In treating HCV patients, several criteria define the selection of a patient population which could eventually, when an optimal dose level has been identified, find a benefit in CYT107 treatment with minimal risk of developing severe reactions.  These include:

• Patients should be chronically infected by genotype 1 HCV. In this sub-population, treatment failures remain frequent. No second line treatment is currently available for patients whose HCV cannot be cleared using standard treatment, leaving them highly vulnerable to progression to cirrhosis and hepatocarcinoma within the following 20-30 years post-treatment.
  
  
• Furthermore, the predictive value of a positive outcome based on an EVR documented 12 weeks after initiation of PEG-interferon-alpha + ribavirin treatment has been better established in patients infected by HCV genotype 1 than in any other genotype.
  
  
• Indeed, before entering the IL-7 clinical trials, patients should be treated by standard therapy (PEG-interferon-alpha + ribavirin) for 12 to 15 weeks, and no EVR should have been achieved at 12 weeks. In this case, the probability of SVR at 48 weeks is below 5% and given the absence of any experimental approach enabling the modification of treatment efficacy, the bi-therapy is usually discontinued.
  
  
• In order not to cloud the assessment of CYT107 safety, the tolerance to the bi-therapy within the previous 12 weeks should have been satisfactory. Any patient who has experienced a dose reduction of PEG-Interferon-alpha and/or Ribavirin should be excluded. Furthermore, there should be no history of severe depression, a contraindication for participation.  Depression is indeed one of the most frequent and serious complications of PEG-Interferon-alpha treatment. Finally, at study entry, hematological parameters should remain compatible with a full dose treatment by PEG- Interferon-alpha and/or Ribavirin.

Trial ID Number: CLI-107-05

Title: A Phase I Dose Escalation Study of Repeated Administration of “CYT107” (glyco-r-hIL-7) Add On Treatment in Genotype 1 HCV Infected Patients Resistant to 12 Weeks Peg-Interferon-Alpha / Ribavirin

Trial Name: ECLIPSE 1 (Evaluation in hepatitis C Liver disease of IL-7 in a Phase I Study of dose Escalation)
Countries: Switzerland, France, Italy
Status: Ongoing
Link to Clinical Trial: Clinical Trials.gov

About the ECLIPSE 1 Study
The HCV trial (CLI-107-05) focuses on patients who are non-responders to the reference treatment (12 weeks of PEG-interferon alpha + ribavirin). This multi-center dose escalation study conducted at sites in Switzerland, France and Italy will include 12-18 patients who will receive weekly injections of CYT107 over a four-week period in addition to the reference treatment. More than one-third of patients do not respond to the reference treatment because they are unable to mount an efficient immune response against the virus. Cytheris expects the addition of CYT107 treatment will restore appropriate T-cell function and help these patients better cope with the virus. 

Tilman Gerlach, MD, Clinic for Gastroenterology and Hepatology, Zurich University Hospital, Zurich, Switzerland, is chair of the study; Patrick Marcellin, MD, Head of the Claude Bernard Research Center on Viral Hepatitis, Service d'Hepatologie and INSERM Unit 481, Hospital Beaujon, Clichy, is the French Coordinating Investigator; Giuseppe Tambussi, MD, Division of Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy, is the Principal Investigator for the Italian study site; and Roberto Speck, MD, Division of Infectious Diseases and Hospital Epidemiology, Zurich University Hospital, is responsible for conducting the immunological research.

Trial ID Number: CLI-107-07

Title: A Phase I/IIa Dose Escalation Study of Repeated Administration of “CYT107” (glyco-r-hIL-7) Add On Treatment in Genotype 1 or 4 HCV Infected Patients Resistant To Pegylated Interferon-Alpha and Ribavirin

Trial Name: ECLIPSE 2 (Evaluation in hepatitis C Liver disease of IL-7 in a Phase I/II Study of dose Escalation)
Countries: Switzerland, France, Italy
Status: Ongoing
Link to Clinical Trial: Clinical Trials.gov

About the ECLIPSE 2 Study
This Phase I/IIa study is designed to evaluate the safety of CYT107 and to assess potential individual benefits, corresponding, to the conversion of a viral failure (i.e., non responder) of pegylated interferon-alpha + ribavirin into a promising response 12 weeks after initiation of the CYT107 cycle of treatment.

Absence of viral response to previous treatments with pegylated interferon-alpha + ribavirin is defined as absence of early viral response (EVR) together with detectable HCV and with a decrease of HCV RNA loads < 2 logs, as measured by a quantitative PCR test after 12 weeks of treatment, compared to baseline levels measured by a similar technique. Or, absence of end of treatment response defined by detectable HCV RNA at the end of treatment (24 weeks or 48 weeks).

The treatment of patients with chronic hepatitis C virus (HCV) improved over the past years. Despite this, nearly half of the patients fail to achieve a sustained virological response (SVR). The decision to retreat a non responder patient should take into consideration several factors which include data regarding the response to the previous therapy and the likelihood that a response can be achieved with retreatment.

It is also important to distinguish the “false” non responder who did not receive a full optimal treatment and the “true” non responder who failed after receiving an optimal treatment. In the first category, the management of the factors of non response or improvement of tolerance to therapy may optimize retreatment with a chance of viral eradication. Conversely, in the “true” non responder, the chance of viral eradication is limited. Recent data demonstrated that about 18% of all patients with previous non response to standard therapy (with or without ribavirin) will achieve an SVR when retreated with pegylated interferon-alpha and ribavirin and nearly 10% in genotype 1. However, no therapy has been shown to be effective for patients who have failed treatment with pegylated interferon-alpha and ribavirin.

Virological failure of the above described optimal and up to date combination therapy remains an unmet medical need. No second line treatment is currently available and the benefit of new molecules currently developed in this indication remains uncertain.

As with the ECLIPSE 1 investigation, Tilman Gerlach, MD, Clinic for Gastroenterology and Hepatology, Zurich University Hospital, Zurich, Switzerland, is chair of the study; Patrick Marcellin, MD, Head of the Claude Bernard Research Center on Viral Hepatitis, Service d'Hepatologie and INSERM Unit 481, Hospital Beaujon, Clichy, is the French Coordinating Investigator; Giuseppe Tambussi, MD, Division of Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy, is the Principal Investigator for the Italian study site; and Roberto Speck, MD, Division of Infectious Diseases and Hospital Epidemiology, Zurich University Hospital, is responsible for conducting the immunological research.

Trial ID Number: CLI-107-09

Title: A Phase I/IIa Dose Escalation Study in Asia of Repeated Administration of “CYT107” (glyco-r-hIL-7) Add On Treatment in Genotype 1 HCV Infected Patients Resistant To Pegylated Interferon-Alpha and Ribavirin

Trial Name: ECLIPSE 3
(Evaluation in hepatitis C Liver disease of IL-7 in a Phase I/II Study of dose Escalation in Taiwan)
Countries: Taiwan
Status: Ongoing
Link to Clinical Trial: Clinical Trials.gov

About the ECLIPSE 3 Study
Similar in trial design to ECLIPSE 2 being conducted in Europe, the ECLIPSE-3 study will evaluate (at Week 12) the safety of biologically active doses of CYT107 added to a combination therapy of pegylated interferon-alpha (peg-INF) and ribavirin (RBV) in Asian patients with chronic infection by genotype 1 HCV who have not responded to this combination therapy (no EVR after Week 12 or no response after 24 or 48 weeks).

This is a multicenter, Phase I/IIa inter-patient dose escalation study. Patients chronically infected with HCV genotype 1 will be assessed for study participation if, based on past treatment history, they are considered resistant to standard bitherapy treatment with peg-INF and RBV (no EVR at Week 12, HCV RNA detectable at Week 24 or Week 48). Standard bitherapy will be initiated in these previously treated “non-responder” HCV infected patients and administered for 6-10 weeks. CYT107 will then be added for a cycle of four weekly subcutaneous injections at defined dose levels while standard bitherapy is continued for 9 weeks after CYT107 treatment is discontinued. The duration of the study is approximately 60 weeks, with 20-25 weeks of bitherapy.

The study will be conducted at four sites, two in Taipei and one each in Tainan and Kaohsiung. Wang-Long Chuang, MD, PhD, Chief, Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University is the Chairman of the Steering Committee and the Coordinating Investigator for Taiwan.  As with the ECLIPSE 1 and 2  investigations, Tilman Gerlach, MD, Clinic for Gastroenterology and Hepatology, Zurich University Hospital, Zurich, Switzerland, and Patrick Marcellin, MD, Head of the Claude Bernard Research Center on Viral Hepatitis, Service d'Hepatologie and INSERM Unit 481, Hospital Beaujon, Clichy, France, will serve as Co-Chairs on the study.