Cytheris Announces Interim Results of Phase I Study Showing That Recombinant Human Interleukin-7 (CYT107) Promotes T-Cell Recovery Following T-Cell Depleted Allogeneic Hematopoietic Stem Cell Transplantation

Early clinical results from study conducted at Memorial Sloan-Kettering Cancer Center suggest that CYT107 enhances immune recovery without causing graft-versus-host disease in immunodeficient transplant recipients who are vulnerable to a variety of bacterial, viral, and fungal infections

PARIS--(BUSINESS WIRE)--Dec 7, 2010 - Cytheris SA, a clinical stage biopharmaceutical company focused on research and development of new therapies for immune modulation, today announced interim results from a Phase I clinical trial of its investigational drug candidate, recombinant human Interleukin-7 (CYT107), in the treatment of post-transplant patients with T-cell depleted (TCD) bone marrow or peripheral blood stem cell transplants. Preliminary assessment of the immunological effects of CYT107 in 8 evaluable patients demonstrates a median increase in CD4 T cells exhibiting a naïve or central memory phenotype of 69% over baseline, and a median increase in CD8 T cells exhibiting a naïve or effector memory phenotype of 94% over baseline.

The study is being conducted at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York City, where Marcel R.M. van den Brink, M.D., Ph.D., Head, Division of Hematologic Oncology, and Miguel-Angel Perales, M.D, Director, Adult Bone Marrow Transplantation Fellowship Program, serve as Principal Investigator and co-Principal Investigator, respectively.

The interim results, Recombinant Human Interleukin-7 (CYT107) Enhances CD4 and CD8 T Cell Recovery Following T-Cell Depleted Allogeneic Hematopoietic Stem Cell Transplant In Patients with Myeloid Malignancies (Abstract 674), were presented by Dr. Perales in an Oral Session entitled Clinical Care - Acute and Chronic GVHD, Infectious Complications and Immune Reconstitution of Transplantation II at the 52nd Annual Meeting of the American Society of Hematology (ASH) held in Orlando, Florida.

“Delayed and deficient reconstitution of T cell populations together with consequent development of opportunistic infections remains a common cause of transplant failure and constitutes a major obstacle to the success of a hematopoietic stem cell allograft,” said Dr. Perales. “The interim study results reported here suggest that the administration of CYT107, which is known to stimulate thymopoiesis and peripheral T cell survival/expansion with minimal toxicity, may represent a new and promising therapeutic pathway leading to enhancement of post-transplant immune recovery in recipients of a T-cell depleted allo-HSCT without causing graft-versus-host disease.”

Currently, there are a limited number of interventions available to promote immune reconstitution post-transplant. The therapeutic efficacy of hematopoietic stem cell transplantation (HSCT) is contingent not only on the eradication of malignancy, but also on the quality and rate of immunologic reconstitution. Despite more precise human leukocyte antigen (HLA) typing, effective methods to prevent graft rejection and/or reduce the incidence and severity of acute GVHD, infection remains a common cause of transplant failure in patients receiving an allograft from a matched sibling or a matched unrelated donor.

“These results in post-transplant patients are entirely consistent with similar effects observed in our HIV studies, where immunocompromised patients treated with CYT107 show a greatly expanded T cell repertoire that is both functional and long-lasting,” said Michel Morre, DVM, President and Chief Executive Officer of Cytheris. “As in the study reviewed here, this development and expansion of CD4 and CD8 T cells appears to result in an immune system recovery which may be associated with a lower incidence of opportunistic infections and a longer life expectancy, a clinical benefit that we hope to demonstrate in future large-scale randomized clinical studies.”

About the Study -- www.clinicaltrials.gov

Delays in B and T cell reconstitution in allo-HSCT patients are associated with an increased risk of infection, relapse and secondary malignancy. Strategies to enhance post-transplant T-cell reconstitution could therefore improve morbidity and mortality after allo-HSCT. The cytokine Interleukin-7 (IL-7 or CYT107) is a unique therapeutic candidate to promote immune reconstitution because it has a central role in T cell development and survival

The primary objective of the investigation is to determine the safety and a recommended dose of CYT107 in recipients of an HLA-matched related or unrelated ex vivo T-cell-depleted bone marrow or peripheral blood stem cell transplant after initial engraftment and hematopoietic reconstitution. If toxicities are encountered, the study will also seek to establish the maximum tolerated dose (MTD) and dose limiting toxicities (DLT).

Patients admitted to the study must have histologically confirmed non-lymphoid hematological malignancy such as acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), myelodysplastic syndrome (MDS), a history of an opportunistic infection (including but not limited to cytomegalovirus (CMV) viremia requiring anti-viral therapy), PCP pneumonia, mycobacterial infection, herpes zoster, or viral respiratory infection (influenza, RSV, para-influenza), and have a CD4+ T-cell count < 100/µL at 2 months post-transplant.

In the current study, 9 patients (AML=7, MDS=2), with a median age of 59.3 years (range 27-67 years) have been treated with escalating doses of CYT107 (3 at 10 mcg/kg, 6 at 20 mcg/kg) administered subcutaneously weekly for 3 weeks following TCD allo-HSCT from an HLA compatible donor. Accrual is ongoing in the final cohort at 30 mcg/kg.

CYT107 was started at a median of 96 days post allo-HSCT (range 61-244 days). Most patients experienced transient minor injection site reactions. One patient (20 mcg/kg) developed a biopsy proven hypersensitivity drug rash a week after the first injection and treatment was discontinued. No other significant injection-related toxicities have occurred, no patients have developed GVHD, and no anti-IL-7 antibodies or neutralizing antibodies have developed following CYT107 injection. Two of 9 patients with high-risk AML have relapsed (4 and 9 months post CYT107), an incidence consistent with published data in patients undergoing allo-HSCT for AML in CR, irrespective of T-cell depletion.

Eight patients remain alive with a median follow-up of 14.5 months post IL-7 administration. At baseline, the median T cell counts were 91/mm3 (range 5 – 219 /mm3), 43/mm3 (range 9 – 299 /mm3) and 0 (range 0 – 17 /mm3) for CD4+, CD8+ and CD45RA+ T cells, respectively. Preliminary assessment of the immunological effects of rhIL-7 in 8 evaluable patients has demonstrated an increase in CD4+ T cells exhibiting a naïve or central memory phenotype (69% median increase over baseline at day 21 – range 8% to 35-fold increase), and CD8+ T cells exhibiting a naïve or effector memory phenotype (94% median increase over baseline at day 28 – range 0 to 11-fold increase). There was no observed effect on the frequency of CD4+CD25+FoxP3+ T cells or CD19+ B cells. TCR excision circles (TREC) analysis performed on CD4+ and CD8+ subsets in the first 6 patients, using absolute quantification real-time PCR, demonstrated increases in TRECs in 5/6 patients indicating enhanced T cell production.

Finally, all 3 CMV-seropositive patients developed CD8+ T cell CMV-specific responses detected by intracellular IFNγ production to overlapping CMV-pp65 pentadecapeptides peptide pools after administration of CYT107. In one patient, CMV-specific T-cell frequency was analyzed using HLA-A*0201 restricted MHC-tetramers. The highest CMV-specific response levels were noted in this patient with a history of CMV viremia and low-level CMV-specific CD8+ T cells prior to rhIL-7 (5.3-fold increase to the A0201-restricted immunodominant NLV peptide by tetramer assay after CYT107).

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, on homeostatic expansion of peripheral T-cells.

Clinical trials conducted on more than 160 patients in Europe, North America, South Africa and Taiwan have demonstrated the potential of IL-7 to expand and protect CD4+ and CD8+ T-cells. Currently, Cytheris is conducting multiple international investigations of IL-7 in HIV, HCV, HBV, post-BMT and cancer. Additional studies include a NIAID/NIH-sponsored trial in idiopathic CD4 lymphocytopenia (ICL) and a cancer vaccine study in children with Ewing's sarcoma family of tumors or similar genetic tumors sponsored by US National Cancer Institute.

About Cytheris – www.cytheris.com

Cytheris SA is a privately held clinical-stage biopharmaceutical company focused on research and development of new therapies for immune modulation. These drugs aim at reconstituting and enhancing the immune system of patients suffering from cancer, chronic viral or bacterial infections such as HCV, HBV and HIV, or lympho-depleting treatments such as chemotherapy, radiotherapy, bone marrow transplantation (BMT) and hematopoietic cell transplantation (HCT). The company operates from its headquarters and laboratories in Issy-les-Moulineaux, a suburb of Paris, and its U.S. subsidiary in Rockville, Maryland.

 

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Posted: December 2010

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