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Sangamo Presents Additional Data in Support of Enzyme-Based Functional Cure of HIV/AIDS

Sangamo BioSciences, Inc. (Nasdaq: SGMO), announced on March 6, 2014 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 was 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) (see BioQuick story below). "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 on March 6, 2014 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." [Press release] [Conference on Retroviruses and Opportunistic Infections (CROI 2014) web site]