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© European Medicines Agency, 2011. Reproduction is authorised provided the source is acknowledged.

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7 20 January 2011

EMEA/CHMP/51240/2011

Committee for Medicinal Products for Human Use (CHMP) Guideline on clinical evaluation of medicinal products for the treatment of chronic hepatitis C. Draft

Draft Agreed by Infectious Di

seases Working Party January 2011 Adoption by CHMP for release for consultation 20 January 2011 End of consultation (deadline for comments) 31 August 2011 8 9

Comments should be provided using this template

. The completed comments form should be sent to

IDWPSecretariat@ema.europa.eu

10

Keywords

Hepati tis C, CHC, direct antivirals, interferon, ribavirin, transplantation, SOC,

HCV RNA, EMEA, CHMP, Guideline, drug approval.

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Table of contents

EXECUTIVE SUMMARY........................................................................ .........4

1. INTRODUCTION........................................................................

...............4

1.1. Epidemiology........................................................................

............................. 4

1.2. Natural course of HCV infection........................................................................

.... 5

1.3. HCV therapy........................................................................

.............................. 5

1.4. Direct acting antivirals........................................................................

................ 6

1.5. Host targeting antivirals........................................................................

.............. 6

2. SCOPE........................................................................

..............................6

3. LEGAL BASIS........................................................................

...................6

4. MAIN GUIDELINE TEXT........................................................................

....7

4.1. Subject characteristics and the definition of patient populations................................ 7

4.1.1. Viral genotypes........................................................................

....................... 7

4.1.2. Host IL28B genotype........................................................................

............... 8

4.1.3. Treatment history........................................................................

.................... 9

4.1.4. Special populations........................................................................

.................. 9

4.1.5. Assessment of liver histology........................................................................

.... 9

4.2. Methods to evaluate efficacy........................................................................

...... 10

4.2.1. Determination of HCV-RNA levels..................................................................... 10

4.2.2. Endpoints........................................................................

............................. 10

4.3. Clinical pharmacology, virology and toxicology studies........................................... 11

4.3.1. Pharmacokinetics and drug drug interactions..................................................... 11

4.3.2. Pharmacodynamics and drug resistance............................................................ 12

4.3.3. Toxicology studies........................................................................

................. 13

4.4. Clinical efficacy studies........................................................................

............. 13

4.4.1. Dose finding monotherapy studies................................................................... 13

4.4.2. Early combination dose ranging studies (phase 2a)............................................ 14

4.4.3. Further development of regimens containing one DAA or HTA in combination with

pegIFN and ribavirin........................................................................ ....................... 14

4.4.4. Studies of 2 DAA/HTAs in combination with pegIFN and ribavirin.......................... 16

4.4.5. Studies of 2 or more DAA/HTA without pegIFN, with or without ribavirin............... 16

4.4.6. Specific concerns regarding immunomodulating agents....................................... 17

4.4.7. The use of erythropoesis stimulating agents (ESA) in confirmatory trials............... 18

4.5. Studies in special populations........................................................................

.... 18

4.5.1. Treatment of patients with decompensated liver disease and/or pre-transplant...... 18

4.5.2. Post transplant treatment........................................................................

....... 19 3/23

4.5.3. HCV/HIV coinfected patients........................................................................

... 19 51 52
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4.5.4. PegIFN and ribavirin intolerant patients............................................................ 20

4.5.5. Patients with prior DAA experience................................................................... 20

4.5.6. Studies in children........................................................................

................. 21

4.6. Clinical safety evaluation........................................................................

........... 22

5. Definitions and Abbreviations:..............................................................23

4/23

EXECUTIVE SUMMARY 58

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100 This guideline provides guidance on the clinical development of compounds for the treatment of

Chronic Hepatitis C (CHC), including directly acting antivirals (DAAs) as well as host targeting antivirals

(HTA). It should be read in conjunction with updated and recognised clinical treatment guidelines. Various combination regimens, including a DAA or HTA together with peginterferon (pegIFN) and ribavirin, regimens with more than one DAA/HTA in combination with pegIFN + ribavirin, as well as regimens excluding either or both of these agents, are considered. While the primary investigation of new DAA/HTA in combination with pegIFN + ribavirin in patients with genotype (GT) 1 remains important, it is recognised that other paths of drug development, focussing on wider or alternative populations, or other drug combinations (such as more than one DAA/HTA with or without ribavirin, or 2 DAA/HTAs in combination with pegIFN+ribavirin) are warranted and ongoing. The guidelines emphasize the importance of new DAA/HTA for usage in special populations including patients with decompensated liver disease, patients pre/post transplantation, HCV/HIV co-infected patients, patients intolerant to pegIFN and bavirin and patients with prior DAA experience.

When studying novel agents in combination with pegIFN and ribavirin, the comparator in pivotal trials

should be a licensed first line recommended regimen; notwithstanding this, European regulators

recognise the need for licensed DAA/HTAs from several classes, with different side effects profiles and

resistance patterns, which is seen as a benefit per se. When studying novel drug combinations without

pegIFN, it is recommended that patients previously failing therapy with pegIFN+ribavirin that do not have an immediate treatment need be avoided prior to obtaining proof-of-concept of sustained virological response (SVR), as the consequences of acquired drug resistance in terms of retreatment

success has still not been investigated. For drugs to be used in combinations eschewing pegIFN, it is

recognised that patients that do not tolerate pegIFN have no presently licensed therapeutic options

and a probability of viral clearance close to zero. Thus, for licensure, response rates would be weighed

in relation to this fact. Regarding special populations, the need to start trials as early as can safely be

done for groups with an important unmet medical need (e.g., patients with decompensated liver disease or HCV/HIV coinfection) is emphasised, Since the previous guidelines were adapted, host IL-28B genotype has emerged as a very important predictor of the efficacy of pegIFN, and it is recommended that stratification by IL28B genotype be employed whenever the studied drug regimen includes this drug. Regarding future developments, proof-of-concept of SVR with treatment combination excluding pegIFN,

as well as data on retreatment of patients that have failed therapy that has selected for DAA-resistant

variants, but whose dominant population has subsequently reverted to wild-type, are eagerly awaited.

Such data are likely to greatly impact regulatory considerations within the field. It is recognised that

this is a rapidly moving therapeutic area, and that a further revision of these guidelines may be mandated within the foreseeable future.

1. INTRODUCTION 95

1.1. Epidemiology 96

Hepatitis C virus (HCV) is the most common infectious cause of chronic liver disease in Europe, and is

globally second only to Hepatitis B virus. Worldwide, approximately 3% of the population is estimated

to be infected, corresponding to around 200 million people at risk of developing serious liver related

morbidity. In Europe, where the vast majority of CHC cases are reported among patients with past 5/23 blood transfusion (before 1991) or with a history of intravenous drug use, the prevalence varies by geographic region, from about 0.5% in the Northern countries to 2% and higher in the Mediterranean countries and in Eastern Europe. HCV of genotype (GT) 1 is the predominant genotype globally as well as in most European regions. In Europe and in the US, approximately 30% of HIV-infected patients are co-infected with HCV, ranging up to 50% in some regions. 101 102 103 104
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1.2. Natural course of HCV infection 106

Around 60-80% of those infected with HCV become chronic carriers. Studies in patients who acquired CHC by blood transfusion prior to the availability of HCV-screening indicate that, after 20 years of infection, around 20-30% will have progressed to cirrhosis, 5-10% will have end stage liver disease

and 4-8% will have died of liver-related causes. In patients with cirrhosis, the 5-year risk of hepatic

decompensation is approximately 15-20% and the risk of hepatocellular carcinoma 10%. The prognosis of HIV infection has greatly improved due to modern antiretroviral therapy. Among those co-infected with HIV and HCV, however, liver failure due to CHC is now a leading cause of

mortality. In co-infected patients, the progression of liver disease seems to be more rapid, at least in

individuals with low CD4+ T-cell counts. According to biopsy studies, the proportion of patients with

cirrhosis is around twice as high in HIV/HCV co-infected middle-aged patients, compared to individuals

of a similar age who have only HCV infection.

1.3. HCV therapy 118

The general aim of therapy is to achieve sustained viral response (SVR), defined as the absence of detectable virus 24 weeks after the planned end of therapy. This ends the progression of HCV-related hepatic injury, Despite SVR however, the risk of cirrhosis-related complications, including

hepatocellular carcinoma, still remains in patients that have developed significant liver injury due to

the infection. Over approximately 15 years, HCV therapy has evolved from the use of a standard (non-pegylated)

interferon alone, via combination therapy with a standard interferon + ribavirin, to the combination of

a pegylated interferon and ribavirin. For GT 1 virus, SVR rates in treatment naive patients with GT1 virus with 48 weeks of standard interferon therapy were approximately 10 percent, whereas with combination therapy of an unpegylated interferon and ribavirin for 48 weeks, SVR rates were about

30-35%. With the combination of pegIFN 2a or 2b and ribavirin for 48 weeks, which remains the

present standard of care pending the approval of the first DAAs, response rates in GT1 or 4 have been

approximately 40-50% in the pivotal trials. Lower SVR rates, however, are seen in some sub- populations such as those with HCV/HIV co-infection. In contrast, around 70-85% of treatment naive patients infected with HCV GT 2 and 3 achieve SVR after a 6-month treatment course with pegIFN and

ribavirin. The first generation of directly acting antivirals (DAA, see below) has been developed for use

with PegIFN and ribavirin in patients with GT1, showing response rates of around 70% in treatment

naïve patients. The response rate to a first generation DAA added to pegIFN+ribavirin is even higher

when re-treating the selected patient group that achieved an end-of-treatment response with

pegIFN+ribavirin therapy, but subsequently relapsed. Also in patients with prior non- or null response

to pegIFN+ribavirin, SVR rates are substantially increased with the addition of a first generation DAA.

Still, even after the approval of the first generation DAAs there will remain a need for development of

new treatment approaches for numerous patient categories, including those that do not tolerate PegIFN or ribavirin or those in whom the background regimen of PegIFN and ribavirin has limited activity, and therefore gives insufficient support to the DAA. 6/23

1.4. Direct acting antivirals 144

A large number of direct acting antivirals (DAAs) from different drug classes are currently under investigation. The life-cycle of HCV offers several molecular targets for inhibition. Among these, inhibitors of the N3/4A protease, the NS5B polymerase, and the NS5A co-factor are presently furthest

in development, with the marketing approval of the first NS3/4A inhibitors expected in 2011. HCV is an

RNA virus with a high mutation rate. Variants with specific mutations conferring reduced sensitivity to

DAAs have generally been shown to be present prior to the initiation of DAA. Such variants are

selected to a varying degree under drug pressure, both in vitro and by non-suppressive therapy in vivo.

Available data indicate that the barrier to resistance varies greatly between drugs in the DAA category.

Within class cross-resistance is likely, e.g. among hitherto investigated NS3/4A inhibitors and among

non-nucleoside inhibitors of NS5B binding to the same allosteric site. Resistant variants, rather than

wild type HCV, have usually been recovered from patients with virological failure or who relapsed after

achieving an end-of-treatment response (ETR) following treatment with an NS3/4A inhibitor in combination with PegIFN and ribavirin. The impact of resistance on subsequent treatment attempts remains unknown. The development of drug resistance should therefore be regarded as potentially harmful, and must be taken into account in the design of clinical studies and in the benefit-risk assessment of DAAs. Strategies to minimize the risks of resistance should be explored, and incorporated in the design of the clinical studies. 145 146 147 148
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