Interim data from Cytheris CYT107 Phase I/IIa combination study on HCV

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 2 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 1 and 4 treatment experienced patients defined as nonresponders to SOC, induces a broad immune response associated with HCV viral clearance in genotype 1 and 4 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 3 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 1 and 4 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 #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 1 and 4 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, Benhamou Y, Beq S, Demol P, Croughs T, Morre M, Marcellin P) at The Liver Meeting^®, the 62^nd 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 2 is an open-label, dose-escalating study (3, 10 and 20µg/kg/week). CYT107 was administered subcutaneously, one injection per week for 4 weeks (D0 to D21), as an add-on therapy to 24 or 48 weeks of SOC, peginterferon and ribavirin. SOC was initiated 9 weeks (median) before CYT107. Six patients were included at each dose level and 6 more if at least 2 patients showed a HCV RNA drop > 2 logs. Patients <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 3 or 10 µg/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 orclinically relevant abnormalities in biological parameters related to CYT107 treatment. 78.6% of AEs were of grade ≤1, primarily injection-site reactions, and no neutralizing IL-7 antibodies were detected.

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

• A T cell increase +341 CD4/µl(+168%) and +209 CD8/µl (+179%) more than correcting the initial pre-CYT107-SOC induced lymphopenia (-147/µL CD4)
• A broadening of the T cell receptor repertoire (TCR) diversity (+25%) in the 4 patients with low diversity at D0 (45%)
• An increased number of CD3 expressing the α4β7 receptors (+73%)

These increases in T cell counts, diversity and functionality were associated with HCV viral elimination at Week 12 in 1/6 patients treated at 3µg/kg and in 5/12 patients treated at 10µg/kg. At CYT107 initiation, all 6 responding patients had a moderate viral load (<4.5 log/mL), showed an increased rate of viral clearance (+25%), 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 10µg/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, 5 of these resistant patients among the 12 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 6 weeks: 2 weeks to allow for a sufficient drop in antigen load (contributing to the rescue of PD-1 exhausted T cells) and 4 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.

Source: Cytheris