Sangamo Presents Clinical Data At CROI 2014 Demonstrating Enhancement Of SB-728-T Engraftment - Continued Control Of HIV Viral Load For 31 Weeks Without ART In SB-728-T Treated Subject

Company Outlines Future Plans for HIV "Functional Cure"

Mar 06, 2014, 12:16 ET from Sangamo BioSciences, Inc.

RICHMOND, Calif., March 6, 2014 /PRNewswire/ -- Sangamo BioSciences, Inc. (Nasdaq: SGMO) today announced the presentation of data from its SB-728-T program to develop a 'functional cure' for  HIV/AIDS at the Conference on Retroviruses and Opportunistic Infections (CROI 2014).  The conference is being held in Boston from March 3 to 6, 2014.  Data from an earlier Phase 1 clinical study in this program were also published in the March 6, 2014 issue of the New England Journal of Medicine (NEJM).

"The achievement of over 7 months of ongoing functional control of viral load without antiretroviral therapy and the progress that we are making in understanding how to best deploy this novel therapy are very exciting," commented Gary Blick, M.D., AAHIVS, Medical & Research Director, CIRCLE CARE Center, who presented the data at CROI and is an investigator on both studies that were reported at the meeting. "The data that have been generated over the course of the clinical investigation of SB-728-T demonstrate immune reconstitution, enhanced survival of the zinc finger nuclease-modified T-cells in the presence of the virus and associated reductions in viral load and the levels of viral reservoir, all of which are necessary to provide functional control of the virus."

At CROI, data were reported from a Phase 1 /2 clinical trial, SB-728-1101, designed to evaluate the effect of increasing doses of Cytoxan preconditioning as a method to increase  the numbers of circulating T-cells, including cells that were zinc finger nuclease (ZFN) modified at the CCR5 gene (SB-728-T). The data demonstrate that increasing doses of Cytoxan preconditioning prior to a single infusion of SB-728-T led to a dose-dependent increase in both engraftment of CCR5-modified cells and notable increases in total CD4 cells above the baseline.  In addition, researchers observed the greatest decrease in viral load (VL) (a drop of 1.9 logs from peak) during a treatment interruption (TI) from antiretroviral therapy (ART) at the highest Cytoxan dose (1.0 g/m2).  Two of the three subjects treated at this dose remain on TI with detectable but stable VLs of several weeks duration. In addition, Sangamo updated the status of a subject from its SB-728-902, Cohort 5 study, who has demonstrated ongoing control of VL for 31 weeks without ART, and who remains on TI.

SB-728-T is an autologous CD4+ T-cell product in which the gene for CCR5, a co-receptor for HIV entry, is modified via ZFN-mediated genome editing to prevent the CCR5 protein from being expressed, mimicking a natural mutation (CCR5 delta-32).  Individuals that carry the CCR5 delta-32 mutation on both of their CCR5 genes are protected from infection by the most common strain of HIV.  Sangamo is developing SB-728-T as a potential functional cure for HIV/AIDS and has been conducting clinical trials that are designed to expand findings of a study that was published today in the NEJM.  In this study, researchers observed that ZFN-modified cells (SB-728-T) had a selective advantage over non-modified cells such that they survived longer when exposed to the virus. Several of the six subjects that underwent a 12-week TI experienced a drop from peak in their VL, including one subject who achieved a decrease in VL to a level that was below the limit of quantification. This subject was later found to carry the CCR5 delta-32 mutation in one of the two CCR5 genes (making the individual a CCR5 delta-32 heterozygote).  Thus, following exposure to the ZFNs targeting CCR5, this subject had a greater percentage of T-cells that were modified at both sites (biallelic modification) and were therefore fully resistant to HIV infection. Subsequent analyses have shown statistically significant relationship between estimated level of circulating cells with biallelic modification of CCR5 and control of VL.  Sangamo has been carrying out clinical studies in HIV-infected subjects who have one copy of the natural mutation, so called CCR5 delta-32 heterozygotes (SB-728-902, Cohort 5), and in subjects undergoing Cytoxan pre-conditioning (SB-728-1101) to further study this relationship.

"Using our ZFN genome editing technology we can engineer immune system cells to achieve control of the virus without ART," said Geoff Nichol, M.B., Ch.B., Sangamo's executive vice president of research and  development. "Our studies have generated valuable data that will enable us to maximize the potential of this novel immunologic therapy for HIV and help optimize patient selection and treatment.  We now better understand the baseline immunologic parameters that are required for viral control, including the threshold level of T-cells that have undergone biallelic modification; the capability of the immune system to respond to the virus; the size of the viral reservoir and the inflammatory status of the HIV-infected individual as identified by cell surface marker and gene expression profiles of immune system cells."

Dr. Nichol added, "In addition, having established that SB-728-T treatment is safe and well tolerated, Sangamo has developed a new proprietary manufacturing process to use mRNA delivery of the ZFNs used in CCR5 genome modification of the T-cells.   This modification to the protocol will enable retreatment, if necessary, and offers the potential for greater CCR5 biallelic modification. We have expanded our SB-728-1101 study of Cytoxan preconditioning to six more subjects to determine the optimal Cytoxan dose, and plan to treat an additional 12 subjects through 2014. These further studies are designed to provide proof of principle, and will incorporate much of what we have learned thus far in previous trials. We expect to enroll these additional studies by the end of 2014."

Cytoxan at doses up to 1.0 g/m2 was shown to be safe and well tolerated in HIV infected subjects, although as expected, nausea and vomiting increased with dose, necessitating the use of a prophylactic anti-emetic. The trial has been extended to study six additional subjects in order to determine the optimal dose of Cytoxan.  Early data from this cohort suggest that an optimal dose may lie between 1.0 and 2.0 g/m2, as more Cytoxan side-effects, particularly severe symptoms of nausea, were observed at 2.0 g/m2.  At the optimal Cytoxan dose a further 12 subjects will be treated. 

"The data presented at CROI and published today in the New England Journal of Medicine support our development program for SB-728-T as a potential functional cure for HIV/AIDS," stated Edward Lanphier, Sangamo's president and CEO. "In the next clinical trial of SB-728-T, which is expected to begin in the first half of 2014, we will implement mRNA delivery of the ZFNs to the cells, which will provide both process- and cost-saving advantages over viral delivery as well as the potential to re-dose.  With positive data from this study, Sangamo intends to seek a partner for further development."

Clinical Data Summary
Abstract #141: Cyclophosphamide Enhances SB-728-T Engraftment to Levels Associated With HIV-RNA Control
Thursday, March 6, 2014
HIV-infected subjects were enrolled in a Phase 1/2 clinical trial (SB-728-1101) in three cohorts.  Each received a single dose of SB-728-T (5 to 30 billion cells) after a dose of Cytoxan 200 mg (n=3), 500mg/m2 (n=6) or 1.0 g /m2 (n=3). All subjects were on ART and had stably controlled undetectable levels of HIV in their blood.

The study evaluated safety and tolerability, changes in CD4+ T-cell counts and the ratio of CD4+ to CD8+ T-cells, as well as levels of SB-728-T in the blood and viral loads during a 16 week TI that began six weeks post SB-728-T treatment.

Analysis of data from subjects in the study presented today demonstrated:

  • Cytoxan was well tolerated at all doses, except for low grade gastrointestinal side-effects which were treated with anti-emetics.
  • A dose-related increase in total CD4 count and engraftment of CCR5 modified cells was observed with engraftment of estimated bi-allelic CCR5 modified CD4 cells at the 1.0 g/m2 Cytoxan dose, approaching levels associated with pronounced anti-viral effects in CCR5 delta-32 heterozygote HIV subjects.
  • An approximately 0.8 to 1.1-log VL reduction from peak was observed in two subjects at the 500 mg/m2 dose level and in a 1.9 log decrease in another subject at the 1.0 g/m2 dose level during a 16 week TI.
  • Two subjects in the 1.0 g/m2 dose level experienced stable reduced levels of virus and remain on TI.
  • Cytoxan conditioning may be a useful strategy to 1) maximize the engraftment and anti-viral effects of SB-728-T adoptive T-cell therapy in HIV subjects and 2) may be an important immunomodulatory chemotherapeutic agent for immunotherapy in HIV.

In addition, data were presented at CROI 2014 from Sangamo scientists and collaborators in the following abstracts:

Abstract #294. Monocyte Activation Markers in HIV Infected Subjects: A Biomarker for HIV Immunotherapy
Wednesday, March 5, 2014
Previous studies had  found that baseline levels of monocyte activation inversely correlated with levels of SB-728-T engraftment as well as with levels of long-term CD4 T cell reconstitution (years 1 and 3) in immunologic non –responders enrolled in the SB-728-902 study (Cohorts 1-3). A similar correlation was observed when this analysis was extended to Cohort 5 from this trial. This study was undertaken in order to better understand and define the optimal host environment for cure-related gene therapy such as SB-728-T.  The findings provide guidance for identifying HIV- infected individuals who may have a more intact immune system and are thus more suitable for HIV immunotherapy.

Abstract #419. Modeling Functional Cure of HIV in Nonhuman Primates Using Gene-Modified Hematopoietic Stem Cells
Wednesday, March 5 (Poster); Thursday, March 6, 2014 (Themed Discussion)
To better understand the mechanism of hematopoietic stem cell (HSC)-driven HIV control, researchers in collaboration with Sangamo scientists developed a model of ART-suppressed HIV infection in the pigtailed macaque which is applicable to an HSC-transplant-based cure strategy such as our SB-728-HSC application. Initial findings demonstrate that bone marrow transplant alone is not sufficient to produce lasting viral control and suggests that cell must be protected by either natural resistance to the virus or by genome modification to engineer such protection, such as by ZFN-modified CCR5 disruption. Sangamo expects to file an Investigational New Drug application for this program in 2014.

Abstract #431. Cross-Clade Inhibition of HIV on Primary Cells by CXCR4 or CCR5 Fused To the C34 Peptide From gp41HR2
Thursday, March 6, 2014 
The data demonstrate potent inhibition of HIV infection in cells expressing a chimeric protein comprising a portion of the HIV envelope fused to either the CXCR4 or CCR5 HIV co-receptors. Scientists fused the C34 peptide from the gp41portion of the HIV envelope to the amino terminus of either the CXCR4 (C34-X4) or CCR5 (C34-R5) proteins. Importantly, both C34-X4 and C34-R5 demonstrated potent inhibition of infection by either anX4-tropic or R5-tropic HIV-1 isolate in primary CD4+ T cells, the natural target of HIV.

Webcasts of all the presentations at CROI 2014 can be accessed via the following link:

About SB-728-T

SB-728-T is an autologous CD4+ T-cell product in which the gene for CCR5, a co-receptor for HIV entry, is modified via ZFN-mediated genome editing to disrupt the CCR5 protein.  T-cells with a disrupted CCR5 protein are resistant to infection by the most common strain of HIV.

About the SB-728-1101 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 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, and it is into this "growth" environment that SB-728-T is infused. 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.

By protocol, nine HIV-infected subjects on ART were enrolled into three dose-escalating cohorts (three subjects/cohort), and received intravenous Cytoxan (200 mg, 500 mg/m2 or 1.0 g/m2). In cohort two, an additional three subjects were evaluated on an improved anti-emetic protocol due to an adverse event of Grade 2 nausea observed in two subjects at that dose level. Within each cohort, treatment was staggered so that each subsequent subject was infused with Cytoxan two weeks after the preceding subject. One to three days after receiving Cytoxan, subjects were infused with SB-728-T (8.2 to 36.2 billion cells). Six weeks after SB-728-T infusion, subjects with CD4 cell counts ≥500 cells/mm3underwent a 16 week TI during which time their anti-retroviral therapy was discontinued. ART was reinstituted in subjects whose CD4 T-cell counts dropped to <500 cells/mm3and/or whose HIV-RNA increased to >100,000 copies/mL for three consecutive measurements.  At the end of the TI, subjects with a sustained detectable viral load >10,000 copies/mL or CD4 T-cell count <500 cells/mm3 were reinstituted on ART. Subjects with a viral load  >10,000 copies/mL and CD4 T-cell count >500 cells/mm3 can remain off ART until HIV RNA levels are >10,000 copies/mL for three consecutive weeks or their CD4 T-cell count drops below 500 cells/mm3 for two consecutive weekly measurements.

About Sangamo
Sangamo BioSciences, Inc. is focused on Engineering Genetic CuresTM for monogenic and infectious diseases by deploying its novel DNA-binding protein technology platform in therapeutic gene regulation and genome editing. The Company has ongoing Phase 2 clinical trials to evaluate the safety and efficacy of a novel ZFP Therapeutic® for the treatment of HIV/AIDS (SB-728-T) and NGF-AAV for Alzheimer's disease (CERE-110). Sangamo's other therapeutic programs are focused on monogenic and rare diseases.  The company has formed a strategic collaboration with Shire International GmbH to develop therapeutics for hemophilia, Huntington's disease and other monogenic diseases, and with Biogen Idec for hemoglobinopathies, such as sickle cell disease and beta-thalassemia. The Company has also established strategic partnerships with companies,  including Dow AgroSciences and Sigma-Aldrich Corporation, in non-therapeutic applications of its technology. For more information about Sangamo, visit the Company's website at
ZFP Therapeutic® is a registered trademark of Sangamo BioSciences, Inc.

This press release may contain forward-looking statements based on Sangamo's current expectations. These forward-looking statements include, without limitation, references relating to research and development of novel ZFP TFs and ZFNs and therapeutic applications of Sangamo's ZFP technology platform for the treatment of HIV/AIDS, 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 expansion of studies to treat additional subjects, the future plans for the HIV/AIDS program, including potential partners for the program, and the initiation of additional preclinical and clinical studies of ZFN-gene modification. Actual results may differ materially from these forward-looking statements due to a number of factors, including uncertainties relating to the initiation and completion of stages of our clinical trials, whether the clinical trials will validate and support the tolerability and efficacy of ZFNs, technological challenges, Sangamo's ability to develop commercially viable products and technological developments by our competitors. For a more detailed discussion of these and other risks, please see Sangamo's SEC filings, including the risk factors described in its Annual Report on Form 10-K and its most recent Quarterly Report on Form 10-Q. Sangamo BioSciences, Inc. assumes no obligation to update the forward-looking information contained in this press release.

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