Sangamo BioSciences Announces Presentation of Phase 1b ZFPTherapeutic Data at American Diabetes Association MeetingPresentation Details Statistically Significant and Clinically Relevant Results for SB-509 in Development for Treatment of Diabetic Neuropathy
SAN FRANCISCO, June 8, 2008 /PRNewswire-FirstCall/ -- Sangamo BioSciences, Inc. announced today the presentation of encouraging Phase 1b clinical data from its ZFP Therapeutic(TM) program at the 68th Scientific Sessions of the American Diabetes Association (ADA). As disclosed in an oral presentation entitled, "Evidence of Neuroregeneration Using Vascular Endothelial Growth Factor (VEGF) Zinc Finger Protein Activator (SB-509) in Diabetic Neuropathy: A Chronic Degenerative Polyneuropathy," results of Sangamo's Phase 1b clinical trial (SB-509-401) demonstrated statistically significant improvements in measurements of nerve health and function in subjects with diabetic neuropathy.
"We are excited by the clinically relevant magnitude of improvements that were observed in measurements of nerve health and function in subjects with mild to moderate diabetic neuropathy over the six month trial period after a single administration of SB-509," commented the presenter, Mark Kipnes, M.D., lead investigator on the Phase 1 trial and an endocrinologist at the Diabetes and Glandular Disease Clinic, San Antonio, Texas. "Analgesics and antidepressants designed to control pain symptoms are the only drugs currently approved to treat this condition. In contrast, SB-509 is designed to address the actual nerve damage. These data demonstrate that SB-509 may have a neuroprotective and a neuroregenerative effect."
The data presented at ADA were collected from subjects with mild to moderate diabetic peripheral neuropathy enrolled in Sangamo's Phase 1b study of SB-509 (SB-509-401). Subjects received a single treatment in both legs of either placebo (12 subjects) or SB-509 (12 subjects who received 60 mg total dose, 30 mg per leg). All of the subjects completed 6-month follow-up testing. SB-509 was well tolerated and no drug-related severe adverse events were observed. Clinically relevant and statistically significant improvements were seen in neurologic examination using the Neurological Impairment Score - Lower Limbs (NIS-LL) and quantitative sensory testing (QST) which quantifies perception of vibration. In addition, there was a trend towards improvement in nerve conduction velocity (NCV), a measure of the ability of a nerve to transmit an applied electrical signal, in both sensory and motor nerves.
Specifically, improvement in neurologic evaluation by NIS-LL in SB-509-treated subjects was measured as a statistically significant, clinically relevant improvement of 1.9 point change from baseline levels compared to a 0.7 point worsening in the placebo group (a delta in NIS-LL of 2.6, p=0.043). In addition, there was a 25.3% improvement in detection of mechanical sensation compared to baseline, as measured by QST testing, in SB-509-treated patients compared to a 5.1% worsening in the placebo group (a delta in QST of 30.4%, p=0.02). The mean improvement in sensory (sural) NCV measurements 180 days post treatment was 1.2 Meters/sec with SB-509 treatment compared to -0.4 Meters/sec with placebo (a delta in NCV of 1.6 Meters/sec). The mean sum of improvement of all lower extremity motor NCV measurements 180 days post treatment was 0.8 Meters/sec with SB-509 treatment compared to -0.9 Meters/sec with placebo (a delta in NCV of 1.7 Meters/sec).
While the primary end-point of Sangamo's Phase 1b study (SB-509-401) was safety, data were also collected that were designed to measure changes in neurological health. Quantitative sensory testing (QST) using the Vibratron II is used as a method of assessing a subject's change in vibration sensitivity. Direct measurement of the speed and amplitude of an applied electrical impulse or nerve conduction velocity (NCV) in both sensory and motor nerves is a method of assessing the integrity or health of the nerve. A broader approach to quantification of clinical benefit involves the use of one of the many available composite scoring systems. These include the Total Neuropathy Score (TNS) and the narrower Neuropathy Impairment Score in the Lower Limbs (NIS-LL). The NIS-LL is a validated instrument that can be used to measure a clinically meaningful change in the neurological status of patients with DN over time. NIS-LL includes measures of motor and sensory nerve heath as well as reflex testing and is a quantifiable score of neurologic exam. These three measurements have all been used as primary or secondary endpoints of clinical benefit in Phase 3 studies.
"We are very encouraged by the safety of SB-509 and the improvements that we have seen in subjects with mild to moderate DN up to six-months after administration of a single dose of SB-509," stated Dale Ando, M.D., Sangamo's vice president of therapeutic development and chief medical officer. "Particularly interesting are the encouraging and correlative gains observed in the NIS-LL and QST measurements of treated subjects which are independent and confirmatory. Both NIS-LL and QST have been used as end-points in previous pivotal large scale trials of other non-analgesic approaches for diabetic neuropathy. "
From a safety perspective, the Phase 1b data were consistent with previous observations that a single treatment of SB-509 was well tolerated and that no drug-related severe adverse events were observed. Injection site reactions were the most common adverse events reported and were mild and reversible. Importantly, subjects in the study were treated within the pharmacologically effective dose range that was demonstrated to be efficacious in preclinical animal studies.
"Although the primary end-point of the SB-509-401 study was safety, we also observed statistically significant and clinically relevant improvements in a number of quantitative measures of neurological health," said Edward Lanphier, Sangamo's president and CEO. "We believe that SB-509 represents a new therapeutic approach for diabetic neuropathy, designed to directly protect and possibly restore nerve function, in contrast to the current standard of care designed to address the pain associated with this condition. We are encouraged by the data so far and are swiftly moving forward to the next stage of clinical development with our ongoing Phase 2 clinical trials. We expect to have data from our double blind Phase 2 clinical trial (SB-509-601) available in the fourth quarter of this year."
SB-509 is an injectable formulation of a plasmid encoding a zinc finger DNA-binding protein transcription factor (ZFP TF(TM)) designed to upregulate the expression of the gene encoding vascular endothelial growth factor (VEGF-A). VEGF-A has been demonstrated to have direct 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 the SB-509 Clinical Program
Sangamo has three ongoing Phase 2 studies in diabetics with sensory/motor neuropathy:
Phase 2 study of SB-509 for mild to moderate DN (SB-509-601)
The clinical trial is a double-blind, placebo-controlled, repeat-dosing study designed to evaluate the clinical safety and clinical effects of repeat administration of SB-509 in diabetics with mild to moderate diabetic peripheral sensory motor neuropathy in the legs. The trial is being conducted at multiple sites and is fully enrolled; data is expected to be available in the fourth quarter of 2008.
Approximately 100 subjects have been enrolled into the trial. Subjects have been randomized to one of two groups in a 2:1 ratio. The larger group (approximately 66 subjects) will be treated by intramuscular injection of 60 mg of SB-509 (30 mg of SB-509 per leg) into the lower limb every 2 months. The remaining group (approximately 33 subjects) will receive an equal volume of placebo on the same schedule. Each subject will receive a total of three treatments (Day 0, 60 and 120). Subjects will receive injections in a distribution pattern that targets the major peripheral nerves in the legs and feet.
The symptoms of diabetic peripheral neuropathy and any changes that occur during the trial will be evaluated based on neurological examination data, electrophysiological testing data, subject neurological questionnaire, and subject pain assessment. Specifically, investigators will use the following tests: the visual analog scale for pain intensity (VASPI), a modified Neuropathy Impairment Score - Lower Limbs (NIS-LL) scoring system as well as total neuropathy score (TNS) to assess signs and symptoms of the condition. A quantitative neurologic exam such as NIS-LL is widely regarded by neurologists as the most comprehensive approach to evaluating changes in nerve health. In addition, data from electrophysiological testing using nerve conduction velocity (NCV) to assess the rate at which a nerve can conduct an electrical signal, and quantitative sensory testing (QST) with the Vibratron II instrument, to assess the threshold of detection of vibration are also being collected. Skin biopsies will also be taken to evaluate the direct therapeutic effect of SB-509 on nerve regrowth. This test is a very sensitive marker of DN severity and may provide an important mechanistic marker for efficacy.
Phase 2 study of SB-509 for moderate to severe DN (SB-509-701)
The clinical trial is a single-blind, placebo-controlled, repeat-dosing study designed to evaluate the clinical safety and clinical effects of repeat administration of SB-509 in diabetics with moderate to severe diabetic peripheral sensory motor neuropathy in the legs. The trial is being conducted at multiple sites, accrual has been completed and plans recently announced to expand the study and enroll additional subjects.
In the initial trial, 45 subjects have completed enrollment. Subjects were randomized to one of two groups in a 2:1 ratio. The larger group (approximately 30 subjects) was treated by intramuscular injection of 60 mg of SB-509 (30 mg of SB-509 per leg) into the lower limb and will be treated every 3 months. The remaining group (approximately 15 subjects) received an equal volume of placebo on the same schedule. Each subject will receive a total of two treatments (Day 0 and 90). Subjects receive injections in a distribution pattern that targets the major peripheral nerves in the legs and feet.
As announced on June 6, 2008, Sangamo will expand the Phase 2 study by enrolling approximately 45 additional subjects in the trial. Subjects will again be randomized to one of two groups in a 2:1 ratio. The larger group (approximately 30 subjects) will be treated by intramuscular injection of 60 mg of SB-509 (30 mg of SB-509 per leg) into the lower limb every 2 months. The remaining group (approximately 15 subjects) will receive an equal volume of placebo on the same schedule. Each subject will receive a total of three treatments (Day 0, 60 and 120). Subjects will receive injections in the same pattern used in the initial part of the trial.
The symptoms of diabetic peripheral neuropathy and any changes that occur during the trial will be evaluated based on neurological examination data, electrophysiological testing data, subject neurological questionnaire, and subject pain assessment. Specifically, investigators will assess pain using VASPI, and use scoring systems such as a modified NIS-LL and TNS to quantify neurologic exam and assess signs and symptoms of the condition.
For each subject the trial is expected to take approximately fourteen months: two months for screening, three months for subject treatment and a further nine months for subject follow-up. Individuals interested in participating in this trial should visit http://www.clinicaltrials.gov/ .
Phase 2 Study of SB-509 to Evaluate Stem Cell Mobilization (SB-509-703)
Twenty subjects will be enrolled in the stem cell mobilization Phase 2 trial. Subjects will be randomized to one of four cohorts with 5 subjects in each cohort. Cohorts 1 and 2 will receive a single treatment of 30 mg into one leg or 60 mg (30 mg in each leg) of SB-509, respectively, by intramuscular (IM) injection on Day 0. Cohort 3 will receive a single treatment of an equal volume of placebo by IM injection into a lower limb on Day 0. Cohort 4 will receive two treatments of 60 mg of SB-509 (30 mg in each leg) by IM injection (Day 0 and 90). Subjects will receive injections in a distribution pattern that targets the major peripheral nerves in the legs and feet.
Peripheral blood samples taken before and at various times post-treatment with SB-509 will be assayed and the numbers of circulating stem cells will be assessed using stem cell-specific enzymatic activity (aldehyde dehydrogenase staining), culture-based assays, as well as assays of cell surface expression of stem cell-specific markers.
The signs and symptoms of diabetic peripheral neuropathy and any changes that occur during the trial will also be evaluated based on neurological examination data (NIS-LL), electrophysiological testing data, subject neurological questionnaire, and subject pain assessment (VASPI). Specifically, investigators will use the following tests: QST with the Vibratron II instrument, to assess the threshold of detection of vibration and electrophysiological testing. A total neuropathy composite score (TNS) will also be computed to evaluate changes in nerve health.
For each subject, the trial is expected to take 14.5 months: 2.5 months for screening and subject treatment and a further 12 months for subject follow-up. Individuals interested in participating in this trial should visit http://www.clinicaltrials.gov/ .
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 20.8 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 Therapeutic(TM) development program is currently in Phase 2 clinical trials for evaluation of safety and clinical effect in patients with diabetic neuropathy. Phase 1 clinical trials are ongoing to evaluate a ZFP Therapeutic for peripheral artery disease. Other therapeutic development programs are focused on ALS, cancer, HIV/AIDS, 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(TM)) that can control gene expression and, consequently, cell function. Sangamo is also developing sequence-specific ZFP Nucleases (ZFN(TM)) for gene modification. Sangamo has established strategic partnerships with companies outside of the human therapeutic space including Dow AgroSciences, Sigma-Aldrich Corporation and several companies applying 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 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 the it's 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.
CONTACT: Elizabeth Wolffe, Ph.D., Sangamo BioSciences, Inc.,+1-510-970-6000, x271, firstname.lastname@example.org
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Posted: June 2008