Phase 1 ZFP Therapeutic Data Is Encouraging
Sangamo BioSciences presents encouraging Phase 1 clinical data from its ZFP Therapeutic program.
As disclosed in an oral presentation entitled, "Improved Neurologic Exam and Nerve Conduction Velocities in Diabetic Neuropathy Patients Treated with Vascular Endothelial Growth Factor (VEGF) Zinc Finger Protein Activator (SB-509)," results of Sangamo's Phase 1b clinical trial demonstrated statistically significant improvements in subjects with diabetic neuropathy. SB-509 is a formulation of a zinc finger DNA-binding protein transcription factor (ZFP TF) designed to upregulate the expression of the gene encoding vascular endothelial growth factor (VEGF-A). Sangamo is currently evaluating SB-509 in two ongoing Phase 2 clinical trials for the treatment of diabetic neuropathy.
"We are very excited by the significant improvements that we observed in several measurements of nerve health in subjects with mild to moderate diabetic neuropathy over six months 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. "The data obtained in this clinical trial demonstrate that SB-509 appears to have not only a neuroprotective but possibly also a neuroregenerative effect. Currently, the only treatment options are analgesics and antidepressants to control pain symptoms. In contrast, SB-509 is designed to address the actual nerve damage and therefore could have a profound impact on the lives of patients suffering with diabetic neuropathy."
In addition, Sangamo announced today that two zinc finger nuclease (ZFN) pre-clinical therapeutic programs -- modification of the CCR5 gene in human primary T-cells for the treatment of HIV/AIDS and a novel therapy for the treatment of glioblastoma -- were reviewed and unanimously approved by the National Institutes of Health Recombinant DNA Advisory Committee (RAC) earlier this week. Sangamo filed applications for both programs with the RAC earlier this year, and a unanimous decision was made during the RAC's public review process which took place from June 19-21.
"This is an important step toward our goal of initiating Phase 1 clinical trials of both ZFP Therapeutic programs by the end of this year," said Edward Lanphier, president and CEO of Sangamo. "The fact that the RAC unanimously approved both programs is very gratifying and a testimony to the hard work and tireless preparation by the research and development groups at Sangamo."
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. Subjects received a single treatment in both legs of either placebo (6 subjects) or SB-509 (6 subjects who received 60 mg total dose or 30 mg per leg). All of the subjects completed 6-month follow-up testing. Clinicians observed statistically significant clinical improvements in quantitative sensory testing (QST) which quantifies perception of vibration and in nerve conduction velocity (NCV), a measureof the ability of a nerve to transmit an applied electrical signal. Specifically, mean QST testing compared to baseline in SB-509 treated patients showed a 42% improvement compared to 13% worsening in the placebo group (a delta in QST of 55%, p<0.0077) and the mean sum of improvement of all lower extremity motor NCVs was 1.9 Meters/sec with SB-509 treatment compared to -2.3 Meters/sec with placebo (a delta in NCV of 4.2 Meters/sec, p<0.047). Clinicians also observed a trend for improvement in SB-509 treated patients in a composite measure of nerve health, the Total Neuropathy Score or TNS. The TNS is a comprehensive approach to evaluating changes in nerve health and includes assessment of several factors, including neurologic exam, QST, electrophysiologic studies and neurologic symptoms.
In addition, data were presented from a subject with a "blocked nerve" in the leg. "Blocked nerves" are nerves, that in response to electrical stimulus, have no measurable induced nerve conduction velocity or NCV but are still functional. Typically, diabetics with blocked nerves have more severe symptoms of neuropathy. Following a single treatment with SB-509, recovered and improved NCV were observed in this subject over a six-month follow-up period.
Dale Ando, M.D., Sangamo's vice president of therapeutic development and chief medical officer, stated, "In addition to improvement in TNS and QST, three subjects in our Phase 1b study with 'blocked nerves' showed recovered and improved NCV during a six-month follow-up period after a single treatment with SB-509. This suggests that SB-509 may have a role in nerve regeneration, which is consistent with preclinical observations in a spinal cord paralysis model of statistically significant improvement in hind limb function. To further investigate and confirm this finding of a potential nerve regeneration activity of SB-509 in DN we have initiated a repeat-dosing, single-blind Phase 2 trial in subjects with moderate to severe DN."
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 severe adverse events were observed. Importantly, subjects in the study were treated within the pharmacologically effective dose range that was demonstrated to be efficacious in preclinical animal studies. Injection site reactions were the most common adverse events reported and were mild and reversible.
"We are pleased that our SB-509 diabetic neuropathy program Phase 1 update was selected for an oral presentation at the most significant US diabetes meeting of the year," 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 expect to provide an additional update on the progress of this trial later in the year. We are encouraged by the data so far and are swiftly moving forward to the next stage of clinical development with our two ongoing Phase 2 clinical trials."
Phase 1b study to assess the safety and clinical effects of a single administration of SB-509 to subjects is ongoing. Subjects were randomized and administered either SB-509 or placebo in both legs by intramuscular injection. Two dose levels of SB-509 have been tested. At the first dose level, three subjects were administered placebo and three subjects were treated with a total of 30 mg of SB-509, 15 mg per leg. Accrual of these subjects is complete. A further twenty-two subjects have been treated at the second dose level with either placebo or a total dose of 60 mg of SB-509, administered as 30 mg per leg. Subjects in this Phase 1b study will be monitored for both the safety and tolerability of SB-509 treatment as well as evaluation of pain and clinical effects on lower limb diabetic neuropathy at one, two, three and six months post-treatment.
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 will be conducted at multiple sites.
Approximately 100 subjects will be enrolled into the trial. Subjects will be 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), total neuropathy score (TNS) to assess signs and symptoms of the condition. A composite scoring system is widely regarded by neurologists as the most comprehensive approach to evaluating changes in nerve health. In addition to qualitative assessment of symptoms, the TNS includes 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. In addition, skin biopsies will 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.
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 will be conducted at multiple sites.
Approximately 45 subjects will be enrolled in the trial. Subjects will 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 3 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 two treatments (Day 0 and 90). 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), total neuropathy score (TNS) to assess signs and symptoms of the condition.
SB-509 is administered as an injectable formulation of plasmid DNA that encodes a ZFP TF, 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 (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.