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Cytheris Initiates INSPIRE 3, a Phase II Clinical Trial of Recombinant Human Interleukin-7 (CYT107) in Chronically Infected HIV Patients
  Study Will Assess Safety and Biological Activity of Repeated Cycles of CYT107 Administered to Restore and Maintain CD4 T-lymphocyte Counts Above 500 Cells/µL in HIV Immune Non-Responding (INR) Patients with CD4 counts remaining between 101-350 cells/µL after at least 2 years of Highly Active Anti-Retroviral Therapy (HAART)
PARIS--(BUSINESS WIRE)--Cytheris SA, a clinical stage biopharmaceutical company focused on research and development of new therapies for immune modulation, today announced that it has begun enrolling patients in INSPIRE 3, a Phase II clinical program 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.
"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."
"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/µL, 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 µg/kg/week in patients with CD4+ T cell counts which have remained between 101-350 cells/µL after at least 2 years of HAART and with plasma HIV RNA < 50 copies/mL 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/µL 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/µL.
"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/µL 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."
About the INSPIRE HIV Clinical Program
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 µg/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 µg/kg of CYT107 reaching CD4+ T cells counts > 500 cells/µL at W12
* All treated patients showed a very significant increase in their CD4+ T cells counts: from a baseline average at 270 CD4+/µL, patients remained at about 400 CD4+/µL 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 µg/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.
About the INSPIRE 3 Study (CLI-107-14)
INSPIRE 3 is a multicenter, open-labeled, controlled, randomized Phase II 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.
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 (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
About Immune Non-Responders (INR)
Approximately 25% to 30% 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 > 500 cells/µL over 6 years of treatment was only 42% for patients starting treatment at a nadir CD4+ T cell count < 200 cells/µL and 66% for patients with a nadir of < 350 cells/µL3. In a recently reported EUROSIDA cohort of 1835 patients observed for 5 years after HAART, 54.4% of patients did not reach 500 CD4+ T cell/µL after an average of 3.2 years of HAART.
About Interleukin-7 (CYT107)
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).
IL-7: A Multifunctional Cytokine
Interleukin-7(IL-7) is a multifunctional cytokine, mainly produced by non-hematopoietic cells, which is active notably but not only on T cell development and the full maturation of T cells in primates. IL-7 has a critical and, at some points, a non-redundant stimulating effect on T lymphocyte development, on thymopoiesis and downstream from the thymus, on homeostatic expansion of peripheral T cells.
At least two properties of IL-7 justify its development as a drug, both in oncology and infectious disease:
* A quantitative effect consisting of a massive expansion of T cells, which not only contributes to improved immune recovery but also to the elimination of tolerance for chronic stimulation by virus- or tumor-derived antigens;
* A functional enhancement of β-T cell reactivity to weak immunogens, such as proteins, virus-causing chronic infections or tumor-associated antigens.
This broad activity of IL-7 leads to the consideration of several avenues of development for CYT107 (r-hIL-7):
* The restoration of the immune system and the prevention of opportunistic infections in patients who develop severe lymphopenia, such as in HIV infection or treatment with lympho-ablative chemo- or radio-therapies;
* The control of chronic viral infections such as HIV and HCV or in the treatment of cancers, either in the minimal residual disease or in more advanced tumors, where IL-7 could be used as a stand-alone agent or in combination with other immunotherapeutic agents, notably with vaccines or as an adjunct to antiviral drugs.
Considerable evidence from basic immunology, preclinical models and, more recently, from early clinical studies, confirms the unique role of IL-7 in the functioning of the immune system and especially in providing the right cells in sufficient numbers to support and improve specific immune responses against infectious agents and malignant cells. In that light, as with EPO for red blood cells and G-CSF for neutrophils, IL-7 plays a pivotal role in supporting T cell expansion and function.
The Main Features of IL-7 Activity
Two basic scientific findings emphasize the important role of IL-7:
* The knockout of either the IL-7 gene or the gene of its receptor triggers a severe combined immunodeficiency in mice; and, the corresponding IL-7 R gene alteration in humans is also responsible for a SCID syndrome;
* IL-7 is the main homeostatic driver of T cell numbers: IL-7 blood levels are inversely correlated with peripheral T CD4 blood counts in the same way that EPO blood levels are inversely correlated with red blood cells counts.
Current Limitations of Most Immunotherapies
The global potential of immunotherapies is impressive because these new approaches could efficiently target most cancers and infectious diseases. Nevertheless, although encouraging data have started to appear and a few therapeutic vaccines are approaching approval, as of today most immunotherapies have encountered serious hurdles that limit their full efficacy and development.
Examining these limitations in light of the encouraging set of activities now documented by the recently produced pre-clinical and clinical data for IL-7 , makes it possible to see how this cytokine can overcome most of these hurdles and thus open a significant number of indications to therapeutic approach.
The current limitations of most immunotherapies such as adoptive T cell therapies, cancer vaccines, and therapeutic vaccines include the following:
* Insufficient production of T cells;
* Production of short lived T cells, very sensitive to apoptosis;
* Inducement of very narrow responses, targeting a limited set of epitopes;
* Boosting CD4 counts but not CD8 counts, or vice versa;
* Production of inefficient T cells that quickly reflect an "exhausted" profile;
* Production of effector T cells with short lived activity but not central memory T cells that are responsible for long term protection (the "Holy Grail" of immunotherapy);
* Occasional production of more Th-2 or suppressor T-regs than the required active Th-1 cells.
How IL-7 Resolves These Current Limitations
Based on some 10 years of preclinical and laboratory data and now partly confirmed in early clinical studies in oncology and HIV, it can reasonably be stated that IL-7 will fully or partly resolve most of the limitations of current immunotherapies in the following ways:
* IL-7 administration systematically increases the number of CD4 and CD8 T cells in both animal models and in clinical studies, including SIV infected monkeys and HIV infected patients;
* This effect is potent and sustained -- the more the animal or patient is lymphopenic, the more pronounced the effect;
* IL-7 administration is very potent at producing "new T cells" (i.e. naïve T cells and recent thymic emigrants);
* The T cells produced are long lived due to the various anti-apoptotic effects of IL-7 ;
* The repertoire of T cells produced by IL-7 is broad both because IL-7 supports thymopoïetic activity and because IL-7 promotes a response against sub-dominant epitopes;
* The improvement of various specific immune responses against tumors and viruses has been broadly documented at the preclinical level; Cytheris is now producing early confirmation of this effect in human clinical trials;
* Data are also accumulating to demonstrate that if IL-7 does not trigger the production of central memory T cells, it does very efficiently support this effect, at least for CD8 T cells;
* IL-7 is a modest activator of effector T cells, cells that quickly lose their IL-7 receptor after activation; this also explains why the global clinical tolerance of IL-7 is satisfactory and why IL-7 does not induce the typical cytokine "storm syndrome."
Most Promising Targets for IL-7 Therapy
Two main immunological settings which correspond to various life threatening pathologies are currently under investigation by Cytheris:
* The specific case of lymphopenia, more precisely CD4 T cell lymphopenia, whatever the cause of the drop in CD4 counts;
* The case of inefficient specific immune response against massive antigen load such as that associated with chronic viral infections and cancer.
In the setting of lymphopenia, Cytheris has initiated clinical studies in:
* HIV infected patients who are immune non-responders, defined as patients treated with HAART therapy for more than a year who do not recover an appropriate number of T cells but whose viral load is controlled;
* Severe lymphopenia subsequent to allogeneic bone marrow transplantation (BMT) or stemcell transplantation (SCT) in the context of T cell depletion;
* Various cases of idiopathic lymphopenia where the patient has a documented history of opportunistic infection and where there is the possibility of documenting specific T cell response.
In the context of an inefficient specific immune response to massive antigen load, there are several therapeutic areas that appear promising:
In Chronic Infectious Diseases:
* Full recovery of immune status in HIV patients who do not recover a minimum of 500 CD4 T cells, sufficient to achieve a life expectancy comparable to the normal population;
* Possibility of responding to and clearing the virus in those HCV infected patients who are non-responders to the standard reference treatment (PEgIFN + Ribavirin).
In Oncology:
* Immune support of cancer therapeutic vaccines;
* Immune support of various chemotherapies to clear residual disease.
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