SB-509 represents a new approach in treating diabetic neuropathy, designed to directly protect and restore nerve function by upregulating the expression of the gene encoding vascular endothelial growth factor (VEGF-A) in diabetics suffering from peripheral neuropathy. The study, designed primarily to test clinical and laboratory safety, was a single blind, single treatment, dose-escalation trial in patients with mild to moderate diabetic peripheral neuropathy. Twelve subjects were treated, with SB-509 administered by intramuscular injection in a distribution along the major peripheral nerves in the legs and feet. Monitored for safety throughout the study, the subjects were also evaluated for changes in symptoms and underwent neurological examination and quantitative sensory testing at one, two, three and six months.
All of the safety end-points of the study were met. Adverse events were limited to mild injection site reaction, there were no serious drug-related events (SAEs), and no dose-limiting toxicities were observed. In addition, improvements in pain, numbness and neurological symptoms were observed in approximately 50 percent of patients who received a single treatment of SB-509. Anecdotal improvements were also reported in neurologic exam scores and electrophysiologic testing.
"We are pleased and very encouraged by the data from our Phase 1 study of SB-509 in subjects with diabetic neuropathy," stated Dale Ando, M.D., Sangamo's vice president of therapeutic development and chief medical officer. "SB-509 appears to be safe and well-tolerated. Furthermore, we saw that a single treatment of our ZFP Therapeutic resulted in improvements in symptoms of pain, numbness and nerve testing in a number of subjects. Most significantly, we did not observe any dose-limiting toxicity, and we were able to treat subjects within the pharmacologically effective dose range that we had demonstrated to be efficacious in preclinical animal studies. This is important, as previous therapies designed to halt or reverse the nerve deterioration that is characteristic of this condition had dose-limiting toxicities that prevented testing at dosing proven to be effective and tolerated in animal studies. For this reason, we are looking forward to initiating a placebo-controlled Phase 2 clinical trial of SB-509 in the second half of 2006."
"Existing treatments for diabetic neuropathy are limited to the use of anti-depressants, analgesics or other agents for the management of pain," commented Mark Kipnes, M.D., a principal clinical investigator for Sangamo and Endocrinologist at the Diabetes and Glandular Disease Clinic in San Antonio, Texas. "Strict control of blood glucose prevents loss of nerve function, however this is very difficult for patients to maintain. There is a compelling need to explore new approaches, such as SB-509, for their ability to protect and restore nerve function. The anecdotal reports of improvement in symptoms are very encouraging. It is also significant that future efficacy studies of SB-509, including the planned Phase 2 trial, will be conducted using a dose of SB-509 that has already been demonstrated to be therapeutically relevant in preclinical animal studies."
"The presentation of the first ever clinical data for a ZFP Therapeutic is an historic and significant event for Sangamo," said Edward Lanphier, Sangamo's president and CEO. "Diabetes is a chronic disease and peripheral neuropathy is a significant complication for the majority of long-term diabetics. We believe that SB-509 may provide a much-needed therapeutic approach that directly addresses the underlying nerve damage. We optimistically look forward to the next stage of development of this novel therapeutic."
About the Study
All subjects in the Phase 1 dose-escalation study of Sangamo's ZFP Therapeutic received a single treatment of SB-509 in one leg (four dose levels of drug were tested – 1, 5, 15 and 30 milligrams) and placebo in the other leg and were examined at 1, 2, 3 and 6 months post-treatment. Twelve subjects with mild to moderate diabetic neuropathy were enrolled and treated in the study. There were no subject dropouts, and the only adverse event reported was mild injection site reaction in four of the twelve subjects that resolved quickly. Most of the subjects had type 2 diabetes.
In addition to assessments of clinical and laboratory safety, subjects were evaluated for changes in pain, numbness, perception of vibration, strength, sensation, reflexes and nerve conduction studies. Pain was assessed using one of the most frequently used measurement scales in health care research, the Visual Analog Scale (VAS). The VAS is an 11-point scale from 0 to 10 with 0 being equivalent to "no pain at all" and 10 being "worst possible pain". In the Phase 1 study of SB-509, 50 percent of patients experienced a 2-point decrease in their VAS score over the course of the study. When questioned about their perception of feeling, 50 percent of subjects also reported that they were no longer experiencing numbness. Total neuropathy scores (TNS) were also assessed for each subject. The TNS score represents combined measurements of neurologic symptoms, neurologic examination, nerve conduction velocity studies (NCV) and quantitative sensory tests (QST) each assessed on a 5-point scale. Fifty percent of subjects showed 2-point improvements in their TNS scores. 9 of the 12 subjects showed 2-point improvements in their QST scores, 4 subjects in the SB-509 treated leg alone, 3 subjects in both legs and 2 patients in the placebo treated leg alone. Studies to evaluate these bilateral clinical effects are ongoing and include measurements of serum VEGF levels as well as retrograde or neurovascular transport of SB-509 and/or VEGF. Future studies will use separate treatment and control groups treated in both legs.
These encouraging anecdotal analyses will require a placebo-controlled evaluation in a larger number of patients. Sangamo is proposing to undertake a placebo-controlled, multi-treatment Phase 2 study in diabetic subjects with mild to moderate sensory/motor neuropathy. Subjects will be assigned to one of three treatment groups which will be administered a placebo, SB-509 every 2 months for three treatments or SB-509 every 3 months for three treatments. Subjects receiving SB-509 will be treated with the maximum tolerated dose of the ZFP Therapeutic by intramuscular injection in both legs. Safety will be monitored throughout the study. Clinical evaluations will include evaluation of pain intensity, neurological examination and electrophysiological testing. The study will be conducted at multiple centers and subject enrollment is expected to take approximately twelve months.
SB-509 is administered as an injectable formulation of plasmid DNA that encodes a zinc finger DNA-binding protein transcription factor (ZFP TFTM), designed to upregulate the VEGF-A gene. VEGF-A has been demonstrated to have direct neurotrophic and neuroprotective properties. In preclinical animal efficacy studies in a diabetic rat model, SB-509 has proven effective in protecting motor and sensory nerve function from disease-induced nerve damage.
About Diabetic Neuropathy
Diabetic peripheral neuropathy is one of the most frequent complications of diabetes. Symptoms include numbness, tingling sensations and pain particularly in the toes or feet. This gradually evolves to loss of sensation and motor function as nerve damage progresses. Ulcers and sores may appear on numb areas of the foot because pressure or injury goes unnoticed. Despite adequate treatment, these areas of trauma frequently become infected and this infection may spread to the bone, necessitating amputation of the leg or foot. More than 60 percent of non-traumatic lower-limb amputations in the United States occur among people with diabetes. In the period from 2000 to 2001, this translated to approximately 82,000 amputations. The American Diabetes Association estimates that there are approximately 18.3 million people with diabetes in the United States and that of those about 60 percent to 70 percent have mild to severe forms of neuropathy. According to the Centers for Disease Control, diabetes is becoming more common in the United States. From 1980 through 2002, the number of Americans with diabetes more than doubled.
Sangamo BioSciences, Inc. is focused on the research and development of novel DNA-binding proteins for therapeutic gene regulation and modification. The most advanced ZFP TherapeuticTM development programs are currently in Phase I clinical trials for evaluation of safety in patients with diabetic neuropathy and peripheral artery disease. Other therapeutic development programs are focused on macular degeneration, ischemic heart disease, congestive heart failure, neuropathic pain, and infectious and monogenic diseases. Sangamo's core competencies enable the engineering of a class of DNA-binding proteins known as zinc finger DNA-binding proteins (ZFPs). By engineering ZFPs that recognize a specific DNA sequence, Sangamo has created ZFP transcription factors (ZFP TFTM) that can control gene expression and, consequently, cell function. Sangamo is also developing sequence-specific ZFP Nucleases (ZFNTM) for therapeutic gene modification as a treatment for a variety of monogenic diseases, such as sickle cell anemia, and for infectious diseases, such as HIV. Sangamo has established several Enabling Technology Agreements with companies to apply its ZFP Technology to enhance the production of protein pharmaceuticals. For more information about Sangamo, visit the company's web site at www.sangamo.com.
This press release may contain forward-looking statements based on Sangamo's current expectations. These forward-looking statements include, without limitation, references to the clinical trials of SB-509, research and development of novel ZFP TFs and ZFNs and therapeutic applications of Sangamo's ZFP technology platform. 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 the SB-509 clinical trial, whether the SB-509 clinical trial will validate and support tolerability and efficacy of SB-509, technological challenges, Sangamo's ability to develop commercially viable products and technological developments by our competitors. See the company's SEC filings, and in particular, the risk factors described in the company's Annual Report on Form 10-K and its most recent 10-Q. Sangamo BioSciences, Inc. assumes no obligation to update the forward-looking information contained in this press release.
Sangamo BioSciences, Inc.
Elizabeth Wolffe, Ph.D.
Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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