Sangamo BioSciences, Inc., a leader in therapeutic genome editing, announced that the US Food and Drug Administration (FDA) has cleared the company's Investigational New Drug application (IND) for SB-913, a zinc finger nuclease (ZFN)-mediated approach designed as a single treatment with the potential to provide a long-lasting therapy for Mucopolysaccharidosis Type II (MPS II, Hunter syndrome). The IND is now active and enables Sangamo to initiate a phase 1/2 clinical trial (SB-913-1602) to assess the safety, tolerability and potential efficacy of SB-913 in adults with MPS II.

"Our team has successfully prepared and filed three IND applications in short succession, for hemophilia B, MPS I and now MPS II, meeting our stated goal for filing the third IND application for our IVPRP genome editing approach in the first half of 2016," said Geoff Nichol, M.B., Ch.B., Sangamo's executive vice president of research and development. "Our next goal is to continue this momentum and initiate the SB-913-1602 clinical study for MPS II in the second half of 2016. With positive clinical and safety data in adults, our intention with this, and all of our IVPRP programs, is to extend trials into pediatric populations who could benefit most from early intervention with a genome editing approach designed to provide stable expression of therapeutic enzyme throughout the patient's lifetime."

"Our gene-based approach is designed to give the patient the ability to make their own replacement enzyme and has the potential to provide significant clinical and quality of life advantages over repeatedly administered enzyme replacement therapy, which is the current standard of care for MPS II and a number of other genetic diseases," said Sandy Macrae, M.B., Ch.B., Ph.D., Sangamo's president and chief executive officer. "Unlike conventional, non-integrating AAV gene therapy that has the potential to 'wash out' over time as the patient's liver cells divide and turn over, SB-913 has the potential to provide a uniquely durable solution through genome editing. Ultimately, our target population will include pediatric patients who can benefit from a more durable solution. We believe that a ZFN-mediated genome editing approach can best serve the broadest group of MPS II patients and their families."

Dr. Macrae added, "I am very impressed by the ability of our research and development team to successfully prepare and file several IND applications in short succession, while simultaneously working to open study sites and initiate two clinical trials for hemophilia B and MPS I. One of my first objectives as CEO will be to further expand our clinical team so that we continue to build on these achievements and swiftly translate our efforts into clinical data."

MPS II is an X-linked recessive lysosomal storage disorder that occurs almost exclusively in males. It is caused by mutations in the gene encoding the iduronate 2-sulfatase (IDS) enzyme, resulting in a deficiency of IDS which normally degrades the glycosaminoglycans (GAGs), dermatan sulfate and heparan sulfate. The inability to degrade GAGs leads to their accumulation within lysosomes throughout the body, and individuals with IDS mutations experience multi-organ dysfunction and damage. The rate of progression and degree of symptoms depend on the severity of the mutation. Individuals with the severe form of MPS II (approximately two thirds of the patient population) experience developmental and neurocognitive impairment, organomegaly, valvular heart disease, upper airway obstruction, joint stiffness, skeletal deformities and hearing loss from early childhood, while the attenuated form of MPS II is characterized by later onset of symptoms and little or no effect on the central nervous system (CNS). According to the National MPS Society, one in 100,000 to one in every 150,000 male births will result in MPS II. There are approximately 2,000 MPS II patients worldwide with 500 in the U.S. The current standard of care for MPS II is enzyme replacement therapy (ERT) with recombinant human IDS (hIDS). However, ERT requires life-long, weekly infusions because the hIDS is often cleared from circulation within hours of treatment due to its short half-life and has not been shown to cross the blood brain barrier. Hematopoietic stem cell transplantation has not been shown to limit neurological deterioration in MPS II patients and is not recommended as a form of treatment.

SB-913 is a ZFP Therapeutic based on Sangamo's IVPRP approach and is a single treatment strategy designed to produce continuous, durable therapeutic levels of IDS, the enzyme that is missing or defective in patients with MPS II. Preclinical data from the company's IVPRP approach tested in mouse models of MPS II were presented earlier this year by Sangamo scientists and their collaborators at the University of Minnesota at the 2016 Annual WORLDSymposium Meeting and the Annual Meeting of the American Society for Gene and Cell Therapy (ASGCT). The data demonstrated stable, continuous production of active hIDS enzyme from the liver, which was secreted into circulation and taken up by various secondary tissues, including the liver, spleen, kidneys, lungs, heart, muscle and brain of MPS II mice after a single administration of SB-913. This resulted in a significant increase in hIDS enzyme activity and reduction of glycosaminoglycan (GAG) biomarkers in the plasma and secondary tissues. Treated animals also demonstrated preserved cognitive function when assessed using a Barnes Maze, which evaluates spatial learning and memory.

SB-913-1602 is a phase 1/2 open-label, dose-escalation study in male subjects over eighteen years of age with MPS II (Hunter syndrome). The study will begin enrolling up to nine subjects, with the possibility of expanding to 12 subjects, to evaluate the safety, tolerability and efficacy of a single administration of SB-913. SB-913 is formulated as adeno-associated virus (AAV) vector preparations encoding the therapeutic hIDS enzyme and ZFNs specific for the albumin locus, and will be administered as a single intravenous infusion.

The IVPRP approach makes use of the albumin gene locus, a highly expressing and liver-specific genomic "safe-harbor site," that can be edited with zinc finger nucleases (ZFNs) to accept and express any therapeutic gene. The platform is designed to enable the patient's liver to permanently produce circulating, therapeutic levels of a corrective protein product, such as Factor VIII or IX to treat hemophilia, or replacement enzymes to treat lysosomal storage disorders. With such a large capacity for protein production (approximately 15g/day of albumin), targeting and co-opting only a very small percentage of the albumin gene's capacity is sufficient to produce the needed replacement protein at therapeutically relevant levels with no significant effect on albumin production. Ultimately, the target population for IVPRP programs will include pediatric patients for whom it is critical to be able to produce stable levels of therapeutic protein for the lifetime of the patient.