"We are delighted to be able to open these two important clinical studies ahead of schedule," said
The new studies employ two approaches to increase the number of engrafted T-cells in which both CCR5 gene copies are modified (biallelically modified) in SB-728-T-treated, HIV-infected subjects. The first, an extension of an ongoing trial (SB-728-902, Cohort 5), is designed to further investigate the effect of SB-728-T treatment on HIV viral load in subjects that are naturally heterozygous for the CCR5 delta-32 gene mutation (i.e. one of their two CCR5 gene copies has the mutation and one is normal). The second study (SB-728-1101), in HIV-infected subjects without the CCR5 delta-32 mutation, employs a conditioning pretreatment designed to significantly enhance the number of engrafted biallelically modified T-cells.
The rationale for the Phase 2 studies is based on data obtained in a Phase 1 trial of SB-728-T that demonstrated a statistically significant relationship between the number of engrafted biallelically modified T-cells and the reduction in HIV viral load in treated subjects. In this earlier trial, the viral load of an SB-728-T treated-subject decreased to undetectable levels during a scheduled treatment interruption (TI). This subject was heterozygous for the CCR5 delta-32 gene mutation, thus doubling the number of biallelically modified T-cells after SB-728-T treatment.
"We are focused on applying our ZFP Technology platform to develop novel therapeutics to address unmet medical needs," stated
About the SB-728-T Program
Sangamo is developing SB-728-T, a ZFN approach to the treatment of HIV/AIDS. In addition to the newly initiated Phase 2 studies, SB-728-T is being evaluated in an ongoing Phase 1/2 and two Phase 1 clinical trials to evaluate the safety and clinical efficacy of this approach in CD4+ T-cells. Sangamo's ZFNs are designed to permanently modify the DNA sequence encoding CCR5, a co-receptor that enables HIV to enter and infect cells of the immune system. Individuals carrying a naturally occurring mutation in both of their CCR5 genes (homozygotes), a variant known as CCR5 delta-32, have been shown to be resistant to HIV infection. Building on this observation, a study published in Blood in
About SB-728-902 Cohort 5 — Phase 2 Study
Up to 20 HIV-infected subjects heterozygous for the CCR5 delta-32 mutation (i.e. with one CCR5 gene that is naturally modified) who are currently on Highly Active Anti-retroviral Therapy (HAART) will be enrolled and will receive a single intravenous infusion of SB-728-T (5 to 30 billion modified cells). Two months after SB-728-T treatment, subjects will undergo a 16 week TI during which time their anti-retroviral therapy will be discontinued. HAART will be reinstituted in subjects whose CD4 T-cell counts drop to < 350 cells/mm3 and/or whose HIV-RNA increases to > 100,000 /mL for three consecutive weekly measurements. At the end of the TI, subjects with a sustained detectable HIV viral load will be reinstituted on HAART. Subjects with an undetectable viral load will remain off HAART until HIV RNA levels are detectable or their CD4 T-cell count drops below 350 cell/mm3 for three consecutive weekly measurements.
About SB-728-1101 — Phase 1/2 Study
SB-728-1101 is an open-label, dose escalation, multi-center study designed primarily to evaluate the safety and tolerability of escalating doses of cyclophosphamide (Cytoxan®) administered one day prior to SB-728-T infusion. Cytoxan is a drug that is used to transiently reduce the numbers of T-cells in the body which then rapidly repopulate once the drug is discontinued. Such lymphodepletive treatment has been used to enhance engraftment of adoptively transferred T-cells in the treatment of cancer and as therapy for numerous autoimmune diseases. The drug has been previously used in HIV-infected individuals and studies demonstrate that, while the drug was transiently lymphodepleting, it did not significantly reduce total CD4 T-cell counts over the long term and was adequately tolerated.
In addition to safety, the study will evaluate the effect of escalating doses of Cytoxan on SB-728-T engraftment, the effect of SB-728-T treatment on viral load following HAART interruption, the change in CD4+ T-cell counts in peripheral blood and the long-term persistence of SB-728-T.
At least 9 HIV-infected subjects on HAART will be enrolled into 3 dose-escalating cohorts (3 subjects/cohort), and will receive intravenous Cytoxan (200 mg, 500 mg or 1000 mg). Within each cohort, treatment will be staggered so that each subsequent subject cannot be infused with Cytoxan until at least 2 weeks after the preceding subject. One day after receiving Cytoxan, subjects will be infused with SB-728-T (5 to 30 billion cells). Six weeks after SB-728-T infusion, subjects with CD4 cell counts > 500 cells/mm3 will undergo a 16 week TI during which time their anti-retroviral therapy will be discontinued. HAART will be reinstituted in subjects whose CD4 T-cell counts drop to < 500 cells/ mm3 and/or whose HIV-RNA increases to > 100,000 copies/ mL for three consecutive weekly measurements. At the end of the TI, subjects with a sustained detectable viral load or CD4 T-cell count < 500 cells/mm3 will be reinstituted on HAART. Subjects with an undetectable viral load will remain off HAART until HIV RNA levels are detectable or their CD4 T-cell count drops below 500 cells/ mm3 for three consecutive weekly measurements.
About Sangamo's HIV Pipeline of Programs
As part of a collaboration with scientists at
HIV stands for Human Immunodeficiency Virus. HIV infection kills or impairs cells of the immune system progressively destroying the body's ability to fight infections and certain cancers resulting in AIDS (Acquired Immune Deficiency Syndrome). Individuals diagnosed with AIDS are susceptible to opportunistic infections, infections that usually are not as frequent or severe in healthy individuals. At the end of 2008, an estimated 1,178,000 persons aged 13 and older were living with HIV infection in
ZFP Therapeutic® is a registered trademark of
This press release may contain forward-looking statements based on Sangamo's current expectations. These forward-looking statements include, without limitation, references to clinical trials of ZFP Therapeutics in HIV/AIDS, the timing and availability of clinical data, the research and development of novel ZFP TFs and ZFNs as ZFP Therapeutics, applications of Sangamo's ZFP Therapeutics to treat specific human disease as well as establishing strategic partnerships for therapeutic programs and references to anticipated cash and investment balance. Actual results may differ materially from these forward-looking statements due to a number of factors, including technological challenges, uncertainties relating to the initiation, completion and outcome of stages of ZFP Therapeutic clinical trials, Sangamo's ability to develop commercially viable products and technological developments by
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