Sangamo BioSciences, Inc. Announces Presentation of Top-Line Statistically Significant Phase 2 Data in Diabetic Neuropathy at Society for Neuroscience Meeting Improvement in Intraepidermal Nerve Fiber Density Demonstrates Neuroregenerative Mechanistic Pr
RICHMOND, Calif., Oct. 20 /PRNewswire-FirstCall/ -- Sangamo BioSciences, Inc. announced today the presentation of top-line, statistically significant Phase 2 clinical data from its ZFP Therapeutic(TM) program to develop SB-509 as a treatment for diabetic neuropathy (DN) at the Society for Neuroscience Annual Meeting held in Chicago.
Top-line data from Sangamo's SB-509-601 Phase 2 clinical trial demonstrated a direct neuroregenerative effect of SB-509 treatment that resulted in a statistically significant (p value=0.02) increase in small unmyelinated nerve fibers in the skin, or intraepidermal nerve fiber density (IENFD), in subjects with DN.
Data were also presented that provided additional evidence of the positive effect of SB-509 on large fiber sensory nerve health as measured by improvements in nerve conduction velocity (NCV), in subjects with elevated markers of vascular damage (ICAM-1), and improvements in the muscle components of the neurologic exam (NIS-LL) 30-days after each of the three administrations of SB-509. Together these data confirm the neuroregenerative activity of SB-509 in patients with DN and define a drug-responsive population for future trials.
"The IENFD data presented today provide direct histologic evidence of nerve regrowth with SB-509 treatment and a mechanistic proof of concept for the neuroregenerative effects of this ZFP Therapeutic," stated Dale Ando, M.D., Sangamo's Vice President of Therapeutic Development and Chief Medical Officer. "The relationship between reduced IENFD and severity of DN has been well established and correlates with decreased levels of VEGF-A and an increase in inflammatory growth factors such as ICAM-1, a marker of vascular disease. In addition, in subjects with more severe DN, with elevated levels of ICAM-1 in their blood, there is a greater improvement in sural NCV in SB-509 treated subjects. Together these data provide support for our hypothesis that the dual neuroregenerative and angiogenic functions of SB-509 are important for improvement of nerve health by counteracting the pathologic effects of diabetes on nerves and blood vessels in these subjects. In future clinical studies, IENFD and ICAM-1 levels will serve as an important baseline measurement to aid in identification of a target population of SB-509 responsive DN patients and as a stratification variable to ensure that we have well-balanced treatment and placebo groups."
IENFD is a validated, direct biologic measurement of small unmyelinated sensory nerve fibers in the skin, the primary nerves involved in DN. It has also been demonstrated to correlate with neuropathy severity in diabetes, nerve fiber densities derived from sural nerve biopsies and levels of vascular endothelial growth factor-A (VEGF-A).
Data were also presented that demonstrate that in subjects with more severe neuropathy, as judged by their baseline IENFD, a greater nerve regrowth response to SB-509 treatment was observed compared to regrowth responses in placebo-treated subjects. In addition, subgroup analyses using baseline severity of disease as a selection criterion, demonstrated that SB-509 treatment resulted in correlative clinically relevant improvements in NIS-LL and sural NCV in subjects with moderate to severe disease.
"Loss of small unmyelinated nerve fibers is an early symptom of DN and the positive IENFD data have given us insight into the population of subjects that we expect will show the greatest response to SB-509 treatment over the 180 day clinical study period," said Edward Lanphier, Sangamo's president and CEO. "This is the first large placebo controlled study to show the value of IENFD in clinical studies of DN and we have gathered a significant amount of clinically relevant correlative data that will aid in the development of future clinical studies. We are grateful to the Juvenile Diabetes Research Foundation for their support and funding of our studies using this promising endpoint."
Details of Presentation of IENFD Data from SB-509-601 Study
Tuesday, October 20, 2009
IENFD and IENFD Regrowth (IENFDR) measurements were prospectively defined endpoints in Sangamo's double-blind, repeat dosing Phase 2 clinical study (SB-509-601) in which subjects were treated at 0, 60 and 120 days. Evaluation of SB-509 treatment on IENFD and IENFDR was carried out in collaboration with Michael Polydefkis, M.D., Associate Professor of Neurology, Johns Hopkins University Medical School and funded by a grant from the Juvenile Diabetes Research Foundation (JDRF).
IENFD derived from 3mm skin punch biopsies taken from the thigh at baseline (Day 0) and thirty days after the final treatment (Day 150) were obtained from both SB-509 and placebo treated subjects. In addition, IENFDR was determined by applying a capsaicin patch to the skin of the thigh to produce a standardized nerve injury on Days 150 and 151 and using serial skin biopsies over time, post capsaicin treatment, up to Day 360, to determine nerve regrowth in both SB-509 and placebo-treated subjects.
In SB-509 treated subjects an increase in mean change in nerve fiber density from baseline was observed compared to a decrease for placebo treated subjects (p-value = 0.02). Importantly, a rank sum analysis of these data was also statistically significant (p-value = 0.03) with a 13.3 difference in average rank. A trend towards improved IENFDR was also observed in SB-509 treated subjects compared to placebo. Taken together these data are direct histological evidence of improved axonal regeneration with intramuscular administration of SB-509.
As previously described, no overall difference was seen at 180 days between placebo and SB-509-treated subjects in the SB-509-601 study in the following measures of nerve health and function: Abbreviated Neuropathy Impairment Score in the Lower Limbs (A-NIS-LL), Nerve Conduction Velocity (NCV), and Quantitative Sensory Testing (QST). However, analysis of the data demonstrated that subjects entering the SB-509-601 trial had significantly milder DN by all of these measures than subjects in either the prior Phase 1 SB-509-401 study in a mild to moderate population or a second Phase 2 SB-509-701 study in a more severe population (p value=0.0001). When the effect of baseline severity of DN as determined by IENFD was analyzed, a statistically significant and clinically relevant improvement in IENFD was observed in subjects with more severe DN (i.e. fewer nerve fibers per mm). Thus subjects with lower baseline IENFD demonstrated a greater response to SB-509 treatment by this measure.
When other clinical responses to SB-509 compared to placebo were analyzed in subjects with more severe disease (baseline IENFD below 9 fibers per mm) improvements in NIS-LL and sural NCV were observed to be clinically relevant and durable. Furthermore, in this group, when the muscle component of the NIS-LL was specifically analyzed, treatment dependent muscle strength improvements were evident in SB-509-treated compared with placebo-treated subjects. When multiple baseline measures of disease severity were considered (IENFD, ICAM-1, NCV and NIS-LL), a drug responder population was identified that demonstrated a clinically relevant change in NIS-LL compared to placebo (p value= 0.004).
SB-509 has been shown to have effects on angiogenesis, or blood vessel growth, as well as nerve protection and regeneration. When the severity of vascular disease in the 601 study's subjects was taken into account using baseline levels of plasma ICAM-1, a marker of vascular damage, SB-509-treated subjects with more severe vascular disease (higher ICAM-1 levels) showed a statistically significant (p value= 0.01) improvement in mean sural NCV change from baseline compared to placebo treated, providing strong support for both a neuroregenerative and angiogenic mechanism of action of SB-509.
Other Sangamo Abstracts Presented at Society for Neuroscience Meeting
In addition to the presentation of Sangamo's data from its SB-509 clinical program in diabetic neuropathy, data were presented from its preclinical programs in Parkinson's disease and spinal cord injury:
Tuesday, October 20, 2009
Researchers observed in vivo efficacy in an animal model of Parkinson's disease, demonstrating functional neuroprotection provided by upregulation of GDNF using a ZFP transcription factor (ZFP TF) activator. This study was funded by the Michael J Fox Foundation for Parkinson's Research
Researchers observed that in an animal model of spinal cord injury, 24 hour delayed administration of a ZFP TF that upregulates VEGF-A (a form of SB-509) decreased the degradation of NF200, a marker of cell injury, decreased apoptosis or cell death of nerve cells in and around the spinal cord and enhanced new blood vessel growth around the injured cord.
About SB-509
SB-509 is an injectable plasmid encoding a DNA-binding Zinc Finger DNA-binding Protein (ZFP) transcription factor (ZFP TF) designed to upregulate the endogenous expression of the gene encoding vascular endothelial growth factor (VEGF-A). VEGF-A has been demonstrated to have direct angiogenic, neurotrophic and neuroprotective properties. In preclinical animal efficacy studies in a diabetic rat model (Diabetes, June 1, 2006; 55(6): 1847-1854), SB-509 has proven effective in protecting motor and sensory nerve function from disease-induced nerve damage.
About Diabetic Neuropathy
Diabetic neuropathy is a progressive degenerative disease that is one of the most frequent complications of diabetes, affecting between 14 and 16.5 million Americans in 2007. High blood glucose levels lead to nerve damage over time, primarily affecting peripheral nerves. Symptoms include numbness, tingling sensations and pain particularly in the toes or feet, which gradually evolve to loss of sensation and motor function as nerve damage progresses. Ulcers and sores may appear on numb areas of the foot as pressure wounds or injuries go unnoticed. Despite palliative 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 2004, this translated to approximately 71,000 amputations. Diabetes is a growing problem. The Centers for Disease Control estimates that from 1980 through 2007, the number of Americans with diabetes increased from 5.6 million to 23.6 million and that of those about 60 percent to 70 percent have mild to severe forms of neuropathy.
About Sangamo
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 Therapeutic(TM) development program is currently in Phase 2 clinical trials for evaluation of safety and clinical effect in patients with diabetic neuropathy and ALS. Sangamo also has two Phase 1 clinical trials to evaluate safety and clinical effect of a ZFP Therapeutic for the treatment of HIV/AIDS. Other therapeutic development programs are focused on cancer, neuropathic pain, nerve regeneration, Parkinson's disease 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 TF) that can control gene expression and, consequently, cell function. Sangamo is also developing sequence-specific ZFP Nucleases (ZFN) for gene modification. Sangamo has established strategic partnerships with companies in non-therapeutic applications of its technology including Dow AgroSciences, Sigma-Aldrich Corporation and several companies applying its ZFP technology to engineer cell lines for the production of protein pharmaceuticals. For more information about Sangamo, visit the company's web site at http://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 trials, whether the SB-509 clinical trials 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 Sangamo's SEC filings, and in particular, 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.
SOURCE Sangamo BioSciences, Inc.
CONTACT: Elizabeth Wolffe, Ph.D. of Sangamo BioSciences, Inc.,
+1-510-970-6000, ext. 271, ewolffe@sangamo.com
Web site: http://www.sangamo.com/