Sangamo presents Phase 2 clinical data in ALS at Society for Neuroscience Meeting

Sangamo BioSciences, Inc. (Nasdaq: SGMO) announced today the presentation of Phase 2 clinical data from its ZFP Therapeutic program to develop SB-509, a zinc finger protein transcriptional activator (ZFP-TF) of the vascular endothelial growth factor (VEGF)-A gene as a treatment for ALS. The data from study SB-509-801 demonstrated that the drug was well-tolerated in subjects with ALS and that 40% of SB-509 treated subjects had delayed deterioration of toe and ankle muscle strength as measured by manual muscle testing (MMT) compared to 23% of baseline-matched historic controls.  In addition, positive improvements in electrophysiological measures of motor nerves were observed in a subset of treated subjects.  The data were presented at the Society for Neuroscience Annual Meeting which is being held in San Diego.  

"These data are consistent with the delay in muscle deterioration that we have observed in both preclinical models of ALS as well as in clinical studies of this drug in subjects with diabetic neuropathy, a condition that is also characterized by degeneration and deterioration of nerve function," stated Dale Ando, M.D., Sangamo's vice president of therapeutic development and chief medical officer. "Our primary aim in this trial was to assess safety and tolerability of treatment with SB-509 in this vulnerable patient population and to conduct a signal-seeking study in which we assessed the effect of treatment on several clinical measures of function in ALS.  As this was an early-stage trial, for safety reasons we treated subjects twice over a 90 day period, although our positive preclinical animal data were achieved with a more frequent dosing schedule.  With that said, the delayed deterioration in muscle strength in the ankle and toe are very encouraging and may reflect the importance of focused regional dosing, as the leg muscles received the highest volume of SB-509 compared to the neck and arms. These data provide valuable information for the design of future studies which would include more frequent and focused dosing with SB-509."

"We are developing SB-509 as a first-in-class, disease modifying drug to protect and restore the function of damaged nerves," stated Edward Lanphier, Sangamo's president and chief executive officer.  "To this end we have assessed the effect of SB-509 in a range of degenerative neurologic conditions and obtained positive clinical data in diabetic neuropathy and ALS, as well as preclinical data in models of spinal cord injury, stroke and traumatic brain injury.  In addition to demonstrating safety, this clinical trial of SB-509 in ALS has provided us with valuable information for the design of future studies in this population in terms of potential end-points and dosing distribution and frequency.  As we have previously reported, our clinical development resources are currently focused on our most advanced clinical program in this area, a Phase 2b study (SB-509-901) in subjects with moderate severity diabetic neuropathy from which we expect to have data in the fourth quarter of 2011."

Details of Presentation of ALS Data from SB-509-801 Study

Wednesday, November 17, 2010

• "Plasmid Gene Transfer of Zinc Finger Protein VEGF-A Transcription Activator (SB-509) for Treatment of Amyotrophic Lateral Sclerosis (ALS) - a Phase 2 Clinical Trial."

Subjects with non-bulbar onset ALS (45 total) were randomized into two groups, both of which were treated at Day 0 and Day 90 either by intramuscular injection of 60 mg of SB-509 bilaterally into the legs, arms and neck (39 subjects) or into the legs only (6 subjects). In addition to the assessment of the safety and tolerability of SB-509 treatment, the effect on ALS progression was assessed over the 120 day study using a variety of measures.  These included the Revised ALS Functional Rating Scale (ALSFRS-R), a validated rating instrument for monitoring the quality of life and progression of disability, manual muscle testing (MMT), a commonly used ALS endpoint which assesses strength of 34 muscles over the whole body, neurophysiological index (NI) to assess neurologic impairment, and forced vital capacity (FVC), a measure of lung function. As a control, SB-509–treated subjects were compared to the entire population of non-bulbar onset subjects and to subjects matched for baseline MMT values from a database from the placebo arm of a Phase 3 clinical trial of minocycline (Lancet Neurol.2007, 6 (12) :1045-53). The minocycline trial database was used as it was the only trial for which MMT data were available.  Baseline characteristics for demographics, FVC, ALSFRS-R and MMT between the SB-509-treated>

At Day 120 a trend for delayed deterioration of ankle and toe muscle strength was observed in 40% of SB-509 treated subjects compared to 23% of baseline matched historic controls and 27% of the global control population.   A subset of SB-509–treated subjects showed a large increase in motor muscle action potential amplitude (AMP), an electrophysiologic measure of muscle activity.  In addition, subjects with positive amplitudes showed trends for decreased worsening in ALSFRS-R motor subscores when compared to subjects with negative amplitudes or matched placebo controls. Positive amplitude changes also correlated with a trend for decreased progression of disease as assessed by the gross and fine motor skill component of the ALSFRS-R score.

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, stroke and spinal cord injury:

Sunday, November 14, 2010

• "Engineered Zinc Finger Protein Transcription Factors Drive Highly Specific Activation of the Endogenous GDNF Gene and Functional Neuroprotection in vivo."

Researchers observed in vivo efficacy in a rat model of Parkinson's disease, demonstrating functional and histological neuroprotection provided by upregulation of GDNF using a ZFP TF activator. This study was funded by the Michael J Fox Foundation for Parkinson's Research (MJFF).  Further studies, also funded by MJFF, are underway in non-human primates.

The study examines the therapeutic effects of VEGF-A upregulation using a ZFP TF following Central Nervous System (CNS) injury and ischemia models of trauma and stroke. The models tested included optic nerve transection (trauma) and ophthalmic artery ligation (ischemia) that result in the degeneration of retinal ganglion cells (RGCs) and a cortical model of focal cerebral devascularization.  Researchers observed that VEGF-ZFP increases retinal ganglion cell survival after axotomy and ischemia and promoted functional improvement of the pupillary light reflex after ischemia although treatment did not alter retinal vasculature.  In a focal cerebral devascularization model, VEGF-ZFP reduced overall lesion volume, promoted wound contraction and increased neuron survival as well as reducing glial reactivity and producing a short term behavioral improvement in forelimb motor function.  Overall, the findings demonstrate that VEGF-ZFP gene therapy has therapeutic potential for the treatment of CNS trauma and stroke.

• "Administration of a VEGF-A Gene Therapy May Have Angiogenic and Neuroprotective Effects When Administered in a Delayed Fashion Following Spinal Cord Injury."

Researchers observed that in an animal model of spinal cord injury, 24 hour delayed administration of a ZFP transcription factor 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.