Date: 2012-03-08
Type of information:
phase: 2
Announcement: results
Company: Cytheris (France)
Product: CYT107 (Recombinant human interleukin-7)
Action mechanism: 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.
Disease: treatment of chronically HIV-1 infected patients classified as Immunological Non Responders (INR) after at least 12 months of highly active anti-retroviral therapy (HAART).
Therapeutic area: Infectious diseases
Country: Canada, USA
Trial
details: INSPIRE 2 is an open-label, multicenter study of subcutaneous intermittent recombinant Interleukin-7 (CYT107) in chronically HIV-infected patients with CD4 Tlymphocyte counts between 101-400 cells/mm3 and plasma HIV RNA< 50 copies/mL after at least 12 months of HAART.
The primary objective of the study is to determine in detail the biological activity and PK profile of CYT107 (20 microg/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/microL. The dose of 20 microg/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 20 microg/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 20 microg/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).
Latest
news: Cytheris has announced results of a multi-center phase II study designed to investigate the potential of recombinant human Interleukin-7 (r-hIL-7, CYT107) therapy to reconstitute CD4 T-cells in chronically HIV-1 infected patients whose CD4 T-cell counts remained low despite treatment with anti-retroviral-therapies (HAART). In addition to providing further evidence of the ability of r-hIL-7 to stimulate the expansion of CD4 and CD8 T-cells in peripheral blood, the results demonstrate the importance of IL-7 in stimulating T-cell repopulation of the lymphoid tissue layer in the mucosa of the gastro-intestinal (GI) tract. This effect, previously demonstrated in SIV infected monkeys, is now confirmed by analysis of rectosigmoid biopsies in this study of HIV infected patients defined as Immunological Non-Responders (INR). The results of the Phase II study (Abstract J-131: Gut mucosa T Lymphocyte restoration in chronically HIV-infected patients treated with recombinant Interleukin-7 (r-hIL-7) by Irini Sereti, Jacob Estes, William Thompson, Margaret Fischl, Therese Croughs, Stephanie Beq, Michael Yao, Mohamed Boulassel, Michael Lederman, and Jean Pierre Routy were presented by William Thompson from the laboratory of Irini Sereti, M.D., M.H.S., NIAID/NIH site study investigator and INSPIRE 2 study co-chair. INSPIRE 2 is an open-label, multicenter Phase II study of CYT107 (r-hIL-7) in chronically HIV-infected persons with CD4 T-cell counts between 101-400 cells/mm3 and plasma HIV RNA less than 50 copies/mL. Twenty two patients were enrolled and received 20 mcg/kg/week of CYT107 for three weeks. All were evaluated at the planned primary end point (CD4 expansion) at week 12. A subset of 12 patients underwent rectosigmoid biopsies both at baseline and between weeks 10-24 (most at week 12). The proportion of gut mucosal CD4 (gated on CD3+) cells increased from 40.3 to 45.8 post-IL7 (P equals 0.05), as did the CD4 number (x10 to the power of 6 cells/gr tissue) from 2.5 to 4.7 (P equals 0.02). The increase was more evident in CD4 cells of central memory phenotype (CD45RO+/CD27+) from 1.8 to 3.6x10 to the power of 6 cells/gr tissue (P=0.01). The proportion and number of gut Th17+ cells did not change significantly. The proportion of cycling (Ki67+) gut mucosal CD4+ and CD8+ T-cells did not change post-IL7 (P equals 0.8 and P equals 0.2 respectively). Quantitative immunohistochemistry confirmed significant increases in gut CD3+ cells in the lamina propria (P equals 0.008). Interestingly, the immunophenotypic analyses of cryopreserved PBMC by flow cytometry at baseline and at week 12 in this subset of 12 patients showed a sustained increase in the expression of the gut homing receptor alpha 4 beta 7 integrin on peripheral CD4 and CD8 T-cells (1.4-fold in both) as early as day seven post first CYT107 administration with a peak increase at day 14 (p equals 0.0001). At week 12, alpha 4 beta 7 integrin remained elevated on peripheral CD4 and CD8 (p equals 0.001:) on T-cells. In addition, administration of CYT107 decreased, at week 12, biomarkers of monocyte activation (sCD14; D0 vs Week 12: 1.93 x 10 to the power of 6 to 1.73 x 10 to the power of 6, p less than 0.01:) and fibrin degradation (D-dimer; D0 vs Week 12: 0.24 to 0.14, p equals 0.05:) that have been linked to disease progression and mortality. The findings in the current study confirm previously reported results in SIV infected monkeys showing the ability of r-hIL-7 treatment to drive T-cells to the gut mucosa and facilitate their expansion (2). (1) Mavigner M et al. Altered CD4+ T cell homing to the gut impairs mucosal immune reconstitution in treated HIV-infected individuals. J Clin Invest 2012; 122(1):62-9. (2) Beq S et al. Injection of glycosylated Recombinant Simian IL-7 provokes rapid and massive T-cell homing in rhesus macaques. Blood 2009; Jul 23; 114(4):816-25.
The data were presented at the 2012 Conference on Retroviruses and Opportunistic Infections (CROI) held in Seattle, March 5 to 8.
CYT107 was clinically well tolerated and without serious adverse events. Median CD4 and CD8 T-cell counts were 260 and 650 cell/mm3 at baseline and increased to 645 and 1390 cells/microlitre at week 12, respectively (both P less than 0.001).
CYT107 expanded both peripheral and gut mucosa T-cells. Numerous experimental and clinical data confirm that T-cell reconstitution in the gut is critical for restoring control over the HIV virus. Administration of r-hIL-7 may have an important effect on immunologic recovery in HIV-infected patients whose HAART regimens have been unsuccessful in restoring CD4 T-cells to a satisfactory level. The sustained immunological efficacy suggests that a short course of CYT107 treatment provides an important avenue for enhancing the immune system and inducing broad proliferative activity of CD4 and CD8 T-cells in the blood, lymph nodes and gastrointestinal tract.
