 versus F3–F4) confers an estimated

9.6% reduction in the cost per SVR and 14.3–15.9% lower lifetime costs [Data on file –

Gilead Sciences EAME – (HCV13000118)]. Harvoni® therapy is also associated with

additional QALYs, relative to comparator therapies, in both treatment-naïve and

treatment-experienced patients [Data on file – Gilead Sciences EAME –



75

(HCV13000120)]. Such findings extend to patients with cirrhosis, in whom both Harvoni®

(GT 1 patients) and Sovaldi® (GT 2, 3 and 4 patients) have demonstrated better

long-term health outcomes, a lower incidence of liver disease complications and greater

cost-efficacy, when compared with current standards of care [Data on file – Gilead

Sciences EAME – (HCV13000111)]. Furthermore, modeling data have suggested that

reduced rates of absenteeism, alone, amongst cirrhotic and non-cirrhotic patients

receiving Harvoni® therapy, as a result of higher SVR12 rates, are associated with

significantly increased work productivity versus baseline and an anticipated economic

gain of $2 billion or more per year in the USA [Data on file – Gilead Sciences EAME –

(HCV13000112)]. Importantly, Harvoni®-based treatment has demonstrated an

incremental cost-effectiveness ratio (ICER) that remains well below $50,000 per QALY

gained, considered the willingness-to-pay threshold for payers in the USA. These

findings indicate that Harvoni® is a cost-effective strategy relative to other available

treatment options, even when variance in clinical, cost and natural history parameters is

taken into account [Data on file – Gilead Sciences EAME – (HCV13000111); Data on file

– Gilead Sciences EAME – (HCV13000120)].

As Harvoni®, like Sovaldi®, has received breakthrough therapy designation by the US

FDA, it seems likely that Harvoni® will achieve a similarly rapid adoption into national and

international treatment guidelines as Sovaldi®. In addition, given the high rates of SVR12

associated with Harvoni® across a wide patient population, including those with

traditionally difficult-to-treat characteristics, Harvoni® may offer a similar level of

cost-effectiveness, with the added benefits of short and simplified all-oral dosing

regimens that do not require the concomitant administration of IFN.



76

13. Summary of regulatory status of the medicine Table 19. Worldwide Marketing Authorization status for Harvoni® tablets

Territory Approval date Trade name

United States of America October 10, 2014 Harvoni®

Canada October 16, 2014 Harvoni®

European Union November 18, 2014 Harvoni®

14. Availability of pharmacopoeial standards

(British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia)

14.1 Specifications of Harvoni® tablets

European Pharmacopoeia:

US Pharmacopoeia:

In-house standards – see Table 20.



77

Table 20. Summary of release tests and acceptance limits for Harvoni® tablets

Test description Access limit

Appearance LDV/SOF Tablets are orange/white, diamond-shaped, film-coated

tablets, debossed with ‘GSI’ on one side and ‘7985’ on the other

side.

LDV/SOF Tablets are packaged in 100-mL, white, high density

polyethylene bottles containing one gram of silica gel desiccant

and a polyester fiber coil. Each bottle contains 28 tablets and is

capped using a white, continuous thread, child-resistant

polypropylene screw cap with an induction-sealed, aluminum-

faced liner.

Identification –

Chromatographic

Retention Time

The retention times of the main peaks in LDV/SOF Tablets are

consistent with the reference standard of each active ingredient.

Identification –

UV Spectrum

The ultraviolet absorption spectrum of LDV/SOF Tablets is

consistent with that of SOF and LDV reference standard solution.

Water Content The water content of LDV/SOF Tablets is not more than 5.0%.

Strength The strength of each active ingredient in LDV/SOF Tablets is not

less than 95.0% and not more than 105.0% of the label strength.

Degradation Product

Content

For SOF: A total of not more than 0.6% of SOF-related

degradation products with not more than 0.30% each of

GS-606965, GS-331007, GS-566500, GS-607669, GS-607670

and phenol, and not more than 0.20% each of any SOF-related

unspecified degradation product.

For LDV: A total of not more than 1.4% LDV-related degradation

products with not more than 1.25% of GS-459666, and not more

than 0.20% each of any LDV-related unspecified degradation

product.

Uniformity of Dosage

Units

LDV/SOF Tablets meet the USP or Ph. Eur. requirements for

content uniformity.

Dissolution LDV/SOF Tablets meet the USP or Ph. Eur. criteria for the

amount of SOF and LDV dissolved at 30 minutes when Q is 80%.

LDV, ledipasvir; Ph. Eur., European Pharmacopoeia; SOF, sofosbuvir;

USP, United States Pharmacopoeia; UV, ultraviolet



78

15. Proposed (new/adapted) text for the WHO Model Formulary

15.1 Other antivirals

Ledipasvir/sofosbuvir

Tablet: 90 mg LDV and 400 mg SOF (Table 21).

Also known as HARVONI®.

Uses: Harvoni is licensed in the USA for the treatment of chronic HCV GT 1 infection in

adult patients (aged ≥18 years). In Europe, Harvoni is also indicated for the treatment of

adult patients with chronic HCV GT 4 infection and some GT 3 patients [Harvoni® US PI,

2014; Harvoni® SmPC, 2014].

Precautions: The concomitant use of Harvoni® and P-gp inducers, such as rifampin or

St John’s wort, is not recommended. In addition, the use of Harvoni® in combination with

other drugs containing SOF, including Sovaldi®, is not recommended.

Dose: One tablet taken orally once daily, with or without food.

Table 21. Summary of drugs comprising the Harvoni® STR and the dose of each agent per tablet

Agent Dose per tablet

LDV

SOF

90 mg

400 mg LDV, ledipasvir; SOF, sofosbuvir

Adverse effects: The most common adverse reactions (incidence greater than or equal

to 10%, all grades) observed with treatment with Harvoni® for 8, 12 or 24 weeks were

fatigue and headache.

Please refer to the Prescribing Information appropriate to the Gilead Access Program

contained in Appendix 1 for further details on Harvoni®.



79

16. References

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Afdhal N, Reddy R, Nelson D, et al. Ledipasvir and sofosbuvir for previously treated HCV

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Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for previously untreated

HCV genotype 1 infection. N Engl J Med 2014c;370:1889–98.

Averhoff FM, Glass N, Holtzman D. Global burden of hepatitis C: Considerations for

healthcare providers in the United States. Clin Infect Dis 2012:55(Suppl 1):S10–15.

Backx M, Lewszuk A, White JR, et al. The cost of treatment failure: resource use and

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Bezemer G, Van Gool AR, Verheij-Hart E, et al. Long-term effects of treatment and

response in patients with chronic hepatitis C on quality of life. An international,

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Bourliere M, Khaloun A, Wartelle-Bladou C, et al. Future treatment of patients with HCV

cirrhosis. Liver Int 2012;32 Suppl 1:113‒9.

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Gilead’s Harvoni® (ledipasvir/sofosbuvir), the first single tablet regimen to treat the

majority of chronic hepatitis C patients with genotype 1 and 4. Available

at: http://www.gilead.com/news/press-releases/2014/11/european-commission-grants-

marketing-authorization-for-gileads-harvoni-ledipasvirsofosbuvir-the-first-single-tablet-

regimen-to-treat-the-majority-of-chronic-hepatitis-c-patients-with-genotype-1-and-4.


Gilead Sciences Inc. Harvoni® US Prescribing Information, October 2014. Available at:

http://www.gilead.com/~/media/Files/pdfs/medicines/liver-disease/harvoni/harvoni_pi.pdf.


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at: http://www.gilead.com/~/media/Files/pdfs/medicines/liver-

disease/sovaldi/sovaldi_pi.pdf. Accessed November 2014.

http://www.gilead.com/news/press-releases/2014/11/european-commission-grants-marketing-authorization-for-gileads-harvoni-ledipasvirsofosbuvir-the-first-single-tablet-regimen-to-treat-the-majority-of-chronic-hepatitis-c-patients-with-genotype-1-and-4



http://www.gilead.com/~/media/Files/pdfs/medicines/liver-disease/sovaldi/sovaldi_pi.pdf

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Available at: https://www.medicines.org.uk/emc/medicine/29471. Accessed November

2014.

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costs in patients with chronic hepatitis C (CHC) virus infection. Hepatology

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contaminated injections given in health care settings. Int J STD AIDS 2004;15:7–16.

Himoto T, Masaki T. Extrahepatic manifestations and autoantibodies in patients with

hepatitis C virus infection. Clin Dev Immunol 2012;2012:871401.

Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3

in patients without treatment options. N Engl J Med 2013;368:1867–77.

Karoney MJ, Siika AM. Hepatitis C virus (HCV) infection in Africa: a review. Pan Af Med

J 2013;14:44.

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for chronic HCV without cirrhosis. N Engl J Med 2014;370:1879–88.

Lawitz E, Poordad F, Pang PS, et al. Sofosbuvir and ledipasvir fixed-dose combination

with and without ribavirin in treatment-naïve and previously treated patients with

genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised, phase 2

trial. Lancet 2014;383:515–23.

Lawitz E, Lalezari JP, Hassanein T, et al. Sofosbuvir in combination with peginterferon

alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3

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year cost associated with chronic hepatitis C virus and associated liver complications in

the United States: a managed care perspective. J Manag Care Pharm 2011;17:531–46.

McCombs JS, Yuan Y, Shin J, et al. Economic burden associated with patients

diagnosed with hepatitis C. Clin Ther 2011;33:1268–80.

Mohd Hanafiah K, Groege J, Flaxman AD, et al. Global prevalence of hepatitis C virus

infection: new estimates of age-specific antibody to HCV seroprevalence. Hepatology

2013;57:1333–42.

Mohsen AH, Easterbrook P, Taylor CB, et al. Hepatitis C and HIV-1 co-infection. Gut

2002;51:601–8.

Naggie S, Sulkowski MS. Management of patients coinfected with HCV and HIV: a close

look at the role for direct-acting antivirals. Gastroenterology 2012;142:1324‒34.

Nelson PK, Mathers BM, Corrie B, et al. Global epidemiology of hepatitis B and hepatitis

C in people who inject drugs: results of systematic reviews. Lancet 2011;378:571–83.

North CS, Hong BA, Adewuyi SA, et al. Hepatitis C treatment and SVR: the gap between

clinical trials and real-world treatment aspirations. Gen Hosp Psychiatry 2013;35:122‒8.

Operskalski EA, Kovacs A. HIV/HCV co-infection: pathogenesis, clinical complications,

treatment, and new therapeutic technologies. Curr HIV/AIDS Rep 2011;8:12–22.



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measures. East Mediterr Health J 2010;16(suppl):S15–23.

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and cost in the United States. Hepatology 2013;57:2164‒70.

Sievert W, Altraif I, Rezavi HI, et al. A systematic review of hepatitis C virus

epidemiology in Asia, Australia and Egypt. Liver Int 2011;31(Suppl 2):6–80.

UNAIDS. UNAIDS World AIDS Day Report 2012. Available

at: http://www.unaids.org/sites/default/files/media_asset/JC2434_WorldAIDSday_results

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Vietri J, Prajapati G, El Khoury, AC. The burden of hepatitis C in Europe from the

patients’ perspective: a survey in 5 countries. BMC Gastroenterology 2013;13:16.

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Appendix 1. Harvoni® Access PI



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FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE HARVONI is indicated for the treatment of chronic hepatitis C (CHC) genotype 1 infection in adults. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage in Adults HARVONI is a two-drug fixed-dose combination product that contains 90 mg of ledipasvir and 400 mg of sofosbuvir in a single tablet. The recommended dosage of HARVONI is one tablet taken orally once daily with or without food [see Clinical Pharmacology (12.3)]. Duration of Treatment Relapse rates are affected by baseline host and viral factors and differ between treatment durations for certain subgroups [see Clinical Studies (14)]. Table 1 below provides the recommended HARVONI treatment durations for treatment-naïve and treatment-experienced patients and those with and without cirrhosis [see Clinical Studies (14)]. Table 1 Recommended Treatment Duration for HARVONI in Patients with CHC Genotype 1 Patient Population Recommended Treatment Duration Treatment-naïve with or without cirrhosis 12 weeks* Treatment-experienced** without cirrhosis 12 weeks Treatment-experienced** with cirrhosis 24 weeks

* HARVONI for 8 weeks can be considered in treatment-naïve patients without cirrhosis who have pre-treatment HCV RNA less than 6 million IU/mL [see Clinical Studies (14)]. **Treatment-experienced patients who have failed treatment with either peginterferon alfa + ribavirin or an HCV protease inhibitor + peginterferon alfa + ribavirin.

2.2 Severe Renal Impairment and End Stage Renal Disease No dose recommendation can be given for patients with severe renal impairment (estimated Glomerular Filtration Rate [eGFR] <30 mL/min/1.73m2) or with end stage renal disease (ESRD) due to higher exposures (up to 20-fold) of the predominant sofosbuvir metabolite [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. 3 DOSAGE FORMS AND STRENGTHS HARVONI is available as an orange colored, diamond shaped, film-coated tablet debossed with “GSI” on one side and “7985” on the other side of the tablet. Each tablet contains 90 mg ledipasvir and 400 mg sofosbuvir.



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4 CONTRAINDICATIONS None 5 WARNINGS AND PRECAUTIONS 5.1 Risk of Reduced Therapeutic Effect Due to P-gp Inducers The concomitant use of HARVONI and P-gp inducers (e.g., rifampin, St. John’s wort) may significantly decrease ledipasvir and sofosbuvir plasma concentrations and may lead to a reduced therapeutic effect of HARVONI. Therefore, the use of HARVONI with P-gp inducers (e.g., rifampin or St. John’s wort) is not recommended [see Drug Interactions (7.2)]. 5.2 Related Products Not Recommended The use of HARVONI with other products containing sofosbuvir (SOVALDI®) is not recommended. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety assessment of HARVONI was based on pooled data from three Phase 3 clinical trials of subjects with genotype 1 chronic hepatitis C (CHC) with compensated liver disease (with and without cirrhosis) including 215, 539, and 326 subjects who received HARVONI for 8, 12 and 24 weeks, respectively [see Clinical Studies (14)]. The proportion of subjects who permanently discontinued treatment due to adverse events was 0%, <1%, and 1% for subjects receiving HARVONI for 8, 12, and 24 weeks, respectively. The most common adverse reactions (≥10%) were fatigue and headache in subjects treated with 8, 12, or 24 weeks of HARVONI. Table 2 lists adverse reactions (adverse events assessed as causally related by the investigator, all grades) observed in ≥5% of subjects receiving 8, 12, or 24 weeks treatment with HARVONI in clinical trials. The majority of adverse reactions presented in Table 2 occurred at severity of grade 1. The side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trial designs.



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Table 2 Adverse Reactions (All Grades) Reported in ≥5% of Subjects Receiving 8, 12, or 24 Weeks of Treatment with HARVONI HARVONI

8 weeks HARVONI 12 weeks

HARVONI 24 weeks

N=215 N=539 N=326 Fatigue 16% 13% 18%

Headache 11% 14% 17%

Nausea 6% 7% 9%

Diarrhea 4% 3% 7%

Insomnia 3% 5% 6%

Laboratory Abnormalities

Bilirubin Elevations: Bilirubin elevations of greater than 1.5xULN were observed in 3%, <1%, and 2% of subjects treated with HARVONI for 8, 12, and 24 weeks, respectively.

Lipase Elevations: Transient, asymptomatic lipase elevations of greater than 3xULN were observed in <1%, 2%, and 3% of subjects treated with HARVONI for 8, 12, and 24 weeks, respectively.

Creatine Kinase: Creatine kinase was not assessed in Phase 3 trials of HARVONI. Isolated, asymptomatic creatine kinase elevations (Grade 3 or 4) have been previously reported in subjects treated with sofosbuvir in combination with ribavirin or peginterferon/ribavirin in other clinical trials.

7 DRUG INTERACTIONS 7.1 Potential for Drug Interaction As HARVONI contains ledipasvir and sofosbuvir, any interactions that have been identified with these agents individually may occur with HARVONI. After oral administration of HARVONI, sofosbuvir is rapidly absorbed and subject to extensive first-pass hepatic extraction. In clinical pharmacology studies, both sofosbuvir and the inactive metabolite GS-331007 were monitored for purposes of pharmacokinetic analyses. Ledipasvir is an inhibitor of the drug transporters P-gp and breast cancer resistance protein (BCRP) and may increase intestinal absorption of coadministered substrates for these transporters.



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Ledipasvir and sofosbuvir are substrates of drug transporters P-gp and BCRP while GS-331007 is not. P-gp inducers (e.g., rifampin or St. John’s wort) may decrease ledipasvir and sofosbuvir plasma concentrations, leading to reduced therapeutic effect of HARVONI, and the use with P-gp inducers is not recommended with HARVONI [see Warnings and Precautions (5.1)]. 7.2 Established and Potentially Significant Drug Interactions Table 3 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with either HARVONI, the components of HARVONI (ledipasvir and sofosbuvir) as individual agents, or are predicted drug interactions that may occur with HARVONI [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)]. Table 3 Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interactiona Concomitant Drug Class: Drug Name

Effect on Concentrationb

Clinical Comment

Acid Reducing Agents

↓ledipasvir

Ledipasvir solubility decreases as pH increases. Drugs that increase gastric pH are expected to decrease concentration of ledipasvir.

Antacids (e.g., aluminum and magnesium hydroxide)

It is recommended to separate antacid and HARVONI administration by 4 hours.

H2-receptor antagonistsc

(e.g., famotidine)

H2-receptor antagonists may be administered simultaneously with or 12 hours apart from HARVONI at a dose that does not exceed doses comparable to famotidine 40 mg twice daily.

Proton-pump inhibitorsc

(e.g., omeprazole)

Proton-pump inhibitor doses comparable to omeprazole 20 mg or lower can be administered simultaneously with HARVONI under fasted conditions.

Antiarrhythmics: digoxin

↑ digoxin

Coadministration of HARVONI with digoxin may increase the concentration of digoxin. Therapeutic concentration monitoring of digoxin is recommended when coadministered with HARVONI.

Anticonvulsants: carbamazepine phenytoin phenobarbital oxcarbazepine

↓ ledipasvir ↓ sofosbuvir ↓ GS-331007

Coadministration of HARVONI with carbamazepine, phenytoin, phenobarbital, or oxcarbazepine is expected to decrease the concentration of ledipasvir and sofosbuvir, leading to reduced therapeutic effect of HARVONI. Coadministration is not recommended.



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Antimycobacterials: rifabutin rifampinc

rifapentine


Coadministration of HARVONI with rifabutin or rifapentine is expected to decrease the concentration of ledipasvir and sofosbuvir, leading to reduced therapeutic effect of HARVONI. Coadministration is not recommended. Coadministration of HARVONI with rifampin, a P-gp inducer, is not recommended [see Warnings and Precautions (5.1)].

HIV Antiretrovirals: efavirenz emtricitabine tenofovir disoproxil fumarate (DF)

↑ tenofovir

Monitor for tenofovir-associated adverse reactions in patients receiving HARVONI concomitantly with the combination of efavirenz, emtricitabine and tenofovir DF. Refer to VIREAD, TRUVADA, or ATRIPLA prescribing information for recommendations on renal monitoring.

Regimens containing tenofovir DF and a HIV protease inhibitor/ritonavir • atazanavir/ritonavir +


• darunavir/ritonavir + emtricitabine/tenofovir DFc

• lopinavir/ritonavir + emtricitabine/tenofovir DF

↑ tenofovir

The safety of increased tenofovir concentrations in the setting of HARVONI and a HIV protease inhibitor/ritonavir has not been established. Consider alternative HCV therapy or ART to avoid increases in tenofovir exposures. If coadministration is necessary, monitor for tenofovir-associated adverse reactions. Refer to VIREAD or TRUVADA prescribing information for recommendations on renal monitoring.

elvitegravir cobicistat emtricitabine tenofovir DF

↑ tenofovir

The safety of increased tenofovir concentrations in the setting of HARVONI and the combination of elvitegravir, cobicistat, emtricitabine and tenofovir DF has not been established. Coadministration is not recommended.

tipranavir/ritonavir


Coadministration of HARVONI with tipranavir/ritonavir is expected to decrease the concentration of ledipasvir and sofosbuvir, leading to reduced therapeutic effect of HARVONI. Coadministration is not recommended.

HCV Products: simeprevirc

↑ ledipasvir ↑ simeprevir

Concentrations of ledipasvir and simeprevir are increased when simeprevir is coadministered with ledipasvir. Coadministration of HARVONI with simeprevir is not recommended.

Herbal Supplements: St. John’s wort (Hypericum perforatum)


Coadministration of HARVONI with St. John’s wort, a P-gp inducer is not recommended [see Warnings and Precautions (5.1)].



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HMG-CoA Reductase Inhibitors: rosuvastatin

↑ rosuvastatin

Coadministration of HARVONI with rosuvastatin may significantly increase the concentration of rosuvastatin which is associated with increased risk of myopathy, including rhabdomyolysis. Coadministration of HARVONI with rosuvastatin is not recommended.

a. This table is not all inclusive. b. ↓ = decrease, ↑ = increase c. These interactions have been studied in healthy adults. 7.3 Drugs without Clinically Significant Interactions with HARVONI Based on drug interaction studies conducted with the components of HARVONI (ledipasvir or sofosbuvir) or HARVONI, no clinically significant drug interactions have been either observed or are expected when HARVONI is used with the following drugs individually [see Clinical Pharmacology (12.3)]: abacavir, atazanavir/ritonavir, cyclosporine, darunavir/ritonavir, efavirenz, emtricitabine, lamivudine, methadone, oral contraceptives, pravastatin, raltegravir, rilpivirine, tacrolimus, tenofovir disoproxil fumarate, or verapamil. See Table 3 for use of HARVONI with certain HIV antiretroviral regimens [see Drug Interactions (7.2)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B There are no adequate and well-controlled studies with HARVONI in pregnant women. Because animal reproduction studies are not always predictive of human response, HARVONI should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal Data Ledipasvir: No effects on fetal development have been observed in rats and rabbits at the highest doses tested. In the rat and rabbit, AUC exposure to ledipasvir was approximately 4- and 2-fold, respectively, the exposure in humans at the recommended clinical dose. Sofosbuvir: No effects on fetal development have been observed in rats and rabbits at the highest doses tested. In the rat and rabbit, AUC exposure to the predominant circulating metabolite GS-331007 increased over the course of gestation from approximately 3- to 6-fold and 7- to 17-fold the exposure in humans at the recommended clinical dose, respectively. 8.3 Nursing Mothers It is not known whether HARVONI and its metabolites are present in human breast milk. When administered to lactating rats, ledipasvir was detected in the plasma of suckling rats likely due to the presence of ledipasvir in milk. Ledipasvir had no clear



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effects on the nursing pups. The predominant circulating metabolite of sofosbuvir (GS-331007) was the primary component observed in the milk of lactating rats, without effect on nursing pups. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for HARVONI and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness of HARVONI have not been established in pediatric patients. 8.5 Geriatric Use Clinical trials of HARVONI included 117 subjects aged 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. No dosage adjustment of HARVONI is warranted in geriatric patients [see Clinical Pharmacology (12.3)]. 8.6 Renal Impairment No dosage adjustment of HARVONI is required for patients with mild or moderate renal impairment. The safety and efficacy of HARVONI have not been established in patients with severe renal impairment (eGFR <30 mL/min/1.73m2) or ESRD requiring hemodialysis. No dosage recommendation can be given for patients with severe renal impairment or ESRD [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment No dosage adjustment of HARVONI is required for patients with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C). Safety and efficacy of HARVONI have not been established in patients with decompensated cirrhosis [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE No specific antidote is available for overdose with HARVONI. If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with HARVONI consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. Hemodialysis is unlikely to result in significant removal of ledipasvir since ledipasvir is highly bound to plasma protein. Hemodialysis can efficiently remove the predominant circulating metabolite of sofosbuvir, GS-331007, with an extraction ratio of 53%. 11 DESCRIPTION HARVONI is a fixed-dose combination tablet containing ledipasvir and sofosbuvir for oral administration. Ledipasvir is an HCV NS5A inhibitor and sofosbuvir is a nucleotide analog inhibitor of HCV NS5B polymerase.



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Each tablet contains 90 mg ledipasvir and 400 mg sofosbuvir. The tablets include the following inactive ingredients: colloidal silicon dioxide, copovidone, croscarmellose sodium, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The tablets are film-coated with a coating material containing the following inactive ingredients: FD&C yellow #6/sunset yellow FCF aluminum lake, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. Ledipasvir: The IUPAC name for ledipasvir is Methyl [(2S)-1-{(6S)-6-[5-(9,9-difluoro-7-{2-[(1R,3S,4S)-2-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-azabicyclo[2.2.1]hept-3-yl]-1H-benzimidazol-6-yl}-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-azaspiro[2.4]hept-5-yl}-3-methyl-1-oxobutan-2-yl]carbamate. It has a molecular formula of C49H54F2N8O6 and a molecular weight of 889.00. It has the following structural formula:

Ledipasvir is practically insoluble (<0.1 mg/mL) across the pH range of 3.0–7.5 and is slightly soluble below pH 2.3 (1.1 mg/mL). Sofosbuvir: The IUPAC name for sofosbuvir is (S)-Isopropyl 2-((S)-(((2R,3R,4R,5R)-5- (2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2- yl)methoxy)-(phenoxy)phosphorylamino)propanoate. It has a molecular formula of C22H29FN3O9P and a molecular weight of 529.45. It has the following structural formula:

Sofosbuvir is a white to off-white crystalline solid with a solubility of ≥2 mg/mL across the pH range of 2–7.7 at 37°C and is slightly soluble in water.



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12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action HARVONI is a fixed-dose combination of ledipasvir and sofosbuvir which are direct-acting antiviral agents against the hepatitis C virus [see Microbiology (12.4)]. 12.2 Pharmacodynamics Cardiac Electrophysiology Thorough QT studies have been conducted for ledipasvir and sofosbuvir. The effect of ledipasvir 120 mg twice daily (2.67 times the maximum recommended dosage) for 10 days on QTc interval was evaluated in a randomized, multiple-dose, placebo-, and active-controlled (moxifloxacin 400 mg) three period crossover thorough QT trial in 59 healthy subjects. At the dose of 120 mg twice daily (2.67 times the maximum recommended dosage), ledipasvir does not prolong QTc interval to any clinically relevant extent. The effect of sofosbuvir 400 mg (maximum recommended dosage) and 1200 mg (three times the maximum recommended dosage) on QTc interval was evaluated in a randomized, single-dose, placebo-, and active-controlled (moxifloxacin 400 mg) four period crossover thorough QT trial in 59 healthy subjects. At a dose three times the maximum recommended dose, sofosbuvir does not prolong QTc to any clinically relevant extent. 12.3 Pharmacokinetics Absorption The pharmacokinetic properties of ledipasvir, sofosbuvir, and the predominant circulating metabolite GS-331007 have been evaluated in healthy adult subjects and in subjects with chronic hepatitis C. Following oral administration of HARVONI, ledipasvir median peak concentrations were observed 4 to 4.5 hours post-dose. Sofosbuvir was absorbed quickly and the peak median plasma concentration was observed ~0.8 to 1 hour post-dose. Median peak plasma concentration of GS-331007 was observed between 3.5 to 4 hours post-dose. Based on the population pharmacokinetic analysis in HCV-infected subjects, geometric mean steady-state AUC0-24 for ledipasvir (N=2113), sofosbuvir (N=1542), and GS-331007 (N=2113) were 7290, 1320, and 12,000 ng•hr/mL, respectively. Steady-state Cmax for ledipasvir, sofosbuvir, and GS-331007 were 323, 618, and 707 ng/mL, respectively. Sofosbuvir and GS-331007 AUC0-24 and Cmax were similar in healthy adult subjects and subjects with HCV infection. Relative to healthy subjects (N=191), ledipasvir AUC0-24 and Cmax were 24% lower and 32% lower, respectively, in HCV-infected subjects. Effect of Food Relative to fasting conditions, the administration of a single dose of HARVONI with a moderate fat (~600 kcal, 25% to 30% fat) or high fat (~1000 kcal, 50% fat) meal increased sofosbuvir AUC0-inf by approximately 2-fold, but did not significantly affect sofosbuvir Cmax. The exposures of GS-331007 and ledipasvir were not altered in



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the presence of either meal type. The response rates in Phase 3 trials were similar in HCV-infected subjects who received HARVONI with food or without food. HARVONI can be administered without regard to food. Distribution Ledipasvir is >99.8% bound to human plasma proteins. After a single 90 mg dose of [14C]-ledipasvir in healthy subjects, the blood to plasma ratio of 14C-radioactivity ranged between 0.51 and 0.66. Sofosbuvir is approximately 61–65% bound to human plasma proteins and the binding is independent of drug concentration over the range of 1 μg/mL to 20 μg/mL. Protein binding of GS-331007 was minimal in human plasma. After a single 400 mg dose of [14C]-sofosbuvir in healthy subjects, the blood to plasma ratio of 14C-radioactivity was approximately 0.7. Metabolism In vitro, no detectable metabolism of ledipasvir was observed by human CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Evidence of slow oxidative metabolism via an unknown mechanism has been observed. Following a single dose of 90 mg [14C]-ledipasvir, systemic exposure was almost exclusively to the parent drug (>98%). Unchanged ledipasvir is the major species present in feces. Sofosbuvir is extensively metabolized in the liver to form the pharmacologically active nucleoside analog triphosphate GS-461203. The metabolic activation pathway involves sequential hydrolysis of the carboxyl ester moiety catalyzed by human cathepsin A (CatA) or carboxylesterase 1 (CES1) and phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 (HINT1) followed by phosphorylation by the pyrimidine nucleotide biosynthesis pathway. Dephosphorylation results in the formation of nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacks anti-HCV activity in vitro. After a single 400 mg oral dose of [14C]-sofosbuvir, GS-331007 accounted for approximately >90% of total systemic exposure. Elimination Following a single 90 mg oral dose of [14C]-ledipasvir, mean total recovery of the [14C]-radioactivity in feces and urine was approximately 87%, with most of the radioactive dose recovered from feces (approximately 86%). Unchanged ledipasvir excreted in feces accounted for a mean of 70% of the administered dose and the oxidative metabolite M19 accounted for 2.2% of the dose. These data indicate that biliary excretion of unchanged ledipasvir is a major route of elimination, with renal excretion being a minor pathway (approximately 1%). The median terminal half-life of ledipasvir following administration of HARVONI was 47 hours. Following a single 400 mg oral dose of [14C]-sofosbuvir, mean total recovery of the dose was greater than 92%, consisting of approximately 80%, 14%, and 2.5% recovered in urine, feces, and expired air, respectively. The majority of the sofosbuvir dose recovered in urine was GS-331007 (78%) while 3.5% was recovered as sofosbuvir. These data indicate that renal clearance is the major



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elimination pathway for GS-331007. The median terminal half-lives of sofosbuvir and GS-331007 following administration of HARVONI were 0.5 and 27 hours, respectively. Specific Populations

Patients with Renal Impairment: The pharmacokinetics of ledipasvir were studied with a single dose of 90 mg ledipasvir in HCV negative subjects with severe renal impairment (eGFR <30 mL/min by Cockcroft-Gault). No clinically relevant differences in ledipasvir pharmacokinetics were observed between healthy subjects and subjects with severe renal impairment.

The pharmacokinetics of sofosbuvir were studied in HCV negative subjects with mild (eGFR ≥50 and <80 mL/min/1.73m2), moderate (eGFR ≥30 and <50 mL/min/1.73m2), severe renal impairment (eGFR <30 mL/min/1.73m2), and subjects with ESRD requiring hemodialysis following a single 400 mg dose of sofosbuvir. Relative to subjects with normal renal function (eGFR >80 mL/min/1.73m2), the sofosbuvir AUC0-inf was 61%, 107%, and 171% higher in mild, moderate, and severe renal impairment, while the GS-331007 AUC0-inf was 55%, 88%, and 451% higher, respectively. In subjects with ESRD, relative to subjects with normal renal function, sofosbuvir and GS-331007 AUC0-inf was 28% and 1280% higher when sofosbuvir was dosed 1 hour before hemodialysis compared with 60% and 2070% higher when sofosbuvir was dosed 1 hour after hemodialysis, respectively. A 4 hour hemodialysis session removed approximately 18% of administered dose [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)].

Race: Population pharmacokinetics analysis in HCV-infected subjects indicated that race had no clinically relevant effect on the exposure of ledipasvir, sofosbuvir, and GS-331007.

Gender: Population pharmacokinetics analysis in HCV-infected subjects indicated that gender had no clinically relevant effect on the exposure of sofosbuvir and GS-331007. AUC and Cmax of ledipasvir were 77% and 58% higher, respectively, in females than males; however, the relationship between gender and ledipasvir exposures was not considered clinically relevant, as high response rates (SVR >90%) were achieved in male and female subjects across the Phase 3 studies and the safety profiles are similar in females and males.

Pediatric Patients: The pharmacokinetics of ledipasvir or sofosbuvir in pediatric patients has not been established [see Use in Specific Populations (8.4)].

Geriatric Patients: Population pharmacokinetic analysis in HCV-infected subjects showed that within the age range (18 to 80 years) analyzed, age



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did not have a clinically relevant effect on the exposure to ledipasvir, sofosbuvir, and GS-331007 [see Use in Specific Populations (8.5)].

Patients with Hepatic Impairment: The pharmacokinetics of ledipasvir were studied with a single dose of 90 mg ledipasvir in HCV negative subjects with severe hepatic impairment (Child-Pugh Class C). Ledipasvir plasma exposure (AUC0-inf) was similar in subjects with severe hepatic impairment and control subjects with normal hepatic function. Population pharmacokinetics analysis in HCV-infected subjects indicated that cirrhosis had no clinically relevant effect on the exposure of ledipasvir [see Use in Specific Populations (8.7)].

The pharmacokinetics of sofosbuvir were studied following 7-day dosing of 400 mg sofosbuvir in HCV-infected subjects with moderate and severe hepatic impairment (Child-Pugh Class B and C). Relative to subjects with normal hepatic function, the sofosbuvir AUC0-24 were 126% and 143% higher in moderate and severe hepatic impairment, while the GS-331007 AUC0-24 were 18% and 9% higher, respectively. Population pharmacokinetics analysis in HCV-infected subjects indicated that cirrhosis had no clinically relevant effect on the exposure of sofosbuvir and GS-331007 [see Use in Specific Populations (8.7)].

Drug Interaction Studies Ledipasvir and sofosbuvir are substrates of drug transporters P-gp and BCRP while GS-331007 is not. P-gp inducers (e.g., rifampin or St. John’s wort) may decrease ledipasvir and sofosbuvir plasma concentrations, leading to reduced therapeutic effect of HARVONI, and the use with P-gp inducers is not recommended with HARVONI [see Warnings and Precautions (5.1)]. Coadministration with drugs that inhibit P-gp and/or BCRP may increase ledipasvir and sofosbuvir plasma concentrations without increasing GS-331007 plasma concentration; HARVONI may be coadministered with P-gp and/or BCRP inhibitors. Neither ledipasvir nor sofosbuvir is a substrate for hepatic uptake transporters OCT1, OATP1B1, or OATP1B3. GS-331007 is not a substrate for renal transporters, including organic anion transporter OAT1 or OAT3, or organic cation transporter OCT2. Ledipasvir is subject to slow oxidative metabolism via an unknown mechanism. In vitro, no detectable metabolism of ledipasvir by CYP enzymes has been observed. Biliary excretion of unchanged ledipasvir is a major route of elimination. Sofosbuvir is not a substrate for CYP and UGT1A1 enzymes. Clinically significant drug interactions with HARVONI mediated by CYP or UGT1A1 enzymes are not expected. The effects of coadministered drugs on the exposure of ledipasvir, sofosbuvir, and GS-331007 are shown in Table 4 [see Drug Interactions (7.2)].



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Table 4 Drug Interactions: Changes in Pharmacokinetic Parameters for Ledipasvir, Sofosbuvir, and the Predominant Circulating Metabolite GS-331007 in the Presence of the Coadministered Druga



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NA = not available/not applicable, ND = not dosed. a. All interaction studies conducted in healthy volunteers. b. Administered as ATRIPLA®

(efavirenz, emtricitabine, tenofovir DF). c. This study was conducted in the presence of two other investigational HCV direct-acting agents. No effect on the pharmacokinetic parameters of ledipasvir, sofosbuvir, and GS-331007 was observed with the combination of abacavir and lamivudine, or emtricitabine, rilpivirine, and tenofovir DF, or raltegravir. Ledipasvir is an inhibitor of drug transporter P-gp and breast cancer resistance protein (BCRP) and may increase intestinal absorption of coadministered substrates for these transporters. Ledipasvir is an inhibitor of transporters OATP1B1, OATP1B3, and BSEP only at concentrations exceeding those achieved in clinic. Ledipasvir is not an inhibitor of transporters MRP2, MRP4, OCT2, OAT1, OAT3, MATE1, and OCT1. The drug-drug interaction potential of ledipasvir is primarily limited to the intestinal inhibition of P-gp and BCRP. Clinically relevant transporter inhibition by ledipasvir in the systemic circulation is not expected due to its high protein binding. Sofosbuvir and GS-331007 are not inhibitors of drug transporters P-gp, BCRP, MRP2, BSEP, OATP1B1, OATP1B3, and OCT1, and GS-331007 is not an inhibitor of OAT1, OCT2, and MATE1. Ledipasvir, sofosbuvir, and GS-331007 are not inhibitors or inducers of CYP or UGT1A1 enzymes. The effects of ledipasvir or sofosbuvir on the exposure of coadministered drugs are shown in Table 5 [see Drug Interactions (7.2)].



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Table 5 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Ledipasvir, Sofosbuvir, or HARVONIa

NA = not available/not applicable, ND = not dosed. a. All interaction studies conducted in healthy volunteers. b. Administered as ATRIPLA® (efavirenz, emtricitabine, tenofovir DF). c. Administered as COMPLERA®

(emtricitabine, rilpivirine, tenofovir DF). No effect on the pharmacokinetic parameters of the following coadministered drugs was observed with ledipasvir or sofosbuvir: abacavir, cyclosporine, darunavir/ritonavir, efavirenz, emtricitabine, lamivudine, methadone, or rilpivirine.



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12.4 Microbiology Mechanism of Action Ledipasvir is an inhibitor of the HCV NS5A protein, which is required for viral replication. Resistance selection in cell culture and cross-resistance studies indicate ledipasvir targets NS5A as its mode of action. Sofosbuvir is an inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is required for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator. In a biochemical assay, GS-461203 inhibited the polymerase activity of the recombinant NS5B from HCV genotypes 1b, 2a, 3a and 4a with IC50 values ranging from 0.7 to 2.6 μM. GS-461203 is neither an inhibitor of human DNA and RNA polymerases nor an inhibitor of mitochondrial RNA polymerase. Antiviral Activity In HCV replicon assays, the EC50 values of ledipasvir against full-length replicons from genotypes 1a and 1b were 0.031 nM and 0.004 nM, respectively. The median EC50 values of ledipasvir against chimeric replicons encoding NS5A sequences from clinical isolates were 0.018 nM for genotype 1a (range 0.009–0.085 nM; N=30) and 0.006 nM for genotype 1b (range 0.004–0.007 nM; N=3). Ledipasvir has less antiviral activity compared to genotype 1 against genotypes 4a, 5a, and 6a, with EC50 values of 0.39 nM, 0.15 nM, and 1.1 nM, respectively. Ledipasvir has substantially lower activity against genotypes 2a, 2b, 3a, and 6e with EC50 values of 21–249 nM, 16–530 nM, 168 nM, and 264 nM, respectively. In HCV replicon assays, the EC50 values of sofosbuvir against full-length replicons from genotypes 1a, 1b, 2a, 3a, and 4a, and chimeric 1b replicons encoding NS5B from genotypes 2b, 5a, or 6a ranged from 14–110 nM. The median EC50 value of sofosbuvir against chimeric replicons encoding NS5B sequences from clinical isolates was 62 nM for genotype 1a (range 29–128 nM; N=67), 102 nM for genotype 1b (range 45–170 nM; N=29), 29 nM for genotype 2 (range 14–81 nM; N=15), and 81 nM for genotype 3a (range 24–181 nM; N=106). In replication competent virus assays, the EC50 values of sofosbuvir against genotypes 1a and 2a were 30 nM and 20 nM, respectively. Evaluation of sofosbuvir in combination with ledipasvir showed no antagonistic effect in reducing HCV RNA levels in replicon cells. Resistance

In Cell Culture HCV replicons with reduced susceptibility to ledipasvir have been selected in cell culture for genotypes 1a and 1b. Reduced susceptibility to ledipasvir was associated with the primary NS5A amino acid substitution Y93H in both genotypes 1a and 1b. Additionally, a Q30E substitution emerged in genotype 1a replicons. Site-directed mutagenesis of the Y93H in both genotypes 1a and 1b, as well as the Q30E substitution in genotype 1a,



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conferred high levels of reduced susceptibility to ledipasvir (fold change in EC50 greater than 1000-fold). HCV replicons with reduced susceptibility to sofosbuvir have been selected in cell culture for multiple genotypes including 1b, 2a, 2b, 3a, 4a, 5a, and 6a. Reduced susceptibility to sofosbuvir was associated with the primary NS5B substitution S282T in all replicon genotypes examined. Site-directed mutagenesis of the S282T substitution in replicons of 8 genotypes conferred 2- to 18-fold reduced susceptibility to sofosbuvir.

In Clinical Trials In a pooled analysis of subjects who received HARVONI in Phase 3 trials, 37 subjects (29 with genotype 1a and 8 with genotype 1b) qualified for resistance analysis due to virologic failure (35 with virologic relapse, 2 with breakthrough on-treatment due to documented non-adherence). Post-baseline NS5A and NS5B deep sequencing data (assay cutoff of 1%) were available for 37/37 and 36/37 subjects’ viruses, respectively.

Of the 29 genotype 1a virologic failure subjects, 55% (16/29) of subjects had virus with emergent NS5A resistance-associated substitutions K24R, M28T/V, Q30R/H/K/L, L31M, or Y93H/N at failure. Five of these 16 subjects also had baseline NS5A polymorphisms at resistance-associated amino acid positions. The most common substitutions detected at failure were Q30R, Y93H or N, and L31M.

Of the 8 genotype 1b virologic failure subjects, 88% (7/8) had virus with emergent NS5A resistance-associated substitutions L31V/M/I or Y93H at failure. Three of these 7 subjects also had baseline NS5A polymorphisms at resistance-associated positions. The most common substitution detected at failure was Y93H.

At failure, 38% (14/37) of virologic failure subjects had 2 or more NS5A substitutions at resistance-associated positions.

In phenotypic analyses, post-baseline isolates from subjects who harbored NS5A resistance-associated substitutions at failure showed 20- to >243-fold reduced susceptibility to ledipasvir.

Treatment-emergent NS5B substitutions L159 (n=1) and V321 (n=2) previously associated with sofosbuvir failure were detected in the Phase 3 trials. In addition, NS5B substitutions at highly conserved positions D61G (n=3), A112T (n=2), E237G (n=2), and S473T (n=1) were detected at low frequency by next generation sequencing in treatment failure subjects infected with HCV GT1a. The D61G substitution was previously described in subjects infected with HCV GT1a in a liver pre-transplant trial. The clinical significance of these substitutions is currently unknown.



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The sofosbuvir-associated resistance substitution S282T in NS5B was not detected in any failure isolate from the Phase 3 trials. NS5B substitutions S282T, L320V/I, and V321I in combination with NS5A substitutions L31M, Y93H, and Q30L were detected in one subject at failure following 8 weeks of treatment with HARVONI in a Phase 2 trial.

Cross Resistance Ledipasvir was fully active against the sofosbuvir resistance-associated substitution S282T in NS5B while all ledipasvir resistance-associated substitutions in NS5A were fully susceptible to sofosbuvir. Both sofosbuvir and ledipasvir were fully active against substitutions associated with resistance to other classes of direct-acting antivirals with different mechanisms of actions, such as NS5B non-nucleoside inhibitors and NS3 protease inhibitors. NS5A substitutions conferring resistance to ledipasvir may reduce the antiviral activity of other NS5A inhibitors. The efficacy of ledipasvir/sofosbuvir has not been established in patients who have previously failed treatment with other regimens that include an NS5A inhibitor. Persistence of Resistance-Associated Substitutions No data are available on the persistence of ledipasvir or sofosbuvir resistance-associated substitutions. NS5A resistance-associated substitutions for other NS5A inhibitors have been found to persist for >1 year in some patients. Effect of Baseline HCV Polymorphisms on Treatment Response Analyses were conducted to explore the association between pre-existing baseline NS5A polymorphisms at resistance-associated positions and relapse rates. In the pooled analysis of the Phase 3 trials, 23% (370/1589) of subjects’ virus had baseline NS5A polymorphisms at resistance-associated positions (any change from reference at NS5A amino acid positions 24, 28, 30, 31, 58, 92, or 93) identified by population or deep sequencing. In treatment-naïve subjects whose virus had baseline NS5A polymorphisms at resistance-associated positions in Studies ION-1 and ION-3, relapse rates were 6% (3/48) after 8 weeks and 1% (1/113) after 12 weeks of treatment with HARVONI. Relapse rates among subjects without baseline NS5A polymorphisms at resistance-associated positions were 5% (8/167) after 8 weeks and 1% (3/306) after 12 weeks treatment with HARVONI. In treatment-experienced subjects whose virus had baseline NS5A polymorphisms at resistance-associated positions, relapse rates were 22% (5/23) after 12 weeks and 0% (0/19) after 24 weeks of treatment with HARVONI. The specific baseline NS5A resistance-associated polymorphisms observed among subjects with relapse were M28T/V, Q30H, Q30R, L31M, H58P, Y93H, and Y93N in genotype 1a, and L28M, A92T, and Y93H in genotype 1b. Subjects with multiple NS5A polymorphisms at resistance-associated positions appeared to have higher relapse rates.



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SVR was achieved in all 24 subjects (N=20 with L159F+C316N; N=1 with L159F; and N=3 with N142T) who had baseline polymorphisms associated with resistance to NS5B nucleoside inhibitors. The sofosbuvir resistance-associated substitution S282T was not detected in the baseline NS5B sequence of any subject in Phase 3 trials by population or deep sequencing. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis and Mutagenesis Ledipasvir: Ledipasvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes, and in vivo rat micronucleus assays. Carcinogenicity studies of ledipasvir in mice and rats are ongoing. Sofosbuvir: Sofosbuvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo mouse micronucleus assays. Two-year carcinogenicity studies in mice and rats were conducted with sofosbuvir. Mice were administered doses of up to 200 mg/kg/day in males and 600 mg/kg/day in females, while rats were administered doses of up to 750 mg/kg/day in males and females. No increase in the incidence of drug-related neoplasms were observed at the highest doses tested in mice and rats, resulting in AUC exposure to the predominant circulating metabolite GS-331007 of approximately 4- and 18-fold (in mice) and 8- and 10-fold (in rats), in males and females respectively, the exposure in humans at the recommended clinical dose. Impairment of Fertility Ledipasvir: Ledipasvir had no adverse effects on mating and fertility. In female rats, the mean number of corpora lutea and implantation sites were reduced slightly at maternal exposures approximately 3-fold the exposure in humans at the recommended clinical dose. At the highest dose levels without effects, AUC exposure to ledipasvir was approximately 5- and 2-fold, in males and females, respectively, the exposure in humans at the recommended clinical dose. Sofosbuvir: Sofosbuvir had no effects on embryo-fetal viability or on fertility when evaluated in rats. At the highest dose tested, AUC exposure to the predominant circulating metabolite GS-331007 was approximately 5-fold the exposure in humans at the recommended clinical dose. 13.2 Animal Toxicology and/or Pharmacology Sofosbuvir: Heart degeneration and inflammation were observed in rats following GS-9851 (a stereoisomeric mixture containing approximately 50% sofosbuvir) doses of 2,000 mg/kg/day for up to 5 days. At this dose, AUC exposure to the predominant circulating metabolite GS-331007 is approximately 17-fold higher than human exposure at the recommended clinical dose. No heart degeneration or



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inflammation was observed in mice, rats, or dogs in studies up to 3 months, 6 months, or 9 months at GS-331007 AUC exposures approximately 24-, 5-, or 17-fold higher, respectively, than human exposure at the recommended clinical dose. In addition, no heart degeneration or inflammation was observed in rats following sofosbuvir doses of up to 750 mg/kg/day in the 2-year carcinogenicity study at GS-331007 AUC exposure approximately 9-fold the exposure in humans at the recommended clinical dose. 14 CLINICAL STUDIES 14.1 Overview of Clinical Trials The efficacy of HARVONI was evaluated in three Phase 3 trials of 1518 subjects with genotype 1 chronic hepatitis C (CHC) with compensated liver disease:

• Study ION-3: noncirrhotic treatment-naïve subjects [see Clinical Studies (14.2)],

• Study ION-1: cirrhotic and noncirrhotic treatment-naïve subjects [see Clinical Studies (14.2)], and

• Study ION-2: cirrhotic and noncirrhotic subjects who failed prior therapy with an interferon-based regimen, including regimens containing an HCV protease inhibitor [see Clinical Studies (14.3)].

All three Phase 3 trials evaluated efficacy of HARVONI (one fixed-dose tablet of 90 mg of ledipasvir and 400 mg of sofosbuvir administered once daily) with or without ribavirin. Treatment duration was fixed in each trial. Serum HCV RNA values were measured during the clinical trials using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System. The assay had a lower limit of quantification (LLOQ) of 25 IU/mL. Sustained virologic response (SVR) was the primary endpoint and was defined as HCV RNA less than LLOQ at 12 weeks after the cessation of treatment. Relapse was a secondary endpoint, which was defined as HCV RNA greater than or equal to LLOQ with 2 consecutive values or last available post-treatment measurement during the post-treatment period after achieving HCV RNA less than LLOQ at end of treatment. 14.2 Clinical Trials in Treatment-Naïve Subjects Treatment-Naïve Adults without Cirrhosis ─ ION-3 (Study 0108) ION-3 was a randomized, open-label trial in treatment-naïve non-cirrhotic subjects with genotype 1 CHC. Subjects were randomized in a 1:1:1 ratio to one of the following three treatment groups and stratified by HCV genotype (1a vs 1b): HARVONI for 8 weeks, HARVONI for 12 weeks, or HARVONI + ribavirin for 8 weeks. Demographics and baseline characteristics were balanced across the treatment groups. Of the 647 treated subjects, the median age was 55 years (range: 20 to 75); 58% of the subjects were male; 78% were White; 19% were Black; 6% were Hispanic or Latino; mean body mass index was 28 kg/m2 (range: 18 to 56 kg/m2);



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81% had baseline HCV RNA levels greater than or equal to 800,000 IU/mL; 80% had genotype 1a HCV infection; 73% had non-C/C IL28B alleles (CT or TT). Table 6 presents the response rates for the HARVONI treatment groups in the ION-3 trial after 8 and 12 weeks of HARVONI treatment. Ribavirin was not shown to increase the response rates observed with HARVONI. Therefore, the HARVONI + ribavirin arm is not presented in Table 6. Table 6 Study ION-3: Response Rates after 8 and 12 Weeks of Treatment in Treatment-Naïve Non-Cirrhotic Subjects with Genotype 1 CHC HARVONI 8 weeks

(N=215) HARVONI 12 weeks

(N=216) SVR 94% (202/215) 96% (208/216)

Outcome for subjects without SVR

On-treatment virologic failure 0/215 0/216

Relapsea 5% (11/215) 1% (3/216)

Otherb 1% (2/215) 2% (5/216)

SVR by genotypec

Genotype 1a 93% (159/171) 96% (165/172)

Genotype 1b 98% (42/43) 98% (43/44)

a. The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment assessment. b. Other includes subjects who did not achieve SVR and did not meet virologic failure criteria (e.g., lost to follow-up). c. One subject without a confirmed subtype for genotype 1 infection was excluded from this subgroup analysis. The treatment difference between the 8-week treatment of HARVONI and 12-week treatment of HARVONI was –2.3% (97.5% confidence interval –7.2% to 2.5%). Among subjects with a baseline HCV RNA <6 million IU/mL, the SVR was 97% (119/123) with 8-week treatment of HARVONI and 96% (126/131) with 12-week treatment of HARVONI.



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Relapse rates by baseline viral load are presented in Table 7. Table 7 Study ION-3: Relapse Rates by Baseline Viral Load after 8 and 12 Weeks of Treatment in Treatment-Naïve Non-Cirrhotic Subjects with Genotype 1 CHC HARVONI 8 weeks

(N=215) HARVONI 12 weeks

(N=216) No. responders at end of treatment 215 216

Baseline HCV RNAa

HCV RNA <6 million IU/mL 2% (2/123) 2% (2/131)

HCV RNA ≥6 million IU/mL 10% (9/92) 1% (1/85)

a. HCV RNA values were determined using the Roche TaqMan Assay; a subject’s HCV RNA may vary from visit to visit. Treatment-Naïve Adults with or without Cirrhosis ─ ION-1 (Study 0102) ION-1 was a randomized, open-label trial that evaluated 12 and 24 weeks of treatment with HARVONI with or without ribavirin in 865 treatment-naïve subjects with genotype 1 CHC including those with cirrhosis. Subjects were randomized in a 1:1:1:1 ratio to receive HARVONI for 12 weeks, HARVONI + ribavirin for 12 weeks, HARVONI for 24 weeks, or HARVONI + ribavirin for 24 weeks. Randomization was stratified by the presence or absence of cirrhosis and HCV genotype (1a vs 1b). The interim primary endpoint analysis for SVR included all subjects enrolled in the 12-week treatment groups (N=431). SVR rates for all subjects enrolled in the 24-week treatment groups (N=434) were not available at the time of interim analysis. Demographics and baseline characteristics were balanced across the treatment groups. Of the 865 treated subjects, the median age was 54 years (range: 18 to 80); 59% of the subjects were male; 85% were White; 12% were Black; 12% were Hispanic or Latino; mean body mass index was 27 kg/m2

(range: 18 to 48 kg/m2); 79% had baseline HCV RNA levels greater than or equal to 800,000 IU/mL; 67% had genotype 1a HCV infection; 70% had non-C/C IL28B alleles (CT or TT); and 16% had cirrhosis. Table 8 presents the response rates for the treatment group of HARVONI for 12 weeks in the ION-1 trial. Ribavirin was not shown to increase response rates observed with HARVONI. Therefore, the HARVONI + ribavirin arm is not presented in Table 8.



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Table 8 Study ION-1: Response Rates after 12 Weeks of Treatment in Treatment-Naïve Subjects with Genotype 1 CHC with and without Cirrhosis HARVONI 12 WEEKS

(n=214) SVRa 99% (210/213)


On-treatment virologic failurea 0/213

Relapsea,b <1% (1/212)

Othera,c 1% (2/213) a. Excluding one subject with genotype 4 infection. b. The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment assessment. c. Other includes subjects who did not achieve SVR and did not meet virologic failure criteria (e.g., lost to follow-up). Response rates for selected subgroups are presented in Table 9. Table 9 Study ION-1: SVR Rates for Selected Subgroups after 12 Weeks of Treatment in Treatment-Naïve Subjects with Genotype 1 CHC with and without Cirrhosis HARVONI 12 WEEKS

(n=214)

Genotypea

Genotype 1a 98% (142/145)

Genotype 1b 100% (67/67)

Cirrhosisb

No 99% (176/177)

Yes 94% (32/34) a. One subject without a confirmed subtype for genotype 1 infection and one subject with genotype 4 infection were excluded from this subgroup analysis. b. Subjects with missing cirrhosis status were excluded from this subgroup analysis. 14.3 Clinical Trials in Subjects Who Failed Prior Therapy Previously-Treated Adults with or without Cirrhosis ─ ION-2 (Study 0109) ION-2 was a randomized, open-label trial that evaluated 12 and 24 weeks of treatment with HARVONI with or without ribavirin in genotype 1 HCV-infected subjects with or without cirrhosis who failed prior therapy with an interferon-based regimen, including regimens containing an HCV protease inhibitor. Subjects were randomized in a 1:1:1:1 ratio to receive HARVONI for 12 weeks, HARVONI + ribavirin for 12 weeks, HARVONI for 24 weeks, or HARVONI + ribavirin for 24



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weeks. Randomization was stratified by the presence or absence of cirrhosis, HCV genotype (1a vs 1b) and response to prior HCV therapy (relapse/breakthrough vs nonresponse). Demographics and baseline characteristics were balanced across the treatment groups. Of the 440 treated subjects, the median age was 57 years (range: 24 to 75); 65% of the subjects were male; 81% were White; 18% were Black; 9% were Hispanic or Latino; mean body mass index was 28 kg/m2

(range: 19 to 50 kg/m2); 89% had baseline HCV RNA levels greater than or equal to 800,000 IU/mL; 79% had genotype 1a HCV infection; 88% had non-C/C IL28B alleles (CT or TT); and 20% had cirrhosis. Forty-seven percent (47%) of the subjects failed a prior therapy of pegylated interferon and ribavirin. Among these subjects, 49% were relapse/breakthrough and 51% were non-responder. Fifty-three percent (53%) of the subjects failed a prior therapy of pegylated interferon and ribavirin with an HCV protease inhibitor. Among these subjects, 62% were relapse/breakthrough and 38% were non-responder. Table 10 presents the response rates for the HARVONI treatment groups in the ION-2 trial. Ribavirin was not shown to increase response rates observed with HARVONI. Therefore, the HARVONI + ribavirin arms are not presented in Table 10. Table 10 Study ION-2: Response Rates after 12 and 24 Weeks of Treatment in Subjects with Genotype 1 CHC with or without Cirrhosis who Failed Prior Therapy HARVONI

12 weeks (N=109)

HARVONI 24 weeks (N=109)

SVR 94% (102/109) 99% (108/109)


On-treatment virologic failure 0/109 0/109

Relapsea 6% (7/108) 0/109

Otherb 0/109 1% (1/109)

a. The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment assessment. b. Other includes subjects who did not achieve SVR and did not meet virologic failure criteria (e.g., lost to follow-up). Among the subjects with available SVR12 and SVR24 data (206/218), all subjects who achieved SVR12 in the ION-2 study also achieved SVR24.



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Response rates and relapse rates for selected subgroups are presented in Tables 11 and 12. Table 11 Study ION-2: SVR Rates for Selected Subgroups after 12 and 24 Weeks of Treatment in Subjects with Genotype 1 CHC who Failed Prior Therapy HARVONI

12 weeks (N=109)


Genotype

Genotype 1a 95% (82/86) 99% (84/85)

Genotype 1b 87% (20/23) 100% (24/24)

Cirrhosisa

No 95% (83/87) 99% (85/86)

Yes 86% (19/22) 100% (22/22)

Prior HCV therapy

PEG-IFN + RBV 93% (40/43) 100% (58/58)

HCV protease inhibitor + PEG-IFN + RBV 94% (62/66) 98% (49/50)

Response to prior HCV therapy

Relapse/breakthrough 95% (57/60) 100% (60/60)

Non-responder 92% (45/49) 98% (48/49)

a. Subjects with missing cirrhosis status were excluded from this subgroup analysis.



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Table 12 Study ION-2: Relapse Rates for Selected Subgroups after 12 and 24 Weeks of Treatment in Subjects with Genotype 1 CHC who Failed Prior Therapy HARVONI

12 weeks (N=109)


Number of responders at end of treatment 108 109

Cirrhosisa

No 5% (4/86)b 0% (0/86)

Yes 14% (3/22) 0 (0/22)

Presence of baseline NS5A resistance-associated polymorphismsc

No 2% (2/85) 0% (0/90)

Yes 22% (5/23) 0% (0/19)

IL28B status

C/C 0% (0/10) 0% (0/16)

Non-C/C 7% (7/98) 0% (0/93)

a. Subjects with missing cirrhosis status were excluded from this subgroup analysis. b. These 4 non-cirrhotic relapsers all had baseline NS5A resistance-associated polymorphisms. c. NS5A resistance-associated polymorphisms include any change at NS5A positions 24, 28, 30, 31, 58, 92, or 93. 16 HOW SUPPLIED/STORAGE AND HANDLING HARVONI tablets are orange, diamond-shaped, film-coated, debossed with “GSI” on one side and “7985” on the other side of the tablet. Each bottle contains 28 tablets (NDC 61958-1801-1), a silica gel desiccant, polyester coil, and is closed with a child-resistant closure. Store at room temperature below 30°C (86°F).

• Dispense only in original container. • Do not use if seal over bottle opening is broken or missing.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Drug Interactions Inform patients that HARVONI may interact with other drugs. Advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products including St. John’s wort [see Warnings and Precautions (5.1) and Drug Interactions (7)].



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Hepatitis C Virus Transmission Inform patients that the effect of treatment of hepatitis C infection on transmission is not known, and that appropriate precautions to prevent transmission of the hepatitis C virus during treatment or in the event of treatment failure should be taken. Administration Advise patients that HARVONI should be taken once daily on a regular dosing schedule with or without food. If a patient did not take HARVONI at the regular time, it should be taken as soon as they remember on the same day. Resume the usual dosing schedule the next day. Advise the patient not to take more than 1 tablet of HARVONI in a day. Manufactured and distributed by: Gilead Sciences, Inc. Foster City, CA 94404 Harvoni, Complera, Sovaldi, Truvada and Viread are trademarks of Gilead Sciences, Inc., or its related companies. Atripla is a trademark of Bristol-Myers Squibb & Gilead Sciences, LLC. All other trademarks referenced herein are the property of their respective owners. © 2014 Gilead Sciences, Inc. All rights reserved. 205834-GS-000



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Patient Information

HARVONI® (har-VOE-nee)

(ledipasvir and sofosbuvir) tablets

Read this Patient Information before you start taking HARVONI and each time you get

a refill. There may be new information. This information does not take the place of

talking with your healthcare provider about your medical condition or your treatment.

What is HARVONI?

• HARVONI is a prescription medicine used to treat chronic (lasting a long time)

hepatitis C genotype 1 infection in adults.

• HARVONI contains the prescription medicines ledipasvir and sofosbuvir

(SOVALDI®).

It is not known if HARVONI is safe and effective in children under 18 years of age.

What should I tell my healthcare provider before taking HARVONI? Before taking HARVONI, tell your healthcare provider if you:

• have liver problems other than hepatitis C infection

• have severe kidney problems or you are on dialysis

• have any other medical condition

• are pregnant or plan to become pregnant. It is not known if HARVONI will harm

your unborn baby.

• are breastfeeding or plan to breastfeed. It is not known if HARVONI passes into

your breast milk.

Tell your healthcare provider about all of the medicines you take, including

prescription and over-the-counter medicines, vitamins, and herbal supplements.

HARVONI may affect the way other medicines work, and other medicines may affect

how HARVONI works.



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You should not take HARVONI if you also take other medicines that contain

sofosbuvir (SOVALDI®).

Especially tell your healthcare provider if you take any of the following medicines:

• an antacid that contains aluminum or magnesium hydroxide. If you take an

antacid during treatment with HARVONI, take the antacid 4 hours before or 4

hours after you take HARVONI.

• carbamazepine (Carbatrol®, Epitol®, Equetro®, Tegretol®)

• digoxin (Lanoxin®)

• efavirenz, emtricitabine, tenofovir disoproxil fumarate (ATRIPLA®)

• elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate (STRIBILD®)

• medicines for indigestion, heartburn, or stomach ulcers, such as nizatidine

(Axid®), famotidine (Pepcid AC®), cimetidine (Tagamet®), ranitidine (Zantac®),

esomeprazole (Nexium®), lansoprazole (Prevacid®), omeprazole (Prilosec®),

rabeprazole (Aciphex®), or pantoprazole (Protonix®)

• oxcarbazepine (Trileptal®, Oxtellar XR®)

• phenytoin (Dilantin®, Phenytek®)

• phenobarbital (Luminal®)

• rifabutin (Mycobutin®)

• rifampin (Rifadin®, Rifamate®, Rifater®, Rimactane®)

• rifapentine (Priftin®)

• rosuvastatin (Crestor®)

• simeprevir (Olysio®)

• St. John’s wort (Hypericum perforatum) or a product that contains St. John’s

wort

• tipranavir (Aptivus®) used in combination with ritonavir (Norvir®)

• tenofovir disoproxil fumarate (VIREAD®, TRUVADA®) used in combination with

atazanavir (Reyataz®) and ritonavir (Norvir®), darunavir (Prezista®) and ritonavir

(Norvir®), or used in combination with lopinavir and ritonavir (Kaletra®)

Know the medicines you take. Keep a list of your medicines and show it to your

healthcare provider and pharmacist when you get a new medicine.



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How should I take HARVONI?

• Take HARVONI exactly as your healthcare provider tells you to take it. Do not

change your dose unless your healthcare provider tells you to.

• Do not stop taking HARVONI without first talking with your healthcare provider.

If you think there is a reason to stop taking HARVONI, talk to your healthcare

provider before doing so.

• Take HARVONI 1 time each day with or without food.

• If you miss a dose of HARVONI, take the missed dose as soon as you

remember the same day. Do not take more than 1 tablet of HARVONI in a day.

Take your next dose of HARVONI at your regular time the next day

• If you take too much HARVONI, call your healthcare provider or go to the

nearest hospital emergency room right away.

What are the possible side effects of HARVONI? The most common side effects of HARVONI include:

• tiredness

• headache

Tell your healthcare provider if you have any side effect that bothers you or that does

not go away.

These are not all the possible side effects of HARVONI. For more information, ask your

healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to

FDA at 1-800-FDA-1088.

How should I store HARVONI?

• Store HARVONI at room temperature below 86°F (30°C).

• Keep HARVONI in its original container.

• Do not use HARVONI if the seal over the bottle opening is broken or missing.

Keep HARVONI and all medicines out of the reach of children.



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General information about the safe and effective use of HARVONI It is not known if treatment with HARVONI will prevent you from infecting another

person with the hepatitis C virus during treatment. Talk with your healthcare provider

about ways to prevent spreading the hepatitis C virus.

Medicines are sometimes prescribed for purposes other than those listed in a Patient

Information leaflet. Do not use HARVONI for a condition for which it was not

prescribed. Do not give HARVONI to other people, even if they have the same

symptoms you have. It may harm them.

If you would like more information about HARVONI, talk with your healthcare provider.

You can ask your healthcare provider or pharmacist for information about HARVONI

that is written for health professionals.

For more information, call 1-800-445-3235 or go to www.HARVONI.com.

What are the ingredients in HARVONI? Active ingredients: ledipasvir and sofosbuvir

Inactive ingredients: colloidal silicon dioxide, copovidone, croscarmellose sodium,

lactose monohydrate, magnesium stearate, and microcrystalline cellulose.

The tablet film-coat contains: FD&C yellow #6/sunset yellow FCF aluminum lake,

polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Manufactured and distributed by:


Foster City, CA 94404

Issued: October 2014



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Harvoni, Sovaldi, Stribild, Truvada and Viread are trademarks of Gilead Sciences, Inc.,

or its related companies. Atripla is a trademark of Bristol-Myers Squibb & Gilead

Sciences, LLC. All other trademarks referenced herein are the property of their

respective owners.

©2014 Gilead Sciences, Inc. All rights reserved.

205834-GS-000

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