Safety Study of MultiGeneAngio in Patients With Peripheral Arterial Disease (PAD)

A Phase I Safety, Dose Escalating Study of MultiGeneAngio in Patients With Peripheral Arterial Disease

The purpose of this study is to evaluate the safety and activity of increasing doses of MultiGeneAngio, a cell therapy product produced from the patient's own cells, as potential treatment for patients with peripheral arterial disease.

Approximately 16 million patients worldwide (1 in 20 people over the age of 50) suffer from peripheral arterial disease(PAD). PAD is characterized by narrowing or occlusion of vessels supplying blood to the lower limbs, most often due to atherosclerosis. Symptoms of PAD include claudication that may progress to critical limb ischemia manifested by rest pain, tissue loss and gangrene, which eventually may necessitate amputation.

MultiGeneAngio is a cell therapy-based product developed for treatment of patients with PAD secondary to narrow or blocked arteries in the legs. MultiGeneAngio is composed of endothelial and smooth muscle cells that are isolated from a short vein segment stripped from the patient's arm. After isolation the cells are expanded, characterized, and gene modified by transfer of angiogenic genes.

MultiGeneAngio is a clear cell suspension injected intra-arterially at the site of blockage using a standard diagnostic catheter, in order to create and expand new collateral arteries, and thereby improve blood flow to an ischemic limb.

Comprehensive pre-clinical studies, as well as clinical experience with PAD patients suffering from claudication showed that production and administration of MultiGeneAngio was feasible and safe, as no apparent drug-related adverse events have been observed. Moreover, follow-up data of peak walking times imply a beneficial trend of this efficacy end-point. Additional follow-up data will continue to be collected to help evaluate the safety and efficacy of MultiGeneAngio.

Inclusion Criteria:

• History of exercise-limiting intermittent claudication and peripheral arterial disease with symptoms in one or both legs, of at least 2 months duration with no change in symptom severity in the 2 months prior to screening.
• A Doppler-measured ankle-brachial index (ABI) of ≤0.80 or toe-brachial index (TBI) of <0.70 in at least one leg after 10 minutes of rest.
• Limitation in walking secondary to claudication with a mean peak walking time (PWT) of between 1 and 10 minutes on a standardized Gardner protocol for exercise treadmill test (ETT).
• Angiographic or equivalent anatomic evidence (MRA) of arterial occlusive disease (>70%) in the distal common femoral artery or superficial femoral artery and its branches of at least one leg within 12 months prior to screening.
• Postmenopausal (females),surgically sterile, or use adequate birth control.

Exclusion Criteria:

• Presence of significant inflow disease [defined as >50% stenosis] in the distal aorta, common or external iliac as assessed by conventional angiogram, digital subtraction angiography (DSA), or magnetic resonance angiography (MRA) performed < 1 year prior to screening.
• Critical limb ischemia, either chronic or acute ischemia manifested by rest pain, ulceration, or gangrene (Category 4 through 6 of Society for Vascular Surgery [SVS] classification [Rutherford]).
• History of malignant neoplasm (except curable non-melanoma skin malignancies).
• Renal failure (serum creatinine >2.0 mg/dL) or end-stage renal disease(requiring hemodialysis or renal replacement therapy).
• Significant hepatic disease (>3-fold elevation in ALT/AST).
• HBV or HCV carriers.
• Severe pulmonary disease (e.g. severe chronic obstructive pulmonary disease).
• Subjects with Acute Stroke within 6 months prior to screening.
• Subjects with uncontrolled diabetes mellitus.
• Specific ophthalmologic conditions that preclude retinal photography,vascular lesions of the anterior segment of the eye, proliferative retinopathy, age-related macular degeneration or intra-ocular surgery within 6 months prior to enrollment.
• Gross obesity (BMI≥40).
• Buerger's disease or other forms of inflammatory arteritis.
• Class IV congestive heart failure, as defined by the New York Heart Association or a myocardial infarction within 6 months prior to screening.
• Subject with deep vein thrombosis within 3 months prior to screening.
• Inability to complete the standardized treadmill protocol for reasons other than claudication including symptoms such as angina, dyspnea, joint pains, or excessive fatigue.
• Percutaneous intervention or surgical revascularization in the index lower limb within 6 months prior to enrollment.
• Heart angioplasty with or without stent or coronary bypass surgery within the past 6 months.
• Participation in a structured exercise treatment protocol within 30 days prior to screen testing.
• Subject is planning to participate in a structured exercise treatment protocol during the 180 days following administration of the investigational product.
• Participation in a previous gene transfer trial in which the subject received active investigational product (placebo subjects are eligible).
• Concurrent or prior participation in another clinical trial within 30 days prior to screen testing.
• Chronic use of Cox-2 inhibitors, defined as subjects needing daily use of the agent for more than 30 days prior to screening.
• Subject is taking any of the following drugs for life-threatening conditions or as part of a life-sustaining treatment: Cyclosporine (Sandimmune®),Systemic androgens/anabolic steroids, systemic corticosteroids.
• History of bleeding diathesis (e.g. hemophilia due to Factor VIII or IX deficiency).
• Pregnancy or breast-feeding.
• Uncontrolled hypertension or significant hypotension.
• Immunodeficiency states (e.g, current HIV positivity, or organ transplant recipient) or subject receiving immunosuppressive medications.
• Alcohol or other substance abuse.