Hepatitis C Clinical Research
WCCT Global wishes to deepen its participation in the medical and scientific initiative to more effectively treat Hepatitis C Virus
Hepatitis C (HCV) is a global disease. HCV in combination with Hepatitis B (HBV), now accounts for 75% of all cases of liver disease around the world. WCCT Global has become a leader in helping the research community better understand this disease through WCCT Global’s Hepatitis Center of Excellence.
Understanding the disease is key:
There are six basic genotypes of HCV infection in the worldwide populations, with 15 recorded subtypes, which vary in prevalence across different regions of the world. Each of these major genotypes may differ significantly in their biological effects – in terms of replication, mutation rates, type and severity of liver damage, and detection and treatment options – however, these differences are all not yet clearly understood.
Results from global epidemiological studies demonstrate wide variance in HCV prevalence patterns with the incidence of HCV being higher among less developed nations. The prevalence of hepatitis C is lowest in Northern European countries, including Great Britain, Germany and France. Higher HCV prevalence rates have been reported in Southeast Asian countries, including India (1.5%), Malaysia (2.3%), and the Philippines (2.3%). The incidence in Japan was 1.2%. Alarming rates were reported for many African nations, reaching as high as 14.5% in Egypt.
Thus, the overall data suggest that over 200 million people around the world are infected with hepatitis C – an overall incidence of around 3.3% of the world’s population. Statistically, as many people are infected with HCV as are with HIV. Many public health experts feel that unless large scale efforts to contain the spread of HCV and treat infected populations, the death rate from hepatitis C will surpass that of AIDS in coming years.
Treatment with a combination of pegylated interferon and ribavirin is the current standard of care for chronic hepatitis C. Unfortunately, nearly 50% of individuals fail to respond to this regimen (sustained virologic response [SVR] defined as undetectable HCV RNA by polymerase chain reaction (PCR)-based assay 24 weeks after the end of treatment). More specifically, up to 60% of patients with HCV genotype 1 infection, the most common genotype in the United States and 20%-30% of patients with HCV genotype 2/3 infection do not respond to initial therapy with the current standard of care. Thus, without a more effective therapy, the risk of developing liver-related complications among those who are chronically infected will increase, not peaking until after the year 2030. This has provided the impetus to develop more novel and effective therapies.
Our new and evolving understanding of the HCV lifecycle has allowed development of agents designed to interrupt viral infection and replication. It is hoped that this new knowledge will translate into effective treatment options for nearly all patients with HCV.
The HCV Lifecycle
HCV is a small, enveloped, linear, single-stranded RNA virus. The genome encodes a single polyprotein that is then processed by both host and viral proteases into smaller proteins that assist in viral replication. Research has identified several steps during this replication process that are fundamental to the HCV lifecycle and thus represent excellent Direct Anti-HCV therapeutic targets.
- Binding, cell entry, nucleocapsid uncoating, and release
- Viral envelope proteins (E1 and E2) bind to host CD81 allowing internalization
- HCV translation
- Amino acid sequencing at RER to form the HCV polyprotein
- Polyprotein processing
- Protease cleavage into 6 NS (nonstructural) proteins that support viral RNA replication
- Assembly of the RNA replication complex
- NS Proteinsare required for assembling the RNA replication complex (replicase)
- RNA synthesis (NS5B RNA polymerase)
- Nearly 1 trillion particles are produced each day
- An exceptionally high mutation rate
- Virus assembly and release
- Phosphorylation of NS5A may trigger the virus to switch from “replication mode” to “assembly mode
The genomic RNA is packaged into the icosahedral protein shell and then enveloped in a host lipid cell membrane. The assembled virulent virus is then released from the hepatocyte through a cellular secretory pathway. Significant strides in drug development have accompanied this increased understanding of the HCV lifecycle. The enthusiasm about the potential of these agents continues to grow as more data confirming anticipated efficacy surface.
Although each aspect of the HCV lifecycle has been targeted for potential therapeutic intervention, many therapeutic strategies are under investigation, including novel interferon products, ribavirin analogues, and drugs targeting viral enzymes required for viral replication (direct-acting antiviral agents [DAAs] or small-molecule therapies). Among these novel anti-HCV therapies on the horizon, the DAAs temporally represent the class of agents most likely to affect disease management. Two protease inhibitors have already reached the commercial market. The polymerase inhibitors will be soon to follow.
The staff at WCCT Global has extensive experience working with Pharma in the development of HCV treatments. While at Schering-Plough, Mel Affrime, WCCT Global’s SVP of Research & Development designed and executed the studies that lead to an industry understanding of interferon’s antiviral mechanism. Mel carried out the initial Schering proof of concept study demonstrating the synergistic activity of ribavirin when combined with interferon and is on the patent which describes the mechanism for the additional HCV activity gained with pegylation of interferon. Mel Heads up WCCT Global’s Hepatitis Center of Excellence.
WCCT Global has carried out numerous healthy volunteer safety and tolerance trials as both an investigational site and a CRO managing an early development PoC study at several sites. They have studied both immediate release interferons and Pegylated interferon with and without ribavirin and WCCT Global has also been a Phase II/III investigational site for several of the new Direct Acting Anti-HCV compounds in development. We leverage this knowledge to strategically help the clients we serve.
As the industry looks to get more data from phase 1 trials, there is an increasing interest in including patient populations in the phase 1 program. WCCT Global, during the protocol development phase, would help sponsors design an integrated SAD/MAD in healthy volunteers intercolated with SAD/MAD proof of concept in Hepatitis C, treatment naïve, patients. Such an integrative design enables the sponsor to collect safety, tolerance and exposure-response information efficiently and enables go/no-go development decisions to be reached much sooner than before WCCT Global is strategically based in a densely populated area of 8 million people found throughout the Southern California region and thus has access to a diverse set of patient populations. Therefore, WCCT Global is able to recruit Hepatitis C treatment naïve subjects within timelines that sponsors need by utilizing their proprietary advertising strategy.
WCCT Global’s Hepatitis Center of Excellence works with sponsors early in development process to offer strategies that more rapidly demonstrate the anti-HCV actions of the novel viral targets being tested. Because WCCT Global has access to healthy volunteers of diverse ethnic lineage and patients with HCV, they work with sponsors to rapidly get the information necessary to launch a Global Development Program months ahead of the classic development paradigms.