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Cytheris SA Announces Results of Phase II Study Indicating That Recombinant Interleukin-7 (CYT107) Expands CD4 T-Cells in Gut Mucosa of Chronically HIV Infected Immunological Non-Responder Patients



3/8/2012 11:55:38 AM

Paris, March 8, 2012 - Cytheris SA, a clinical stage biopharmaceutical company focused on development of new therapies for immune modulation, announces today 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 data were presented at the 2012 Conference on Retroviruses and Opportunistic Infections (CROI) held in Seattle, March 5 to 8.

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.

"CD4 T cell depletion in the gut mucosa is an important pathogenic event in HIV infection that is associated with T-cell activation and partially restored by ART(1)," said Jean Pierre Routy, MD, site study investigator in Mc Gill Hospital, Montreal. "It is now well documented that significant AIDS and non-AIDS morbidity and mortality persists in HIV infection, particularly in patients who fail to restore normal CD4 T-cell counts. The results of the current study indicate that r-hIL-7 administration can expand gut T lymphocyte numbers, predominantly central memory CD4+ T-cells and warrant further investigations of the clinical benefit of r-hIL-7 in HIV-INR patients."

Results of the Phase II (INSPIRE 2) Study

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.

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).

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.

Summary of Presentation Results

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).

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.

"This observation further supports CYT107 therapeutic activity in HIV-INR patient population," said Dr. Croughs, MD and CMO of Cytheris. "In order to establish long term and stable restoration of CD4 counts in these patients, repopulation of T-cells in the gut is crucial to stop cell death induced by residual activation in the GI tract and to restore local immune surveillance."

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.

About Recombinant Human 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 thymopoiesis and, downstream from the thymus, and on homeostatic expansion of peripheral T-cells.

Clinical trials conducted on more than 240 patients in Europe, North America, South Africa and Taiwan have demonstrated the ability of IL-7 to expand and protect CD4 and CD8 T-cells and the potential to induce an antiviral activity. Currently, Cytheris has completed or is conducting multiple international investigations of CYT107 in patients with HIV infections, chronic hepatitis, cancer and after hematopoietic stem cell transplantation (HSCT).

About Cytheris -

Cytheris SA is a privately held clinical-stage biopharmaceutical company focused on development of new therapies for immune modulation. Cytheris develops CYT107 that aims at reconstituting and enhancing the immune system of patients suffering from cancer, chronic viral infections such as HIV and chronic hepatitis, or lympho-depleting treatments such as chemotherapy, and hematopoietic cell transplantation (HSCT). The company operates from its headquarters and laboratories in Issy-les-Moulineaux, a suburb of Paris, and its U.S. subsidiary in Rockville, Maryland.

(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.

Mark Tidmarsh

ANDREW LLOYD & ASSOCIATES

http://www.ala.com

mark@ala.com

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