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Cytheris SA Announces Interim Results from ECLIPSE II Hepatitis C Multicenter Study of IL-7 in Chronically Infected Genotype One and Four Nonresponders to Standard of Care (SOC)


11/8/2011 10:13:16 AM

Paris, November 8, 2011 - Cytheris SA, a clinical stage biopharmaceutical company focused on research and development of new therapies for immune modulation, today announced that data from an interim analysis of its ECLIPSE II Phase I/IIa study indicate that treatment with four weeks of the company's investigative immune-modulator, recombinant human Interleukin-7 (CYT107), added to peginterferon and ribavirin (SOC) in genotype one and four treatment experienced patients defined as nonresponders to SOC, induces a broad immune response associated with HCV viral clearance in genotype one and four treatment experienced patients defined as nonresponders to SOC.

"In the current pursuit of higher cure rates and shorter treatment times utilizing combinations of multiple direct acting antivirals, we are hopeful that IL-7 restoration of T cell immune control may represent an alternate, shorter, IFN-free pathway to achievement of viral clearance. The effect has already been observed in chronic LCMV and in three patients suffering from Progressive Multifocal Leukoencephalopathy (PML) due to the JC virus," said François Habersetzer, MD, principal investigator at Strasbourg University Hospitals, Inserm 748, University of Strasbourg, France and co-chair of the study. "The current study of safety and activity of CYT107 treatment in genotype one and four patients resistant to one or multiple lines of SOC focuses on one of the more difficult segments of the HCV patient population and strongly supports the potential of additional studies with this cytokine."

The data were presented during a late breaker poster session (Abstract No. LB-9: Four weeks of IL-7 (CYT107) added to peginterferon and ribavirin (SOC) induces a broad immune response associated with HCV viral clearance in genotype one and four treatment experienced patients defined as nonresponders to SOC. Habersetzer F, Payen JL, Rouzier R, Alric L, Andreone P, Grando V, Attali P, Hézode C, Serfaty L, Tambussi G, Thabut D, Beq S, Demol P, Croughs T, Morre M, Marcellin P) at The Liver Meeting(R), the 62nd annual meeting of the American Association for the Study of Liver Diseases (AASLD) in San Francisco, November 4-8, 2011.

Interim Results of the Phase I/IIa (ECLIPSE 2) Study

ECLIPSE II is an open-label, dose-escalating study (three, ten and twenty mcg/kg/week). CYT107 was administered subcutaneously, one injection per week for four weeks (D0 to D21), as an add-on therapy to 24 or 48 weeks of SOC, peginterferon and ribavirin. SOC was initiated nine weeks (median) before CYT107. Six patients were included at each dose level and six more if at least two patients showed a HCV RNA drop more than two logs. Patients less than 18 years, with liver cirrhosis, abnormal bilirubin or AP, HIV or HBV co-infection were excluded. Interim results reported at AASLD focus on the 16 patients treated at three or ten mcg/kg/wk.

During the study, there was only one serious adverse event (AE) that did not lead to study drug discontinuation. There were no other SAEs, DLT or clinically relevant abnormalities in biological parameters related to CYT107 treatment. 78.6 per cent of AEs were of grade less than or equal to one, primarily injection-site reactions, and no neutralizing IL-7 antibodies were detected.

At D56, consistent with CYT107 results in HIV, CYT107 (10mcg/kg/wk) induced (median values):

- A T cell increase plus 341 CD4/mcl (plus 168 per cent) and plus 209 CD8/mcl (plus 179 per cent) more than correcting the initial pre-CYT107-SOC induced lymphopenia (minus 147/mcl CD4)

- A broadening of the T cell receptor repertoire (TCR) diversity (plus 25 per cent) in the four patients with low diversity at D0 (45 per cent)

- An increased number of CD3 expressing the ?4B7 receptors ( plus 73 per cent)

These increases in T cell counts, diversity and functionality were associated with HCV viral elimination at Week 12 in one in six patients treated at three mcg/kg and in five in twelve patients treated at ten mcg/kg. At CYT107 initiation, all six responding patients had a moderate viral load (less than 4.5 log/mL), showed an increased rate of viral clearance (plus 25 per cent), and remained undetectable (median current follow up: 11 months).

Summary of Presentation Results

In chronic HCV patients defined as non responders to SOC, CYT107 treatment was safe and expanded both CD4 and CD8 T cells, an effect known to provide an efficient and stable immune response. CYT107 also induces a normalization of the diversity of the TCR repertoire. At ten mcg/kg/wk, this effect was associated with an antiviral effect and disappearance of serum HCV RNA in patients nonresponsive to SOC.

These promising results suggest the need for future studies combining direct acting antivirals (DAAs) and CYT107 which act through immune restoration in order to achieve complementary immune and direct antiviral effect to achieve a rapid elimination of HCV RNA under a shortened regimen. In fact, as noted above, five of these resistant patients among the twelve treated patients quickly became HCV RNA negative after adding CYT107 to SOC.

"With these initial results in mind, the real breakthrough for IL-7 therapy lies in the administration of CYT107 shortly after the massive antigen drop triggered by treatment with two HCV DAAs, a drop which usually occurs less than two weeks following the start of antiviral treatment," commented Thérèse Croughs, MD, chief medical officer of Cytheris. "For most HCV patients, we believe this combination of two antivirals with IL-7 could lead to a successful treatment outcome without the use of peginterferon in perhaps as little as six weeks: two weeks to allow for a sufficient drop in antigen load (contributing to the rescue of PD-1 exhausted T cells) and four weeks to induce a broad repertoire of protective central memory T cells and block any viral escape by mutation. With a large expansion of T cells including in lymph nodes, a massive and broad CTL attack on the HCV virus can be reasonably expected with an associated and permanent SVR resulting in viral cure."

In the absence of peginterferon, small molecules inhibiting HCV polymerase or protease will improve HCV eradication rate only if they are powerful enough to achieve a full inhibition of HCV replication and remain active for a sufficient period of time, without inducing viral resistance or drug-drug interaction. The experience gathered with HIV treatment shows that the emergence of resistance to anti-retroviral molecules sharing the same mechanism of action is frequent. Therefore, these molecules may deserve to be combined with a well tolerated immuno-modulating agent such as CYT107 which facilitates their effects by improving the control of HCV infection by the immune system.

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 including more than 220 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 (ICICLE) in idiopathic CD4 lymphocytopenia (ICL); a cancer vaccine study in children with Ewing's sarcoma family of tumors or similar genetic tumors sponsored by US National Cancer Institute; a collaborative study in metastatic breast cancer sponsored by the Centre Léon Bérard of Lyon; and, a multi-company/institutional study (EraMune 01) sponsored by ORVACS (the international HIV organization funded by the French Bettencourt Schueller Foundation) aimed at attacking the HIV viral reservoir.

About Cytheris -

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 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.

Mark Tidmarsh

ANDREW LLOYD & ASSOCIATES

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mark@ala.com

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