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Sangamo BioSciences, Inc.

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Edward Lanphier, President and CEO, commented on initial data in this trial and predictions for trial completion. He stated, "In December, we presented data from our SB-728-T program in HIV/AIDS. The presentation compared data on a variety of measures of HIV-infected subjects who after Cytoxan preconditioning received doses of ZFN modified CD4 and CD8 T-cells. We compared ZFN delivery to ZFN delivery methods, either mRNA delivery which we used in our 1401 study or adenoviral delivery used in our 1101 Cohort 3 prime study.

While we achieved equivalent modification rates with both delivery methods, we saw the highest sustained rates of viral load control in the absence of antiretroviral medications in subjects treated on the Cohort 3 prime group, with two of the three treated subjects controlling their viral load and remaining off their antiretroviral medication for over a year.

We have expanded this cohort by an additional five subjects and anticipate that we will have final data later this year."
Source: Q4 2015 earnings conference call, 2/9/16

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Sangamo BioSciences Presents Phase 2 Clinical Data From Two SB-728-T HIV Studies
Preliminary Data Suggest Adenoviral Delivery Method Superior for Immune Stimulation and Control of Viral Load in the Absence of Antiretroviral Therapy (ART)
Two of Three Subjects Remain Off ART for More Than One Year
RICHMOND, Calif., Dec. 11, 2015 /PRNewswire/ -- Sangamo BioSciences, Inc. (Nasdaq: SGMO), the leader in therapeutic genome editing, announced the presentation of Phase 2 data from two of the Company's ongoing clinical trials (SB-728-1101 Cohort 3* and SB-728-mR-1401) of SB-728-T, which is being developed for the functional control of HIV/AIDS. The preliminary comparative data suggest that adenoviral delivery of zinc finger nucleases (ZFNs) to T-cells may be uniquely immune-stimulatory for both acute control of infection, and importantly, HIV reservoir reduction.

Sangamo BioSciences, Inc.
"The preliminary Phase 2 data suggest superiority of the SB-728-T product produced using adenoviral delivery to both CD4 and CD8 cells with two of three initially treated subjects remaining off ART for over one year," stated Dale Ando, M.D., Sangamo's vice president of therapeutic development and chief medical officer. "The adenovirus used to deliver the CCR5-modifying ZFNs to the T-cells may act somewhat like an "adjuvant," providing additional immune stimulation beyond Cytoxan preconditioning, and enhancing expansion of CD8 cells once they are infused back into the subject. This expansion may improve the likelihood of viral load control in the absence of ART, particularly in HIV-infected individuals who may have only a narrow repertoire of anti-HIV activity."

"The proportion of treated subjects in the adenoviral modified Cohort 3* who have responded and established sustained control of viral load in the absence of ART is very striking and may reflect reprogramming of the immune system," stated Rafick Pierre Sékaly, Ph.D., co-director, CHAR Proteomics and Systems Biology Core, Department of Pathology, Case Western Reserve University. "These data suggest that Sangamo has developed a product that can potentially protect the immune system, restore T-cell homeostasis and CD4 T-cell function thereby enabling durable immunological control of HIV by CD8 killer T-cells."

"The observation of functional control in some Cohort 3* subjects complements the observation of significant reduction of HIV reservoir in the immunologic non-responder cohort (SB-728-0902 trial). In that study, infusion of CCR5 modified T-cells led to restoration of T-cell homeostasis and an HIV resistant subset of memory stem T-cells that effectively diluted and reduced the HIV reservoir over time," Dr. Sékaly further commented.

The data demonstrate that SB-728-T manufactured using both mRNA and adenoviral delivery of CCR5-modifying ZFNs to CD4 and CD8 T cells were safe and well-tolerated following a Cytoxan conditioning regimen. The mRNA product showed greater accumulation of total CD4, CD8 and CCR5-modified cells with 3 compared to 2 repeat doses, with persistence of modified cells in the circulation. However, preliminary data suggest that adenoviral delivery may enhance the expansion of CD8 cells compared with mRNA delivery. In addition, a higher proportion of HIV infected subjects treated with the adenoviral SB-728-T product achieved durable control of viral load during a treatment interruption (TI) of their ART than those dosed with a product generated using mRNA delivery or adenoviral delivery to only CD4 cells. Both delivery methods achieved similar levels of CCR5 modification of T-cells.

Preliminary data from the two Phase 2 studies were presented by Dr. Ando at the 7th International Workshop on HIV Persistence during Therapy, considered to be the reference workshop on HIV reservoirs and eradication strategies, which is being held in Miami, FL, December 8-11, 2015. Analyses exploring the potential mechanism of action of SB-728-T in promoting reduction of the HIV reservoir in immune non-responder patients with HIV infection will be summarized in a presentation given by Dr. Sékaly today titled, "The Anti-inflammatory Response and the HIV Cure."

Sangamo's earlier studies of this ZFP Therapeutic®, generated using adenoviral delivery of ZFNs, used an SB-728-T product that was depleted of CD8 cells and thus enriched in CD4 cells. Previously published reports have suggested that individuals who naturally control their HIV infection, so called elite controllers, have activated CD8 cells with low CCR5 expression. For this reason, the SB-728-T product evaluated in both studies described in the presentation was manufactured to contain both ZFN-modified CD4 and CD8 T-cells.

The studies compared two cohorts of subjects that both received a Cytoxan preconditioning treatment, and similar doses of CD4 and CD8 T-cells that were ZFN-modified to disrupt expression of CCR5, a critical co-receptor for HIV entry. One group of subjects (SB-728-1101 Cohort 3*), received a single dose of cells that were modified using ZFNs delivered in an adenoviral formulation and the second group (SB-728-mR-1401, n=8) received an equivalent total dose of modified cells spread over two or three treatments that had been manufactured using electroporation of ZFNs delivered as mRNA. In Cohort 3* four subjects have been treated (of a planned total of eight subjects) and three subjects have completed the protocol's 16-week TI. Both methods generate products with similar levels of ZFN-mediated disruption of the CCR5 gene and both treatments were safe and well-tolerated. 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.

"We have previously demonstrated that delivery of ZFNs to both T-cells and hematopoietic stem cells using mRNA and electroporation results in high levels of genome editing at clinical scale and we continue to use this method for all other ex vivo applications," stated Geoff Nichol, M.B., Ch.B., Sangamo's executive vice president of research and development. "Adenoviral delivery of ZFNs to T cells may be uniquely immune-stimulatory for both acute control of infection and, based on our earlier studies, reservoir reduction, in HIV. We look forward to receiving data from an additional five Cohort 3* subjects in 2016."

Summary of Clinical Trial Design

About SB-728-1101 Cohort 3*
SB-728-1101 is an open-label, multi-center study designed primarily to evaluate safety and tolerability of SB-728-T following optimal cyclophosphamide (Cytoxan) pre-conditioning, on engraftment, viral load and total T-cell counts in peripheral blood. Subjects in Cohort 3* of the study will be treated with a preparation of up to 40 billion ZFN-modified CD4 and CD8 T-cells. The study uses an adenoviral vector to deliver the ZFNs to the isolated T-cells. Four weeks after the last SB-728-T infusion, subjects with CD4 cell counts ≥500 cells/mm3 will undergo a 16 week TI during which time their ART will be discontinued. ART will be reinstituted in subjects whose CD4 T-cell counts drop and/or whose HIV-RNA increases to certain pre-defined levels. At the end of the TI, subjects with a sustained detectable viral load or reduced CD4 T-cell count will be reinstituted on ART. Up to eight subjects will be treated, all of which have been accrued
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Source: press release, 12/11/15. http://investor.sangamo.com/releasedetail.cfm?ReleaseID=946687

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Edward Lanphier, President and CEO, commennted on the 1101 and 1401 phase-II studies of SB-728-T for HIV. HE stated, "Additionally on the clinical front, in late February, we presented an update from our 1101 phase-II clinical study of our HIV T-cell program at the Conference on Retroviruses and Opportunistic Infections or CROI. These new data were from a cohort of the 1101 study that incorporated Cytoxan preconditioning combined with treatment with a ZFN modified T-cell product incorporating both CD4 and CD8 cells. In one subject out of three, we observed a major reduction of viral load below the limit of quantification, and a significant delay in onset of detectable virus during a treatment interruption in a second subject. While we continue to follow these subjects to evaluate the durability of the anti-viral response, we also have an ongoing phase-II study, the 1401 study, which incorporates Cytoxan preconditioning, mRNA delivery and a multi-dose treatment schedule. This trial is fully accrued and we expect to have initial data later this year."
Source: Q1 2015 earnings conference call, 2/11/14.

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SB-728mR-1401 - A Phase 1/2, Open-Label Study to Assess the Safety and Tolerability of Repeat Doses of Autologous T-Cells Genetically Modified at the CCR5 Gene by Zinc Finger Nucleases in HIV-Infected Subjects Following Cyclophosphamide Conditioning
Estimated Enrollment: 12
Study Start Date: August 2014
Estimated Study Completion Date: June 2018
Estimated Primary Completion Date: March 2018 (Final data collection date for primary outcome measure)
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Source: clinical trials.gov. https://clinicaltrials.gov/ct2/show/NCT02225665?term=Sangamo+Biosciences...

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Compound/DeviceSpecialtyIndicationCompound ClassTarget
SB-728-TInfectious DiseaseHuman Immunodeficiency Virus (HIV)zinc finger DNA-binding protein transcription factorCCR5

Mechanism of action: SB-728 is a ZFN-based approach for modification of the gene encoding CCR5, the major co-receptor used by HIV to infect cells of the immune system. SB-728-T is a zinc finger DNA-binding protein transcription factor (ZFP TF). It disrupts the gene responsible for making CCR5 co-receptors on the surface of CD4 cells. When CD4 cells are unable to produce these co-receptors it is much harder for HIV to infect them. The aim of SB-728-T therapy is to grow a new population of CD4 cells that are resistant to HIV infection, and thus make antiretroviral therapy unnecessary.

Phase of Development: II

Event Type: Data: Phase II trial results

Dates: 2016-06-01 - 2016-09-30

Results: Pending