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Trial ID Number: CLI-107-06

Title: A Phase I/IIa Randomized Placebo Controlled, Single-Blind Multicenter Dose-Escalation Study of Subcutaneous Intermittent Interleukin-7 CYT107 in Chronically HIV-Infected Patientswith CD4 T-Lymphocyte Counts Between 101-400 Cells/Mm3 and Plasma HIV RNA< 50 copies/mL after at Least 12 Months of HAART.

Trial Name: INSPIRE (INvestigational Study of Placebo versus IL-7
in haaRt-trEated patients)
Countries: United States, Canada, France and Italy
Status: Ongoing
Link to Clinical Trial: ClinicalTrials.gov

About the INSPIRE HIV Study
The HIV trial (CLI-107-06) is a randomized placebo controlled, single-blind multi-center dose-escalation study of chronically HIV-infected patients with CD4 T-lymphocyte counts between 101-400 cells/mm3 and plasma HIV RNA < 50 copies/mL after at least 12 months of Highly Active Anti-Retroviral Therapy (HAART). The dose escalation scheme is designed to establish the safety of biologically active doses of CYT107, to document the residual CD4 increase achieved at 3 months (“targeted sustained activity”) and to define a dose and schedule for phase II investigation.  In addition, potential biologic Dose Limiting Toxicities (DLT), unique to IL-7 (such as viral reactivation or immunogenicity) will be sought.

Michael M. Lederman, MD, the Scott R. Inkley Professor of Medicine and Director of the Case Western Reserve University/University Hospitals Center for AIDS Research, Cleveland, Ohio, will chair the study along with co-chairs Irini Sereti, MD, US National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, and Yves Levy, MD, PhD, Service d’Immunologie Clinique, Hôpital Henri Mondor, Créteil, France. 

Results of two promising Phase I studies of Cytheris’ IL-7 in HIV patients, one conducted by Dr. Levy’s team and the other by the US National Institutes of Health/AIDS Clinical Trials Group (ACTG), were reported at the 2007 Conference on Retroviruses and Opportunistic Infections (CROI) held in Los Angeles. Dr. Levy also presented long-term follow-up results (at week 48) of the French study at the 2008 Conference on Retroviruses and Opportunistic Infections (CROI) held in Boston. This study has since been published in Lévy Y, et al Enhanced T cell recovery in HIV-1-infected adults through IL-7 treatment. J Clin Invest. 2009, Vol. 119, No. 4: 997-1007.

Trial ID Number: CLI-107-13

Title: An open-label, multicenter study of subcutaneous intermittent recombinant Interleukin-7 (CYT107) in chronically HIV-infected patients with CD4 T-lymphocyte counts between 101-400 cells/mm³ and plasma HIV RNA< 50 copies/mL after at least 12 months of HAART.

Trial Name: INSPIRE 2
Countries: United States, Canada
Status: Ongoing
Link to Clinical Trial: ClinicalTrials.gov

About the INSPIRE 2 HIV Study
INSPIRE 2 is an open-label, multicenter study of subcutaneous intermittent recombinant Interleukin-7 (CYT107) in chronically HIV-infected patients with CD4 T-lymphocyte counts between 101-400 cells/mm3 and plasma HIV RNA< 50 copies/mL after at least 12 months of HAART. The study will be conducted across4 investigative sites in the United States and Canada.

This phase IIa confirmatory study is designed to further demonstrate the biological activity of CYT107 and provide data that will help in the design of phase IIb/III trials. The study objectives include characterization of CYT107 pharmacokinetics and pharmacodynamics in patients with moderate to severe lymphopenia, delineation of the relationship between CYT107 dose and biological activity, and confirmation of the relevance of the treatment schedule evaluated in the first INSPIRE study reported in an oral late breaker session at the 49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) held September 12-15, 2009, in San Francisco, CA (Abstract H-1230a).

The primary objective of the study is to determine in detail the biological activity and PK profile of CYT107 (20 µg/kg/week), during a 12 week study period with a follow up period of up to 1 year, in an HIV-infected cohort with CD4 counts of 101-400 cells/µL. The dose of 20 µg/Kg/week that will be evaluated in this study has shown a good safety profile and biological activity in the first INSPIRE study CLI-107-06) conducted in a similar population.

Secondary objectives are:

• To characterize the pharmacokinetics and pharmacodynamics of CYT107 in the targeted population.
  
  
• To further evaluate the safety profile established with CYT107 at 20µg/kg. Safety assessments will include a close monitoring of the impact OF CYT107 on HIV RNA viral load and immunogenicity.
  
  
• To further evaluate the immunological effects established with CYT107 at 20µg/kg.
  
  
• To document the potential sustained CD4 increase achieved at D21, D28, Weeks 9 and 12 (“targeted sustained activity”)
  
  
• To document safety and sustained CD4 increase quarterly until the end of the first year.
  
  
• To document other immunological properties of IL-7, (i.e. T-cell homing within the lower GI tract).
  
  

Trial ID Number: CLI-107-14

Title: A Phase II multicenter, open-labeled, controlled, randomized study of recombinant Interleukin-7 (CYT107) treatment to restore and maintain CD4 T-lymphocyte counts above 500 cells/µL in HIV-infected patients with CD4 counts remaining between 101-350 cells/µL after at least 2 years of HAART and plasma HIV RNA < 50 copies/mL for 18 months.

Trial Name: INSPIRE 3
Countries: Italy, Switzerland, South Africa
Status: Ongoing
Link to Clinical Trial: Clinical Trials.gov

About the INSPIRE 3 HIV Study
The primary objective of this 24 month study is to investigate the biological activity and safety of repeated cycles of CYT107 at 20 µg/kg/week over 2 weeks, for a maximum of 4 cycles within 21 months and a maximum of 3 cycles within 12 months. The dose of 20 µg/Kg/week that will be evaluated in this study was selected based on the good safety profile and biological activity shown in two other trials, the first INSPIRE study (CLI-107-06) and the ongoing INSPIRE 2 (CLI-107-13) study, both conducted in a similar INR population. A total of 80 patients will be randomized to two arms, a CYT107 arm and control arm (placebo) with a ratio 3:1 (3 CYT107:1 control).

Secondary objectives are:

1. To further characterize long term safety in a context of repeated cycles of CYT107
2. To characterize CYT107 Pharmacokinetics (PK) / Pharmacodynamics (PD)
3. To build a population PK/PD model of CYT107 activity
4. To characterize the key immuno-pharmacological effects such as:
   • Increase of T cell cycling
   • Inhibition of T cell apoptosis
   • Increase of thymopoiesis and recovery of T cell repertoire diversity
   • Increase of T cell homing
   • To assess anti-HIV specific responses
   • To assess the recall antigen response
5. To assess the effect of CYT107 on HIV-induced chronic systemic immune hyper-activation and its consequences
6. To measure the time spent under prophylactic treatment for opportunistic infections

 

Trial ID Number: Sponsored by Objectif Recherche VACcin Sida (ORVACS)

Title: A Phase II international, multicenter, randomized, non-comparative controlled study of therapeutic intensification plus immunomodulation in HIV-infected patients with long-term viral suppression.

Trial Name: EraMune 01
Countries: France, Spain, Italy, United Kingdom
Status: Ongoing
Link to Clinical Trial: ClinicalTrials.gov

About the EraMune 01 HIV Study
Antiretroviral therapy (ART) has been one of the most successful fields of therapeutic research in the last twenty years. The extensive use of highly active antiretroviral therapy (HAART) since 1996 has led to a marked decrease in morbidity and mortality of HIV-1 infection, transforming a uniformly lethal disease into a chronic infection. The goal of therapy is a durable suppression of viral replication, the almost unique condition for immune reconstitution, control of disease progression, prevention of the emergence of drug resistance, and, ultimately, potentially normal life span. However, in the absence of any alternative treatment to durably control viral replication and the lack of current strategy to eradicate HIV from an infected person, antiretroviral therapy has to be administered life-long. Nevertheless, life-long use of antiretroviral therapy raises other crucial issues such as long-term tolerability and compliance, risk of emergence of resistance in case of incomplete viral suppression, sustainability of drugs supplies worldwide.

The first step and the focus of this study is to explore the strategy of ARV treatment intensification with the addition of an immunomodulating agent that can activate latently-infected cells. This will be investigated in a pilot study in patients with fully controlled HIV replication as measured by viral RNA and cell-associated HIV DNA. The first proof of concept clinical study outlined here will include 28 patients, each randomized in an open label non-blinded manner to one of three arms (14 per group):

1. Antiretroviral intensification (cART + raltegravir and maraviroc)
2. Antiretroviral intensification + immunomodulatory intervention (added after 8 weeks of antiretroviral intensification) with 2 cycles of 3 r-hIL-7 (CYT107) injections.

Primary objective:

• Important decrease in the HIV-1 viral reservoir

Secondary objectives:

• Eradicate HIV in the lymphoid reservoirs of HIV in the gut
• To describe the immunologic effects of treatment intensification with and without immunmodulatory therapy
• Develop a model for HIV DNA decay in patients receiving treatment intensification with and without immunomodulatory therapy
• Determine the safety of treatment intensification with and without immunomodulatory therapy.