Considerations for the Design and Conduct of Clinical Trials for Hepatitis C

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Considerations for the Design and Conduct of Clinical Trials for Hepatitis C

Executive Summary Worldwide, up to 170 million people are chronically infected with the hepatitis C virus (HCV). As it replicates, HCV constantly changes and mutates. During the replication process, the virus makes errors in the genetic make-up of the newly replicated viruses. This process helps the virus elude the body’s immune response. When a dominant quasispecies (a genetically related variant) is quashed, another emerges. Therefore, the host’s immune system must constantly identify and eliminate the newly emerged quasispecies. Experts believe each person infected with HCV has millions of different HCV quasispecies that are unique to that person because each individual’s immune response to HCV and quasispecies constantly changes. The variability of HCV has made it difficult to treat and to develop a vaccine that will protect against every HCV strain.

There are currently six genotypes and more than 50 subtypes of HCV. The genetic heterogeneity of the virus may account for some of the differences in disease outcome and response to treatment among those infected with HCV. There is no vaccine against HCV. The extensive genetic variation among different genotypes is a significant challenge to vaccine development, as is the absence of a clearly defined protective immune response. But several promising approaches have been pursued to develop an HCV vaccine. In addition, we are entering a new and exciting era of drug development with specifically targeted antiviral therapies for HCV (STAT-Cs). This paper features key elements sponsors should consider to successfully complete an HCV study, including start-up timelines, patient population, country-specific requirements, sites and investigators, patient retention, follow up, genotype and coinfection.

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Considerations for the Design and Conduct of Clinical Trials for Hepatitis C

Introduction The World Health Organization estimates that up to 170 million people, worldwide, are chronically infected with the hepatitis C virus (HCV).1 HCV infection rates vary widely throughout the world (see map). The highest rates of infection tend to be in the less developed nations. Because of the asymptomatic, often latent nature of the disease prior to clinical presentation, global incidence rates of HCV are difficult to calculate. Most studies of prevalence use blood donors to report the frequency of HCV. This may underestimate the actual prevalence of the virus.

As it replicates, HCV constantly changes and mutates. During the replication process, the virus makes errors in the genetic make-up of the newly replicated viruses. This process helps the virus elude the body’s immune response. When a dominant quasispecies (a genetically related variant) is quashed, another emerges. Therefore, the host’s immune system must constantly identify and eliminate the newly emerged quasispecies. Experts believe each person infected with HCV has millions of different HCV quasispecies that are unique to that person because each individual’s immune response to HCV and quasispecies constantly changes. The variability of HCV has made it difficult to treat and to develop a vaccine that will protect against every HCV strain.2

HCV INFECTIONS WORLDWIDE EUROPE

WESTERN PACIFIC

8.9 Million (1.03%)

62.2 Million (3.9%)

SOUTHEAST ASIA AMERICAS

EASTERN MEDITERRANEAN

13.1 Million (1.7%)

32.3 Million (2.15%)

21.3 Million (4.6%)

AFRICA 31.9 Million (5.3%)

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Considerations for the Design and Conduct of Clinical Trials for Hepatitis C

Characteristics of the Disease HCV Genotypes There are currently six genotypes and more than 50 subtypes of HCV.3 The genetic heterogeneity of the virus may account for some of the differences in disease outcome and response to treatment among those infected with HCV. The most common are genotypes 1a and 1b. They account for approximately 60% of global infections.4 GENOTYPE DISTRIBUTION NORTH AMERICA

NORTH EUROPE

CENTRAL AFRICA

RUSSIA

JAPAN

SOUTH AMERICA

SOUTH EUROPE

SOUTH AFRICA

CHINA

SOUTH-EAST ASIA

AUSTRALIA/NEW ZEALAND

1a

1b

2

3

4

5

6

The Molecular Biology of Hepatitis C Virus: Genotypes and Quasispecies. Clinics in Liver Disease 3(4), 1999.

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Considerations for the Design and Conduct of Clinical Trials for Hepatitis C

Disease Progression HCV tends to cause chronic liver disease with liver injury that persists for a prolonged period, if not for life. Approximately 70% to 85% of patients with acute HCV develop chronic infection. Although it is not known why between 15% and 30% of patients recover from infection, one contributing factor may be the patient’s ability to mount an appropriate cellular immune response to a rapidly mutating virus. Recovery may also be influenced by the route of infection and the age of acquisition. Researchers estimate that at least 20% of patients with chronic HCV develop cirrhosis over at least 10 to 20 years. After 20 to 40 years, a small percentage of patients develop liver cancer.5 HCV remains one of the leading causes of death related to chronic liver disease and is the most common indication for liver transplantation. Studies demonstrate that 55% to 85% of those who develop acute HCV will remain infected.6 Infants and young women are more likely to experience spontaneous resolution than those who develop acute hepatitis when they are older.

SPECTRUM OF DISEASE ACUTE HCV INFECTION

CHRONIC HCV INFECTION 70% to 85%

RECOVERY 15% to 30%

CHRONIC HEPATITIS C

MILD

MODERATE

SEVERE

CIRRHOSIS* 1% PER YEAR

END-STATE LIVER DISEASE

LIVER TRANSPLANTATION

HCC 1% to 4% PER YEAR

DEATH

*Cirrhosis will develop in approximately 20%. Adapted from Hoofnagle JH. Hepatology. 1997;26(suppl 1):16S.

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Considerations for the Design and Conduct of Clinical Trials for Hepatitis C

Current Treatment Options – and Their Limitations The goal of HCV therapy is to prevent complications and death. Therefore, treatment responses are described by a surrogate virological parameter, not a clinical endpoint. Short-term outcomes can be measured biochemically (normalization of serum ALT levels), virologically (absence of HCV RNA from serum by a sensitive PCR-based assay) and histologically (i.e., improvement in necroinflammatory score, with no worsening in fibrosis score). There are several types of possible virological responses, which are described by their timing relative to treatment. The sustained virological response (SVR) is the most important. SVR is defined as the absence of HCV RNA from serum by a sensitive PCR assay 24 weeks after therapy has been discontinued. This is considered a “virological cure.” However, liver cancer can occur years later, especially if an individual had cirrhosis when they achieved an SVR.

Current standard of care (SOC) for chronic HCV infection is combination therapy that includes pegylated interferon (PegIFN) and ribavirin (RBV). Patients take PegIFN once a week and RBV twice daily. PegIFN dosing depends on the product (there are two) and RBV dosing depends on weight and genotype. Because SVR with SOC treatment varies by HCV genotype, it is clinically important to test for genotype. • Genotype 1 – 40% to 50% achieve SVR • Genotypes 2 and 3 – 70% to 80% achieve SVR A steadily increasing pool of patients, referred to as “non-responders,” have limited treatment options. Because their disease remains uncontrolled, experts anticipate an increase in mortality and morbidity associated with chronic HCV infection – unless new treatments emerge for these patients.

An end-of-treatment response (ETR) refers to undetectable virus at the end of a 24-week or a 48-week course of therapy (the length of therapy is dependent upon genotype). This does not predict an SVR, but an ETR is necessary to accomplish an SVR.

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Considerations for the Design and Conduct of Clinical Trials for Hepatitis C

We are entering a new and exciting era of drug development with specifically targeted antiviral therapies for HCV (STAT-Cs). Several STAT-C compounds are currently in preclinical and clinical stages of development. STAT-C compounds could revolutionize HCV treatment. Although PegIFN/RBV therapy is likely to remain part of the treatment paradigm for the foreseeable future, the extensive HCV pipeline includes agents that may complement or eventually replace the current SOC regimen.

Promising New Treatment Strategies The mechanisms of HCV replication are becoming more fully understood. This knowledge, combined with the ability to specifically target the proteins involved in viral replication, has led to the development of a number of new agents that are currently being investigated in clinical trials. The goal is to improve upon the efficacy, tolerability and dosing of current SOC therapy. Potential therapeutic targets include viral attachment, viral entry, viral fusion, RNA replication and translation, polyprotein processing and virus assembly and release. HCV INFECTION AND REPLICATION CYCLE

ER, endoplasmic reticulum; MW, membranous web. Note that IRES-mediated translation and polyprotein processing as well as MW formation and RNA replication may occur in a tightly coupled fashion. VIRUS BINDING AND INTERNALIZATION (+) RNA 5' CYTOPLASMIC RELEASE AND UNCOATING

3' ER

IRES-MEDIATED TRANSLATION AND POLYPROTEIN PROCESSING C E1

3

P7 2 E2

5B 5A 4B

4A (-) RNA

VIRION MATURATION AND RELEASE

5'

3' PACKING AND ASSEMBLY (+) RNA 5'

MW 3'

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Considerations for the Design and Conduct of Clinical Trials for Hepatitis C

Types of treatments currently being investigated include: • novel interferons • inhibitors of HCV translation • inhibitors of HCV posttranslational processing • inhibitors of HCV RNA polymerase • cyclophilin B inhibitors • inhibitors of virus assembly and release

Researchers are exploring novel vaccine candidates based on molecular technology such as recombinant proteins (E1 and/or E2 glycoprotein), polypeptides, virus-like particles, plasmid DNA and recombinant viral vectors including adenovirus, modified vaccinia Ankara, canary pox virus and alphavirus.7 Key Considerations for Successfully Completing an HCV Study

Vaccines There is currently no vaccine against HCV. The extensive genetic variation among different genotypes is a significant challenge to vaccine development, as is the absence of a clearly defined protective immune response. Several promising approaches have been pursued to develop an HCV vaccine. Many parallel those used in vaccine research for other persistent infections such as HIV, herpes simplex viruses and malaria.

There are currently a large number of ongoing HCV clinical trials underway across the world. Therefore, patient recruitment is very competitive and challenging. Sponsors should carefully design their recruiting strategy prior to initiating a study and consider the following factors when determining where to locate HCV studies.

HCV CLINICAL TRIALS COMPETITIVE LANDSCAPE

5

21 40 37

6

18

6 3

3 3

2

12 10

*Number of trials conducted across the world.

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Considerations for the Design and Conduct of Clinical Trials for Hepatitis C

Start-up Timelines Typical timelines vary from one country/region to another due to a variety of factors at each site, such as regulatory authorities’ approval timelines and investigator contract negotiations. To avoid delays, sponsors should plan to partner with local personnel who are experienced at working with the investigators and regulatory authorities. Patient Population: Treatment Naïve If the study requires treatment-naïve patients, the health care system organization in some countries can facilitate their identification by registering newly HCV diagnosed patients awaiting treatment. It can take up to a year before treatment with PegIFN/RBV is initiated. Therefore, many consultant hepatologists in these countries have a pool of diagnosed but treatment-naïve patients. Because they allow patients fast access to at least the SOC, clinical trials of PegIFN/RBV, plus or minus any other drug, are very attractive for both patients and treating physicians. Provision of SOC Requirements for providing SOC vary from one country to another. In some countries, it might be possible to have SOC prescribed by the treating physician, with the sponsor putting a reimbursement process in place for those who need it. In some countries the doctors must submit an application to the health care system to authorize the SOC prescription. Therefore, to ensure SOC can be

started upon end of treatment with the investigational product, for short study drug treatment duration (i.e., 28 days), such requests should be made as early as possible because it can take several weeks to receive approval. In some developing countries, the sponsor needs to provide SOC to either meet a requirement from the health authorities and/or an expectation from the ethics committees. In this case, the sponsor needs to buy the SOC and distribute it to the sites to be dispensed for patients. This process can be managed centrally, with SOC distributed from a central drug supplier directly to the sites or via a local drug import depot, depending on the country. Because management time and costs associated with each option vary significantly, the provision of SOC can be dealt with on a country-by-country basis. These additional costs are common in the developing world – and, increasingly, in the developed world because many HCV patients in the developed world are indigent and also need help affording access to SOC.

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Considerations for the Design and Conduct of Clinical Trials for Hepatitis C

Sites and Investigators To enhance efficiency, sponsors should seek investigators experienced in running clinical trials, preferably HCV studies. With the large number of HCV studies currently underway, sites are often selected for more than one study at one time. Sponsors must ensure each site is committed to its study and that investigators will not put patients in a competitor’s study. To accomplish this, sponsors should plan to provide management that does not add unnecessary burdens, such as uncomplicated paperwork, good communication and reasonable compensation. Patient Retention Retention can be challenging for several reasons. Key among them is the length of time it takes to complete HCV studies. But properly locating studies can aid retention. In the United States (U.S.), for instance, a large percentage of patients typically do not finish HCV studies for reasons outside of the protocol requirements of discontinuation (move, non compliance, lost to follow up). Patients in Eastern Europe and Latin America, however, tend to complete a study because clinical trials offer them an opportunity to receive health care they might not otherwise obtain. These individuals also usually develop closer relationships with investigators.

Follow Up Previously, HCV studies have included a six-month follow up to determine whether subjects have maintained an SVR. One concern about oral STAT-C compounds (especially monotherapy) is the potential for quick emergence of resistance. Therefore, some protocols for HCV studies now require up to 36-month follow up to assess for re-emergence of HCV RNA despite attaining SVR. If viral RNA is detected, a sample is sent to assess for resistance mutations. It is important to implement a patient retention plan to ensure enough data are collected during the long-term follow up period. Different approaches can be implemented to optimize the subjects’ compliance with visit schedules and to ensure the sites and patients remain focused on the collecting data. Genotype Because current SOC for HCV is less effective for genotype 1 than the other genotypes, most HCV studies currently focus on subjects who have genotype 1 who are treatment naïve or genotype 1 with prior treatment failures. Genotype 1 is typically treated for 48 weeks, but some experts believe that slow responders should be treated for 72 weeks. SVR for genotype 1 treatment-naïve subjects is up to 50%; SVR for genotype 1 subjects is less than 5% during the second course of treatment.8

Most patients treated with PegIFN/RBV experience one or more adverse events (AEs), which cause many to decline or stop therapy. Helping subjects appropriately manage side effects can encourage retention.

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Considerations for the Design and Conduct of Clinical Trials for Hepatitis C

Most of the studies need a defined ratio of patients presenting with genotype 1a and genotype 1b. It is therefore important to bear this in mind when selecting study locations as the epidemiology and incidence of these two subtypes of genotype 1 vary in the different regions of the globe. The proportion of these genotypes varies widely from one country to another. In Romania, for instance, more than 80% of the patients are genotype 1b, while in Bulgaria it is closer to 60%. It is important to ensure standard reporting of the genotypes. Although local laboratories can be used for the initial assessments, it is highly advisable to have the data confirmed through a central laboratory. Coinfection Because HCV shares transmission pathways with both hepatitis B (HBV) and the human immunodeficiency virus (HIV), there is a high rate of coinfection. It has been estimated that 4 to 5 million of the 33 million people infected with HIV have concomitant HCV infection. Rates of HIV/HCV coinfection vary widely, depending on the primary mode of HIV transmission. The rate of HBV/HCV coinfection is less certain due to a lack of largescale population-based studies. But some estimate it ranges from 9% to 30%, depending on the region of the world.9

When conducting clinical trials for HCV, subjects with coinfection need to be studied under different protocols to avoid confounding data and decreased efficacy. Conclusion The designs of future HCV trials will likely evolve to include: • additional genotype testing for the alleles of the IL-28 • lead-in treatment strategies • direct-acting-antiviral (DAA) combination therapies • expansion of the response guided therapy (RGT) to maximize the response to all patients Because the variability of HCV makes it so challenging to target, developing drugs to treat the various subtypes of HCV will remain an area of intense and competitive study for the foreseeable future. Promising new treatment strategies are propelling us into an exciting era of drug development with specifically targeted antiviral therapies for HCV. There are a number of challenges to designing and conducting clinical trials for HCV compounds in this competitive environment. For many sponsors, partnering with drug development experts ensures the timelines are realistic and that the protocol design supports an efficient study development.

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Considerations for the Design and Conduct of Clinical Trials for Hepatitis C

References 1. Wkly Epid Rec. 1999;74:425-427. World Health Organization. (2003). Hepatitis C: Global Prevalence: Update. (Note: Because of differences in the population groups studied, methods of data collection and interpretation between countries and since only limited data are available for some countries, the prevalence shown does not necessarily represent true prevalence in a country. WHO anticipates new global estimates in 2010.) 2. Hepatitis C Support Project. Fact Sheet. (February 2006). Available at http://www.hcvadvocate. org/hepatitis/factsheets_pdf/genotype_2008.pdf 3. National Digestive Diseases Information Clearinghouse. (November 2006). Chronic Hepatitis C: Current Disease Management. Available at http://digestive.niddk.nih.gov/ddiseases/pubs/chronichepc/)

6. Ghany, M. G., Strader, D. B., Thomas, D. L., & Seeff, L. B. (April 2009). Diagnosis, management and treatment of hepatitis C: An update. Hepatology. Available at http://www.aasld.org/practiceguidelines/ Documents/Hepatitis%20C%20UPDATE.pdf 7. Lian, T. J. (May 20-24, 2009). 13th International Symposium on Viral Hepatitis and Liver Disease (ISVHLD). Washington, DC. The Current Status of HCV Vaccine Development. Abstract SP-28. 8. Ghany, M. G., Strader, D. B., Thomas, D. L., & Seeff, L. B. (April 2009). Diagnosis, management and treatment of hepatitis C: An update. Hepatology. Available at http://www.aasld.org/practiceguidelines/ Documents/Hepatitis%20C%20UPDATE.pdf 9. Mauss, Berg, Rockstroh, Sarrazin, & Wedemeyer. (2009). Hepatology: a clinical textbook. Available for free download at http://www.hepatologytextbook.com

4. World Health Organization. (2002). Fact Sheet. Hepatitis C. 5. National Digestive Diseases Information Clearinghouse. (November 2006). Chronic Hepatitis C: Current Disease Management. Available at http://digestive.niddk.nih.gov/ddiseases/pubs/chronichepc/)

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Considerations for the Design and Conduct of Clinical Trials for Hepatitis C

Case Study Background A company needed to recruit 250 subjects for a Phase IIb study of a novel polymerase inhibitor in combination with PEG/RIBA. The study was conducted in 77 sites in six countries. Objective Meet a 13-month enrollment timeline. Challenges • The company required an “instant” start from PPD • There was an aggressive goal for first patient first visit (FPFV): 79 days from protocol sign off • FDA protocol comments were not available at the start of recruitment • An additional corporate goal was added: 50% of recruitment was to be reached 160 days after final protocol

Solutions • PPD set up study teams immediately after start award • Many pre-site visits (PSVs) were waived, or PSV/ site initiation visits (SIVs) were granted • PPD provided contingency planning for a potential protocol amendment • Countries with quick start-up timelines were targeted for additional sites Outcome Recruitment was accomplished in seven months. © 2010 Pharmaceutical Product Development, Inc. All rights reserved.

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