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Gene Therapy Study Participant Maintains HIV Viral Suppression Off ART, Sangamo Says

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A patient who received genetically modified CD4 T-cells lacking a co-receptor that enables HIV entry has maintained undetectable viral load during an antiretroviral treatment interruption lasting 14 weeks, according to a presentation at the annual meeting of the European Society of Gene and Cell Therapy taking place this week in Madrid.

Sangamo BioSciences has developed a technique that uses a zinc finger nuclease (ZFN) to cut out the gene in CD4 cells that controls expression of the CCR5 co-receptor, one of the gateways HIV uses to enter cells.

People with a naturally occurring genetic mutation known as CCR5-delta-32 do not produce this co-receptor. Researchers have attempted to replicate this natural phenomenon as a potential strategy for curing HIV. The Berlin Patient, who received stem cell transplants to treat leukemia from a bone marrow donor with a double CCR5-delta-32 mutation, appears to be free of HIV several years after stopping antiretroviral therapy (ART).

The zinc finger technique produces the same effect by disrupting the normal CCR5 gene in T-cells -- or, ultimately, hematopoietic stem cells that give rise to all immune cells. A sample of cells is collected through apheresis, treated with the zinc finger protein in a laboratory, and the modified cells -- known as SB-728-T -- are returned to the patient.

Researchers have previously reported that the procedure is generally safe and well-tolerated. SB-728-T cells engrafted, multiplied, and distributed themselves like normal T-cells. Most participants experienced substantial increases in CD4 cells and gains have been maintained up to 3 years.

But the real test is whether the modified CD4 cells can resist HIV infection, which can only be determined by analytic treatment interruption with careful monitoring. Dale Ando of Sangamo presented findings from a cohort of patients with a single CCR5-delta-32 mutation (heterozygotes) -- meaning nature has done half the job -- including 1 person who has maintained viral suppression for more than 3 months off ART.

Below is an edited excerpt from a Sangamo press release describing the latest study findings in more detail.

Sangamo BioSciences Presents Clinical Data from HIV Study Demonstrating Sustained Control ff Viremia

  • Reduction of Viral Load at or Below Limit of Detection Ongoing at 14 Weeks

  • Additional Presentations of Preclinical Data at Annual Meeting of European Society of Gene and Cell Therapy (ESGCT)

Richmond, Calif. -- October 28, 2013 -- Sangamo BioSciences, Inc. (Nasdaq: SGMO) announced today the presentation of new data demonstrating sustained control of HIV viral load (VL) at or below the limit of detection for 14 weeks (at last measurement) in an SB-728-T-treated HIV-infected subject who was not on antiretroviral therapy (ART). The CCR5 delta-32 heterozygote subject is enrolled in Sangamo's clinical trial (SB-728-902 Cohort 5) and, as part of the clinical trial protocol, is undergoing an ART treatment interruption (TI), which is ongoing.

Data were presented at the Annual Meeting of the European Society of Gene and Cell Therapy (ESGCT and SETGyC Collaborative Congress) which is being held in Madrid from October 25-28, 2013.

"These data demonstrate that sustained functional control of HIV in the absence of ART is possible with a single SB-728-T treatment," stated Geoff Nichol, MB, ChBSangamo's executive vice president of research and development. "Our aim is to provide a population of immune memory cells that are protected from HIV infection and are capable of generating an effective immune response against the virus throughout the body. These data represent a further step toward demonstrating the efficacy and durability of this therapeutic approach."

Dr. Nichol added, "We continue to follow these Cohort 5 subjects and look forward to presenting a complete data set from this study, and a second ongoing trial (SB-728-1101), designed to maximize the engraftment of SB-728-T in subjects who are not CCR5 delta-32 heterozygotes, later this year."

Data from Sangamo's Phase 1 and 2 studies demonstrate that VL became undetectable during a TI from ART in three of seven evaluable CCR5 delta-32 heterozygote HIV-infected subjects, including two of six subjects that had completed TI in the ongoing SB-728-902 Cohort 5 study and an additional CCR5 delta-32 heterozygote subject from an earlier Phase 1 clinical trial of SB-728-T. In one SB-728-902 Cohort 5 subject, VL has remained undetectable (at or below the limits of quantification of the current ultra-sensitive assays for HIV) for 14 weeks (to last measurement taken) and the TI is ongoing. Reduction in VL from peak during TI showed a statistically significant correlation (p=0.015) with estimated numbers of engrafted ZFN [zinc finger nuclease] modified cells (SB-728-T) in which both copies of the CCR5 gene had been disrupted (biallelic modification), in line with previously presented data from this program.

Collectively, data from these studies demonstrate that in all trial subjects, SB-728-T treatment results in a durable increase in total CD4 T-cells. In addition, seven of nine subjects enrolled in Sangamo's Phase 1 study (SB-728-902 Cohorts1-3) experienced a longer term reduction in the viral reservoir as measured by HIV DNA in peripheral blood mononuclear cells, a source of chronic HIV infection not addressed by current ART.

Sangamo scientists and collaborators also presented data from preclinical and research programs in hemophilia and lysosomal storage disorders, hemoglobinopathies, cancer, cystic fibrosis, immunodeficiencies and the application of ZFN-mediated CCR5 modification in stem cells for HIV.

"The presentations at the ESGCT meeting demonstrate the diversity and breadth of potential therapeutic applications of Sangamo's ZFP technology," said Edward Lanphier, Sangamo's president and CEO. "We look forward to continuing to update on our progress in the coming months at a translational medicine meeting organized by The Lancet entitled, "What Will it Take to Achieve an AIDS-free World?" in San Francisco, from November 3-5, as well as at the Sixth International Workshop on HIV Persistence, Reservoirs and Eradication Strategies in Miami in early December. In addition, we will present data from Sangamo's preclinical programs at the Annual Meetings of the Society for Neuroscience in November and the American Society of Hematology (ASH) in early December."

Summary of Clinical Trial Design

About SB-728-902 Cohort 5 

Ten 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 have been enrolled and have received 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 ART is discontinued. ART is 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/mm for three consecutive weekly measurements.

A total of ten subjects have been treated in this cohort. 

Of the six evaluable subjects, we observed two subjects in which their VL became undetectable during TI from ART:

  • In one subject, VL suppression at, or below, the limit of quantification (LOQ) of virus was sustained from week 11-25 of TI and the TI is ongoing.
  • In the second subject there was a transient suppression of VL at or below LOQ.
  • A third subject completed the TI with 1-log decrease in VL from peak.

In three subjects, there was no reduction in VL during the TI, one completed the TI and in two the TI was terminated early due to their viral loads exceeding the upper limit allowed in the protocol. A seventh subject has not completed TI and is still being evaluated.

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-T

Sangamo's drug, SB-728-T, is generated by ZFN-mediated modification of the gene encoding the CCR5 receptor in a patient's own T-cells. ZFN modification disrupts the expression of this key co-receptor for HIV entry and renders cells resistant to HIV infection. The approach is based on the observation that a naturally occurring mutation in the CCR5 gene, CCR5 delta-32, provides protection from HIV infection. Individuals in whom both copies of the CCR5 gene carry the delta-32 mutation are generally not susceptible to the most common strain of HIV.

About Sangamo

Sangamo BioSciences, Inc. is focused on research and development of novel DNA-binding proteins for therapeutic gene regulation and genome editing. The Company has ongoing Phase 2 and Phase1/2 clinical trials to evaluate the safety and efficacy of a novel ZFP Therapeutic for the treatment of HIV/AIDS. As part of its acquisition of Ceregene Inc., Sangamo acquired a fully-enrolled and funded, double-blind, placebo-controlled Phase 2 trial to evaluate NGF-AAV (CERE-110) in Alzheimer's disease. Sangamo's other therapeutic programs are focused on monogenic diseases, including hemophilia, Huntington's disease and hemoglobinopathies such as beta-thalassemia and sickle cell anemia. Sangamo's core competencies enable the engineering of a class of DNA-binding proteins known as zinc finger DNA-binding proteins (ZFPs). Engineering of ZFPs that recognize a specific DNA sequence enables the creation of sequence-specific ZFP Nucleases (ZFNs) for gene modification and ZFP transcription factors (ZFP TFs) that can control gene expression and, consequently, cell function. Sangamo has entered into a strategic collaboration with Shire AG to develop therapeutics for hemophilia, Huntington's disease and other monogenic diseases and has established strategic partnerships with companies in non-therapeutic applications of its technology including Dow AgroSciencesand Sigma-Aldrich Corporation. For more information about Sangamo, visit the company's website at www.sangamo.com.

10/30/13

References

D Ando. Infusion of ZFN CCR5-modified CD4 T-cells (SB-728-T) led to long term reconstitution of CD4 T-cells and reduction of HIV-DNA levels in HIV-infected subjects on ART. Annual Meeting of the European Society of Gene and Cell Therapy/ESGCT and SETGyC Collaborative Congress. Madrid, October 25-28, 2013.

D Ando. Functional control of viremia in CCR5-delta-32 heterozygous (delta-32HZ) HIV+ subjects following adoptive transfer of zinc finger nuclease CCR5 odified autologous CD4 T-cells (SB-728-T). Annual Meeting of the European Society of Gene and Cell Therapy/ESGCT and SETGyC Collaborative Congress. Madrid, October 25-28, 2013.

Other Source

Sangamo BioSciences Presents Clinical Data From HIV Study Demonstrating Sustained Control Of Viremia. Press release. October 28, 2013.