RICHMOND, Calif., Dec. 7, 2015 /PRNewswire/ -- Sangamo BioSciences, Inc. (Nasdaq: SGMO), the leader in therapeutic genome editing, announced the presentation of data from its ZFP Therapeutic programs, including data demonstrating the production of therapeutic levels of Factor IX (FIX) clotting protein in non-human primates (NHPs) for the treatment of hemophilia B and disruption of the BCL11A Enhancer for the treatment of hemoglobinopathies. Sangamo's hemophilia B program, SB-FIX, has been cleared by the U.S. Food and Drug Administration (FDA) to initiate a Phase 1/2 clinical trial (SB-FIX-1501) in 2016 and is the first clinical application of Sangamo's proprietary In Vivo Protein Replacement Platform™ (IVPRP™). The data were presented at the 57th Annual Meeting of the American Society of Hematology (ASH) being held in Orlando, FL, from December 5-8, 2015.
"We are pleased to present some of the efficacy and specificity data that supported the Investigational New Drug (IND) Application for our hemophilia B program, which was recently cleared by the FDA," said Edward Lanphier, Sangamo's president and chief executive officer. "We believe that our IVPRP has the potential to be highly disruptive to the enzyme replacement therapy market and we look forward to beginning our first clinical trial of the platform. We intend to move rapidly to open a Phase 1/2 study to evaluate SB-FIX in subjects with hemophilia B. We are also pleased to report that our clinical protocol for SB-318, our first IVPRP lysosomal storage disorder program, for the treatment of MPS I, recently received unanimous approval from the NIH Recombinant DNA Advisory Committee (RAC). We expect to file the IND application for SB-318 with the FDA by the end of 2015 and look forward to advancing additional IVPRP programs in lysosomal storage disorders and hemophilia A into clinical development in the near future."
The NHP studies demonstrate that Sangamo's zinc finger nuclease (ZFN) technology can be used to precisely insert a copy of the human FIX (hFIX) gene into a specific location within the albumin gene of liver cells. The use of ZFN-mediated genome editing to insert the hFIX gene into the genome enables it to be expressed by the powerful albumin promoter for the lifetime of the cells and, importantly, their progeny. Furthermore, due to the high expression rates from the promoter, only a small percentage of the liver cells need to be edited in order for the modified cells to produce stable, therapeutic levels of hFIX protein. Adeno-associated virus (AAV) vectors were used to deliver both the ZFNs and the hFIX sequence.
Specifically, the data presented at the meeting demonstrate that a single intravenous administration of AAV encoding ZFNs specific for a site in the albumin gene and AAV carrying a "donor" sequence encoding the hFIX resulted in clinically-relevant levels of circulating hFIX (>3% of normal) in NHPs. ZFN targeting was assessed using several methods and was found to be very specific, with only a single, weak off-target site (SMCHD1) identified when the ZFNs were administered in excess of potential clinical doses. Genome editing of the albumin locus was well-tolerated in mice and NHPs with no noticeable impact on circulating albumin levels.
In addition, data were presented from Sangamo's collaborative hemoglobinopathy programs with Biogen for the treatment of sickle cell disease (SCD) and beta-thalassemia. The approach uses Sangamo's highly specific ZFN technology to target and disrupt the BCL11A Enhancer in hematopoietic stem and progenitor cells (HSPCs). BCL11A is a critical transcription factor in the regulatory pathway which, in early infancy, switches globin expression from fetal globin to the adult form. Knockout of the BCL11A Enhancer results in reduced expression of BCL11A specifically in cells destined to be red blood cells (RBCs), resulting in elevation of fetal globin levels and reduction of mutant adult globin levels in RBCs. Sangamo and Biogen are developing ZFN-mediated knockout of the BCL11A Enhancer as a single administration, long-lasting treatment for both SCD and beta-thalassemia.
Data were presented at ASH demonstrating that Sangamo's ZFNs are optimized to enable efficient disruption of the BCL11A Enhancer. Modified peripheral blood-derived HSPCs can be manufactured at clinical scale using electroporation of mRNA encoding the ZFNs. These modified stem cells are able to engraft and differentiate normally and, when engrafted into immune-deficient (NSG) mice, are capable of producing elevated level of fetal globin.
"Both our hemoglobinopathy programs and our first IVPRP program in hemophilia B highlight the technical advantages of using ZFN-mediated genome editing over other approaches, including traditional gene therapy," stated Geoff Nichol, M.B., Ch.B., Sangamo's executive vice president of research and development. "The specificity of our technology enables us to achieve a permanent modification of the genome, which is expected to provide lifelong therapeutic benefit. The ability to precisely add a gene into a specific location avoids the risks of insertional mutagenesis that are inherent in permanent gene addition approaches that use lentiviral vectors. Additionally, in contrast to non-integrating approaches, such as conventional AAV gene therapy, in which the therapeutic gene may be diluted out by cell division over the lifetime of the patient, we envision that our IVPRP strategy will be suitable for pediatric patients who can derive the greatest potential benefit. These studies highlight both in vivo and ex vivo applications of Sangamo's ZFN-mediated genome editing technology and demonstrate the versatility of the platform for the potential one-time, life-long treatment of genetic disease."
About Sangamo's IVPRP
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. The ability to permanently integrate the therapeutic gene in a highly specific targeted fashion significantly differentiates Sangamo's IVPRP approach from conventional AAV gene therapy approaches, which are non-integrating, and may "wash out" of the liver as cells divide and turn over. Ultimately, the target population for IVPRP programs will be pediatric patients and it will be important in this population to be able to produce stable levels of therapeutic protein for the lifetime of the patient. 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.
About Sangamo's ZFP Therapeutic Approach to Hemoglobinopathies
Sangamo's proprietary ZFN genome editing technology enables the correction of SCD and beta-thalassemia. Both diseases manifest after birth, when patients switch from producing functional fetal gamma-globin to a mutant form of adult beta-globin, which causes their condition. Naturally occurring increased levels of therapeutic fetal hemoglobin have been shown to reduce the severity of both SCD and beta-thalassemia disorders in adulthood. In hematopoietic stem and progenitor cells (HSPCs), Sangamo's genome editing technology can be used to precisely disrupt a key DNA sequence that acts as a powerful tissue and developmental stage "Enhancer" of BCL11A expression. BCL11A is a key transcriptional regulator of the switch from fetal to adult globin production. Knockout of the Enhancer results in the disruption of that switch leading to elevation of fetal globin and reduction in the expression of adult globin.
A bone marrow transplant (BMT) of HSPCs from a "matched" related donor (allogeneic BMT) is curative for both diseases. However, this therapy is limited by the scarcity of matched donors and the significant risk of graft versus host disease (GvHD) after transplantation of the foreign cells. By performing genome editing in HSPCs that are isolated from and subsequently returned to the same patient, an autologous HSPC transplant, Sangamo's approach eliminates both the need for a matched donor and the risk of acute and chronic GvHD. The ultimate goal of this approach is to develop a one-time, life-long treatment for SCD and beta-thalassemia.
About Sangamo
Sangamo BioSciences, Inc. is focused on Engineering Genetic CuresTM for monogenic and infectious diseases by deploying its novel DNA-binding protein technology platform in therapeutic genome editing and gene regulation. The Company has a Phase 2 clinical program to evaluate the safety and efficacy of novel ZFP Therapeutics® for the treatment of HIV/AIDS (SB-728). Sangamo's other therapeutic programs are focused on monogenic and rare diseases. The Company has formed a strategic collaboration with Biogen Inc. for hemoglobinopathies, such as sickle cell disease and beta-thalassemia, and with Shire International GmbH to develop therapeutics for Huntington's disease. It has also established strategic partnerships with companies in non-therapeutic applications of its technology, including Dow AgroSciences and Sigma-Aldrich Corporation. For more information about Sangamo, visit the Company's website at www.sangamo.com.
ZFP Therapeutic® is a registered trademark of Sangamo BioSciences, Inc.
This press release may contain forward-looking statements based on Sangamo's current expectations. These forward-looking statements include, without limitation, the potential of ZFNs to treat a broad range of human monogenic diseases, including beta-thalassemia, sickle cell disease, hemophilia and MPS I, research and development of novel ZFNs, therapeutic applications of Sangamo's ZFP technology platform in hemoglobinopathies, and using its IVPRP in indications such as hemophilia and lysosomal storage disorders, the anticipated timing and the number of IND filings and initiation and completion of clinical trials for IVPRP; and the collaboration with Biogen. Actual results may differ materially from these forward-looking statements due to a number of factors, including uncertainties relating to the initiation and completion of stages of our clinical trials, whether the clinical trials will validate and support the tolerability and efficacy of ZFNs, technological challenges, Sangamo's ability to develop commercially viable products and technological developments by our competitors. For a more detailed discussion of these and other risks, please see Sangamo's SEC filings, including the risk factors described in its Annual Report on Form 10-K and its most recent Quarterly Report on Form 10-Q. Sangamo BioSciences, Inc. assumes no obligation to update the forward-looking information contained in this press release.
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