Cytheris SA today announced that it has begun enrolling patients in INSPIRE 3, a Phase II clinical programme evaluating the effect of repeated cycles of the company’s investigative immune-modulator, recombinant human interleukin-7 (CYT107), in the treatment of chronically HIV-1 infected patients classified as Immunological Non-Responders (INR) after at least 24 months of highly active anti-retroviral therapy (HAART). The study will enroll a total of 80 patients at investigative sites in Italy, Switzerland and South Africa.
“We are pleased to announce that the INSPIRE 3 clinical program is underway. The repeated treatment cycles of CYT107 in this study mimic the way the product will be used in the clinical setting and should trigger an improved and more prolonged immune reconstitution, a stabilization of patient CD4+ T cell counts above 500/microlitre, and a decrease of the markers of activation/inflammation,” said Michel Morre, DVM, President and CEO of Cytheris. “The safety and efficacy results obtained in this trial will contribute to the clinical profile of CYT107 as a potentially important new option for HIV patients and will also serve to define the clinical end points in subsequent pivotal therapeutic studies.”
The Phase II study is designed to evaluate the safety and biological activity of CYT107 at a dose of 20 microgram/kg/week in patients with CD4+ T cell counts which have remained between 101-350 cells/microliter after at least 2 years of HAART and with plasma HIV RNA less than 50 copies/millilitre for 18 months.
Numerous large cohort studies have shown that the health status and life expectancy of HAART-treated HIV patients able to recover and maintain their CD4+ T cell counts above 500/microliter is comparable to the healthy population. In particular these patients show a lower incidence of AIDS-related or non-AIDS-related malignancies, opportunistic infections and cardiovascular events compared to the HIV-infected population with CD4+ T cell counts below 500/microliter.
“In the INSPIRE 3 trial the goal is to establish the safety and biological activity of repeated cycles of CYT107 administered in a way that will optimize the chances that INR patients will be able to remain above 500 CD4+ T cells/microliter during the study period,” said Giuseppe Tambussi, MD, Head, Experimental Therapies Unit, Infectious Disease Clinic, San Raffaele Hospital, Milan, Italy, and Principal Investigator/Study Chairman for the trial. “This is a key prerequisite for undertaking studies aimed at demonstrating the clinical efficacy of such a therapeutic regimen.”
Various results from the completed INSPIRE study demonstrate the quality of CYT107-induced T cell reconstitution in Immune Non-Responding patients:
* CYT107 administration was clinically and biologically well tolerated.
* 20 microgram/kg/w was the dose with the best efficacy/safety ratio.
* A single cycle (3 subcutaneous injections) induced a rapid and sustained increase of CD4+ and CD8+ T cells, with most patients treated with 20 microgram/kg of CYT107 reaching CD4+ T cells counts more than 500 cells/microliter at W12.
* All treated patients showed a very significant increase in their CD4+ T cells counts: from a baseline average at 270 CD4+/microliter, patients remained at about 400 CD4+/microliter after one year of follow up.
* CYT107 induced a brisk expansion of T cells subsets – increasing RTE, naïve, central memory and effector T cells.
* CYT107 significantly decreased markers of exhaustion (PD-1) and did not induce an increase of markers of T cell activation (HLA-DR).
Cytheris is currently conducting a repeat study, INSPIRE 2, at 20 microgram/kg/week at sites in the US and Canada. This study is designed to provide additional data for refining a PK/PD population model and to further document the ability of CYT107 to target T cells to lymph nodes and the GI tract, sites of major T cell depletion in HIV.
While INSPIRE 2 is designed to confirm the unique ability of CYT107 to trigger and support immune reconstitution in INR patients as previously documented in the first INSPIRE study, INSPIRE 3 represents the next step in the development of CYT107, testing the repeated administration of cycles of CYT107 in order to induce a long lasting immune recovery.
INSPIRE 3 is a multicenter, open-labelled, controlled, randomized Phase II study of recombinant Interleukin-7 (CYT107) treatment to restore and maintain CD4 T-lymphocyte counts above 500 cells/microliter in HIV-infected patients with CD4 counts remaining between 101-350 cells/microliter after at least 2 years of HAART and plasma HIV RNA less than 50 copies/mL for 18 months.
The primary objective of this 24-month study is to investigate the biological activity and safety of repeated cycles of CYT107 at 20 microgram/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 microgram/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 (HAART therapy only) 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.
Approximately 25 per cent to 30 per cent of HIV–infected patients who receive long-term highly active antiretroviral therapy (HAART) do not exhibit a marked increase in their CD4+ T cell count, despite achieving complete suppression of HIV viral load. These patients are referred to as “immunological non-responders.” Notably, the proportion of patients experiencing immunological failure depends on how failure is defined, the observation period, and the patient’s CD4+ T cell count at the start of treatment.
In the longest study conducted to date, the percentage of patients with suppressed viremia who reached a CD4+ T cell count more than 500 cells/µL over 6 years of treatment was only 42 per cent for patients starting treatment at a nadir CD4+ T cell count less than 200 cells/microliter and 66 percent for patients with a nadir of less than 350 cells/microlitre3. In a recently reported EUROSIDA cohort of 1835 patients observed for 5 years after HAART, 54.4 percent of patients did not reach 500 CD4+ T cell/microliter after an average of 3.2 years of HAART.
Recombinant human interleukin-7 (CYT107) is a critical immune-modulator for immune T-cell recovery and enhancement. As a growth factor and cytokine physiologically produced by marrow or thymic stromal cells and other epithelia, IL-7 has a critical and, at some steps, a non-redundant stimulating effect on T lymphocyte development, notably on thymopoïesis and, downstream from the thymus, on homeostatic expansion of peripheral T-cells.
Clinical trials conducted on more than 160 patients in Europe, North America and Taiwan have demonstrated a consistent safety and tolerability profile as well as the potential of IL-7 to expand and protect CD4+ and CD8+ T-cells in various pathologic conditions.
Currently, Cytheris is conducting multiple international investigations of IL-7 in HIV, HBV, HCV, idiopathic CD4 lymphocytopenia (sponsored by NIAID/NIH) and cancer, the latter including an NCI/NIH-sponsored study of IL-7 in combination with dendritic cell vaccines in a pilot study of tumor vaccination in children, and a study designed to restore CD4+ and CD8+ counts following T-cell depletion due to bone marrow or peripheral blood stem cell transplant (being conducted at the Memorial Sloan-Kettering Cancer Center in New York City).
Cytheris SA www.cytheris.com
