Safety and Efficacy Study of Engensis (VM202) in the Treatment of Chronic Non-Healing Foot Ulcers

A Phase III, Double-blind, Randomized, Placebo-controlled, Multicenter Study to Assess the Safety and Efficacy of VM202 to Treat Chronic Nonhealing Foot Ulcers in Diabetic Patients With Concomitant Peripheral Arterial Disease (PAD)

This study will assess the safety and efficacy of using gene therapy via intramuscular injections of the calf for patients with chronic non-healing foot ulcers.

A phase III, randomized, double-blind, placebo-controlled, multicenter, 7-month study designed to assess the safety and efficacy of intramuscular (IM) injections in the calf of Engensis (VM202) in patients with chronic nonhealing foot ulcers. Three hundred patients will be randomized in a 2:1 ratio of VM202 or placebo injections:

• Active -Engensis (VM202) + standard of care - 200 patients
• Control - Placebo (VM202 Vehicle) + standard of care - 100 patients

Inclusion Criteria:

1. Male or female, between 18 and 80 years of age

2. Documented history of symptomatic PAD, with one or more of the following criteria satisfied:

   1. ABI >0.40 and ≤0.90 or >1.4 (i.e., mild to severe PAD without critical limb ischemia) in target limb
   2. TBI ≤0.7 in the target limb
   3. Toe pressure of <55 mmHg in the target limb
   4. A history of lower extremity PAD with previous related intervention in a leg

3. Documented history of Type I or II diabetes with current treatment control (HbA1c of ≤12.0% at Screening) and currently on oral medication, injectable medication, and/or insulin

4. No significant changes were anticipated in diabetes medication regimen

5. At Screening, the subject had one ulcer on the target foot that fulfilled all of the following criteria:

   1. Present for ≥2 weeks and ≤1 year
   2. Full-thickness and not involving bone, tendon, or capsule (probing to tendon or capsule)
   3. No sign of infection or osteomyelitis
   4. Ulcer must have been 0.5 cm2 to 15 cm2 as measured at the Screening visit prior to debridement If more than one ulcer was present on the foot, the largest ulcer that fulfilled the inclusion and exclusion criteria was considered the target (index) ulcer for the study. Subjects underwent protocol-defined standardized wound care during Screening (for two weeks or longer). Subjects were considered screen failures and did not receive study injections on Day 0 (Baseline) if the target ulcer did not meet all entry criteria (see above) as well as being confirmed as nonhealing.

6. Capable of understanding and complying with the protocol and signed the informed consent document prior to being subjected to any study related procedures

7. If female of childbearing potential, negative urine pregnancy test at Screening and used an acceptable method of birth control during the study

Exclusion Criteria:

1. Required revascularization in the target leg within 3 months of randomization
2. In the Investigator's assessment, required an amputation in the target leg within 3 months of randomization
3. Subjects with target foot ulcer with an etiology of vasculitis, pyoderma gangrenosum, necrobiosis lipoidica, hydrostatic pressure/venous insufficiency, any neoplasms (basalioma, Kaposi's sarcoma, squamous cell carcinoma, etc.), or due to a burn
4. The study ulcer increased or decreased by 50% or more at Baseline from Screening (as assessed by comparison of post-debridement photos taken at Screening and Day 0)
5. Evidence of active infection (e.g., cellulitis, osteomyelitis) or deep ulceration exposing bone or tendon in the foot planned for treatment
6. Any gangrene
7. Current fracture in the target foot
8. Target ulcer located on an active (hot) Charcot foot
9. Heart Failure with a New York Heart Association (NYHA) classification of III or IV
10. Body mass index (BMI) >45 kg/m2 at Screening
11. Stroke or myocardial infarction within the last 3 months
12. Unstable angina
13. Uncontrolled hypertension defined as sustained systolic blood pressure (SBP) >200 mmHg or diastolic blood pressure (DBP) >110 mmHg at Baseline/Screening evaluation
14. Ophthalmologic conditions pertinent to proliferative retinopathy or conditions that precluded standard ophthalmologic examination
15. Inflammatory disorder of the blood vessels (inflammatory angiopathy, such as Buerger's disease)
16. Subjects with advanced liver disease including decompensated cirrhosis, jaundice, ascites, or bleeding varices
17. Subjects currently receiving immunosuppressive medications chemotherapy, or radiation therapy
18. Positive human immunodeficiency virus (HIV) or human T-cell lymphotropic virus (HTLV) at Screening
19. Active hepatitis B or C infection as determined by hepatitis B surface antibody (HBsAb), hepatitis B core antibody (immunoglobulin G [IgG] and immunoglobulin M [IgM]; HBcAb), hepatitis B surface antigen (HBsAg), and hepatitis C antibodies (Anti-HCV) at Screening
20. Clinically significant specific laboratory values at Screening (e.g., hemoglobin <8.0 g/dL, white blood cell [WBC] <3,000/μL, platelet count <75,000/mm3, aspartate aminotransferase [AST] and/or alanine aminotransferase [ALT] >3 times the upper limit of normal, or any other clinically significant lab abnormality which in the opinion of the Investigator was exclusionary)
21. Glomerular filtration rate (GFR) <30 mL/min/1.73 m2
22. Subjects with a recent history (<5 years) of or new Screening finding of malignant neoplasm except basal cell carcinoma or squamous cell carcinoma of the skin (if excised and no evidence of recurrence for at least 1 year); subjects with medical history and/or family history of colon cancer in any first degree relative were excluded unless they had undergone a colonoscopy in the last 12 months with negative findings
23. Subjects with any comorbid conditions likely to have interfered with assessment of safety or efficacy or with an estimated life expectancy of less than 1 year
24. Subjects who required >81 mg daily of acetylsalicylic acid. If >81 mg was taken at Screening, subjects could be enrolled if they were willing/able to switch to another medication for the duration of the study
25. Subjects who required regular (daily) COX-2 inhibitor drug(s) or steroids (except inhaled steroids or ocular steroids); subjects could be enrolled if they were willing/able to undergo medication washout prior to the first dosing and refrained from taking these drugs during the study
26. Major psychiatric disorder in the past 6 months
27. History of drug or alcohol abuse/dependence in the past 2 years
28. Used an investigational drug in the past 3 months; used an investigational biologic in the past 12 months; concurrent participation in an investigational protocol or using unapproved therapeutics
29. Was unable or unwilling to give informed consent