Safety Study of Gene Therapy in Treating Critical Leg Ischemia

Phase 1, Dose-Escalation Study to Assess the Safety and Tolerability of VM202 (Engensis) in Subjects With Critical Limb Ischemia

The purpose of this study is to determine the safety, tolerability and preliminary efficacy of intramuscular injections of VM202 for subjects with critical limb ischemia.

Subjects selected for this study will have critical limb ischemia that has not responded to standard therapy with symptoms including pain at rest and/or ischemic ulcers.

The study will consist of four (4) cohorts with a total of 3 subjects enrolled in each cohort to VM202.For each dose cohort, VM202 will be administered as a local intramuscular injection in 2 divided doses with a 2-week interval between the injections. Preliminary efficacy (hemodynamic assessments), safety and tolerability will be evaluated at Baseline (screening) and at designated time points throughout the study.

After the first subject in each cohort completed Day 30 (±2 days), and before the Day 15 dosing of the other 2 subjects in the same cohort, an interim safety evaluation was performed with the submission of safety data to the Data Safety Monitoring Committee.

All four dose cohorts will be followed for up to 5 years from the time of the first dose of study drug administration.

Inclusion Criteria:

• Male or female, between 20 and 90 years of age

• Have critical limb ischemia (Rutherford Class 4 and 5) and considered not a candidate for bypass graft surgery or percutaneous angioplasty due to co-morbid conditions, failure of previous surgical or interventional procedures or caliber of grafting arteries. Critical Limb ischemia is defined as

  1. Stable symptoms on standard therapy including anti-platelet agents, vascular rheologic agents, cilostazol, anticoagulant and pain medication for 30 days.
  2. Pain at rest and/or ischemic ulcers for a minimum of 4 weeks.

• Have diagnostic angiography of the affected limb in the last 12 months demonstrating a significant occlusion of one more of the following arteries: iliac, superficial femoral, popliteal, and one or more infra-popliteal arteries.

• Have a resting ankle systolic pressure (in either the dorsalis pedis or posterior tibial arteries) of less than or equal to 60mmHg or a resting toe systolic pressure of less than or equal to 40 mmHg in the affected limb.

• Be willing to maintain current drug therapy for peripheral arterial disease throughout the course of the study including anti-platelet and statin inhibitor treatment

• Be capable of understanding and complying with the protocol and signing the informed consent document prior to being subjected to any study related procedures

• Women who are surgically sterile or at least 1 year postmenopausal or who have been practicing adequate contraception for at least 12 weeks prior to entering the study. If the subject is of child-bearing potential, she must have a negative serum pregnancy test result prior to study enrollment and must agree to repeat pregnancy screening tests during the study

• If the subject or the subject's partner(s) is of child bearing potential, the subject and the subject's partner(s) must agree to use a "double barrier" method of birth control while participating in this study.

Exclusion Criteria:

• Subjects who have undergone a revascularization procedure or sympathectomy within 12 weeks prior to study entry that remains patent. A failed revascularization procedure in the previous 4 weeks is acceptable.

• Subjects with grade 3 (hemorrhages, exudates) or grade 4 (papilledema) retinopathy.

• Subjects currently receiving immunosuppressive medications, chemotherapy, radiation therapy.

• Subject with aorta-iliac occlusion (greater than 75%).

• Subjects that will require amputation within 4 weeks of randomization.

• Subjects with any co-morbid conditions likely to interfere with assessment of safety or efficacy or with an estimated life expectancy of less than 6 months

• Subjects with history of drug (defined as illicit drug use) or a history of alcohol abuse (defined as regular or daily consumption of more than 4 alcoholic drinks per day) within the past 3 months.

• Subjects with a current history or new screening finding of malignant neoplasm except for basal cell carcinoma of the skin and squamous cell carcinoma of the skin (if excised and no evidence of recurrence).

• Subjects with evidence of active infection (e.g. cellulitis, osteomyelitis) or deep ulceration exposing bone or tendon in the extremity planned for treatment.

• Subjects with a clinically significant abnormality in routine hematology, urinalysis, chemistry, liver function or other laboratory tests, including HIV, Hepatitis B, Cytomegalovirus, hepatitis C virus, Venereal Disease Research Laboratory test, prostate-specific antigen, and chorio-embryonic antigen, or signs of malignant neoplasm by radiological imaging tests, including chest radiography at Screening or Day 1. Specific laboratory exclusion criteria include the following:

  1. Hemoglobin less than 9.0 g/dL
  2. White Blood Cell count less than 3,000 cells/mm3
  3. Platelet count less than 75,000 platelets/uL
  4. Fasting glucose greater than 250 mg/dL
  5. AST and/or ALT greater than 3X upper limit of normal

• Subjects with any other condition that in the opinion of the investigator might put the subject at risk or interfere with his/her participation.

• Subjects unwilling or unable to comply with the protocol or to cooperate fully with the investigator or site personnel.

• Subjects that have received any other investigational drug within the 30 days prior to study drug administration or will receive such a drug during the time frame of this study.

• Subjects with uncontrolled hypertension defined as systolic blood pressure greater than 200 mmHg or diastolic blood pressure greater than 115 mmHg at Baseline evaluation.

• Subjects with advanced liver disease including decompensated cirrhosis, jaundice, ascites, or bleeding varices.