HIV-infected subjects enrolled in Sangamo's ongoing SB-728-902 clinical trial (Cohorts 1-3) received a single infusion of SB-728-T which resulted in a durable increase in total CD4 T-cells driven by increased ZFN-modified CD4 central memory T-cells. The extent of exposure of subjects to circulating zinc finger nuclease (ZFN) CCR5 protected CD4 T cells correlated with a long term decrease in the peripheral blood mononuclear cell (PBMC) HIV reservoir as measured by proviral DNA. In addition, two of four evaluable subjects in Cohort 5 of this study showed a decrease of greater than one log in their viral load during a sixteen week treatment interruption (TI) with one of the subjects achieving a transiently undetectable viral load during the TI period. In subjects in which viral load decreased, a measureable anti-HIV response was observed, specifically a multi-functional response of CD8 T-cells to elements of HIV core proteins.
"These data are quite remarkable," commented
Summary of Clinical Data
SB-728-0902 Cohorts 1-3 in Immunologic Non-Responders (INR)
SB-728-0902 Cohort 5 (CCR5 delta-32 Heterozygotes)
SB-728-1101 Immunologic Responders with Cytoxan Conditioning
Viral load decreases correlate with highest levels of estimated biallelic CCR5 modification
"These data continue to demonstrate the important link between SB-728-T-driven immune reconstitution and HIV viral load depletion," said
"We are very encouraged by our data to date and by our continued progress in understanding the factors required to maximize the potential of this novel immunologic approach to a functional cure for HIV," stated
We observe an unprecedented increase in total CD T-cell levels which correlates with the levels of ZFN-protected CD4 central memory T-cells, and a related long-term decrease in the viral reservoir. We have also observed reduction in viral loads during TI, to undetectable levels transiently in one of four subjects, providing a second example of this observation. Viral load changes during TI continue to correlate with circulating bi-allelic ZFN CCR protected CD4 cells. In addition, we have identified key immunologic markers of inflammation that correlate with the degree of engraftment and can potentially aid in the selection of subjects for which SB-728-T may be most effective."
Dr. Nichol continued, "In our ongoing studies, we will continue to investigate these parameters including the threshold engraftment levels of biallelically modified T-cells and the types of HIV-reactive cells necessary to mount an immune response to the virus. We look forward to presenting the results of these completed studies at the end of 2013."
The data were presented today by
Data will also be presented from Sangamo's Phase 1 clinical trial SB-728-902 Cohorts 1-3 in a second presentation at
Summary of Clinical Trial Design
About SB-728-902 Cohorts 1-3
The study is an open-label Phase 1 clinical trial to evaluate the safety and tolerability of single infusions of an escalating dose of an autologous (a patient's own) CD4+ T-cell product genetically modified at the CCR5 gene by CCR5-specific ZFNs (SB-728-T). The trial enrolled nine HIV-infected subjects (three cohorts of three subjects each) who have sub-optimal T-cell levels and no detectable viral load on long-term ART. Subjects remained on their existing antiviral therapy while receiving treatment with SB-728-T.
About SB-728-902 Cohort 5
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 ART are being 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 undergo a 16 week TI during which time their anti-retroviral therapy is discontinued. ART 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 are reinstituted on ART. Subjects with an undetectable viral load can remain off ART until HIV RNA levels are detectable or their CD4 T-cell count drops below 350 cell/mm3 for three consecutive weekly measurements.
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 is evaluating the effect of escalating doses of Cytoxan on SB-728-T engraftment, the effect of SB-728-T treatment on viral load following ART 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 ART are being enrolled into 3 dose-escalating cohorts (3 subjects/cohort), and will receive intravenous Cytoxan (200 mg, 500 mg/m2 or 1000 mg/m2). Within each cohort, treatment is 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 are infused with SB-728-T (5 to 30 billion cells). Six weeks after SB-728-T infusion, subjects with CD4 cell counts ≥500 cells/ mm3undergo a 16 week TI during which time their anti-retroviral therapy is discontinued. ART will be reinstituted in subjects whose CD4 T-cell counts drop to < 500 cells/mm3and/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/ mm3are reinstituted on ART. Subjects with an undetectable viral load can remain off ART until HIV RNA levels are detectable or their CD4 T-cell count drops below 500 cells/mm3 for three consecutive weekly measurements.
Additional Presentations at ASGCT
Twelve additional presentations from Sangamo and its collaborators will be featured later in the week and include data from preclinical and research-stage human therapeutic programs. Therapeutic areas include additional presentations on HIV/AIDS, ZFP-based approaches for monogenic diseases such as hemophilia, including applications of Sangamo's proprietary In Vivo Protein Replacement Platform, hemoglobinopathies, and oncology. Developments in gene-editing technology applications will also be featured in presentations at the meeting.
All abstracts for the meeting are available online at 2013 ASGCT Meeting Abstracts.
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, the research and development of novel ZFP TFs and ZFNs as ZFP Therapeutics and therapeutic applications and the scope of such applications of Sangamo's ZFP technology platform to specific human diseases and unmet medical needs, including a potential functional cure of HIV/AIDS, the expansion of clinical studies of SB-728-T in HIV-infected individuals, expected timing for the presentation of clinical trial data, the development of ZFP Therapeutics for monogenic diseases and stem cell applications. Actual results may differ materially from these forward-looking statements due to a number of factors, including uncertainties relating to whether clinical trials will validate and support tolerability and efficacy of ZFP
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