Profile: Sangamo Biosciences Inc (SGMO.O)

Sangamo BioSciences, Inc. (Sangamo), incorporated on June 22, 1995, is engaged in the development and commercialization of transcription factors for gene regulation and gene modification. Sangamo’s gene regulation and gene modification technology platform is enabled by the engineering of a class of transcription factors known as zinc finger deoxyribonucleic acid (DNA)-binding proteins (ZFPs). ZFPs can be engineered to make ZFP transcription factors (ZFP TFs), proteins that can be used to turn genes on or off, and ZFP nucleases (ZFNs), proteins that enable to modify DNA sequences in a variety of ways. As ZFPs act at the DNA level, they have applications in areas, including human therapeutics, plant agriculture, research reagents and cell-line engineering. Its ZFP Therapeutic, SB-509 is a plasmid formulation of a ZFP TF activator of the vascular endothelial growth factor-A (VEGF-A) gene. It is under evaluation in three Phase II clinical trials for the treatment of diabetic neuropathy (DN) and one Phase II trial for amyotrophic lateral sclerosis (ALS). SB-728-T represents the first therapeutic application of its ZFN technology. Sangamo also has preclinical development programs of ZFP Therapeutics in spinal cord injury, stroke, traumatic brain injury, neuropathic pain and Parkinson’s disease. It has additional research-stage programs in X-linked severe combined immunodeficiency (X-linked SCID), hemophilia and hemoglobinopathies.

ZFP Therapeutic Product Development Programs

The Company’s lead therapeutic development programs are based on the development of a ZFP TF that has been engineered to activate a patient’s own VEGF-A gene. VEGF-A has been demonstrated to have both angiogenic and direct neuroproliferative, neuroregenerative and neuroprotective properties. The VEGF-A gene encodes multiple forms (isoforms) of the VEGF-A protein, which exhibit slightly different properties and bind to different VEGF-A receptors. The Company is developing formulations of this VEGF-activating ZFP TF, also called SB-509, for the conditions, such as DN and ALS, and are evaluating the ZFP Therapeutic in several ongoing clinical trials. It is also evaluating the VEGF ZFP TF in preclinical animal studies in spinal cord injury, traumatic brain injury and stroke.

Sangamo is developing SB-509, an injectable formulation of plasmid DNA that encodes a ZFP TF, designed to up-regulate the patient’s own VEGF-A gene in an effort to address the underlying nerve damage caused by DN. Human clinical studies have demonstrated that VEGF expression is reduced in diabetic patients with neuropathy. Sangamo has completed preclinical studies of VEGF-A activation using its ZFP Therapeutic, SB-509, in animal models of DN and demonstrated that single and repeat intramuscular injections of SB-509 in rats with diabetes resulted in protection of nerve function in the treated limb as measured by sensory and motor nerve conduction velocities.

The Company initiated a double-blind, placebo-controlled, repeat-dosing multi-center Phase II clinical trial of SB-509 (SB-509-601) in November 2006. It completed enrollment of subjects into this trial in December 2007, and in November 2008, presented data from this study. The data demonstrate that repeat administration of the drug is tolerated in subjects with mild to moderate DN. However, no significant differences were observed between the SB-509 and placebo treated subjects in a number of measures of nerve function and health at the primary analysis point, day 180 post-treatment.

In April 2007, Sangamo initiated a second repeat-dosing placebo-controlled Phase II clinical study (SB-509-701) to evaluate SB-509 in subjects with moderate to severe DN. In June 2008, it expanded this trial to include an additional cohort of subjects (group B) treated with a different dosing schedule. The Company presented an interim analysis of data from the first group (A) in October 2008. The data demonstrated that the drug was tolerated in a repeat dosing setting in this population and among subjects who entered the trial with blocked sural nerves, the Company observed preferential recovery of NCV in SB-509-treated subjects compared with the placebo-treated group during 180 days post treatment in subjects who entered the trial with blocked sural nerves. In January 2008, it initiated a single-blind, placebo-controlled, Phase II clinical trial (SB-509-703) in subjects with mild to moderate DN designed to evaluate the pharmacokinetics of stem cell mobilization into the bloodstream after treatment with varying doses of SB-509, as well as the clinical safety and clinical effects of SB-509 administration. The Company has completed enrollment of this trial.

ALS, commonly referred to as Lou Gehrig’s disease, is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. In September 2008, the Company initiated a Phase II clinical trial (SB-509-801) to evaluate SB-509 in subjects with ALS.

CCR5 is a co-receptor for HIV entry into T-cells and, if CCR5 is not expressed on their surface, HIV is less efficient at infecting these cells. Sangamo is using its ZFN-mediated gene disruption technology to disrupt the CCR5 gene in cells of a patient’s immune system to make these cells permanently resistant to HIV infection. During the year ended December 31, 2008, Sangamo filed an Investigational New Drug (IND) application with the United States Food and Drug Administration (FDA) and initiated a Phase I clinical trial to evaluate SB-728-T for the treatment of human immunodeficiency virus/ acquired immunodeficiency syndrome (HIV/AIDS). This trial began enrolling subjects in February 2009, at the University of Pennsylvania.

ZFP Therapeutic Pre-clinical Stage Programs

The Company has a pre-IND program and multiple preclinical-stage programs (lead ZFP TF molecules in animal efficacy studies), in addition to its ongoing Phase II clinical trials in DN and stem cell mobilization, ALS and its Phase I study in HIV/AIDS. Gliomas are the most common type of primary brain cancers. Glioblastoma multiforme (GM) is the most common type of glioma. In collaboration with clinicians at City of Hope (COH) Sangamo is developing a ZFP Therapeutic that uses its ZFN technology to disrupt the expression of the gene encoding the glucocorticoid receptor. The Company’s collaborators have developed an engineered protein known as an IL-13 zetakine that, when expressed in cytotoxic or killer T-cells, enables them to seek out and destroy glioblastoma cells in the brain.

Neuropathic pain comprises a set of chronic pain disorders that cannot be connected to a physical trauma, as is the case with acute pain. The Company’s scientists have identified ZFP TF candidates that repress the expression of two of these pain targets, Trk-A and PN3, in cell-based models. Trk-A and PN3 fall into the class of non-druggable targets. It has incorporated these ZFP TFs into gene transfer vectors and have demonstrated a reduction of pain in an animal model of bone cancer pain after treatment with Sangamo’s ZFP TF repressor of Trk-A.

Parkinson’s disease is a chronic, progressive disorder of the central nervous system and results from the loss of cells in a section of the brain called the substantia nigra. It is evaluating ZFP TFs that activate the glial cell line-derived neurotrophic factor (GDNF) gene in pre-clinical animal efficacy models of Parkinson’s disease. The Company is evaluating its ZFP TF activator of the VEGF-A gene in pre-clinical animal efficacy models of stroke.