Study of PDA-002 in Subjects With Peripheral Arterial Disease and Diabetic Foot Ulcers

The purpose of this Phase 1 study was to evaluate the safety, tolerability, and maximum tolerated dose (MTD) of PDA-002, a human placenta-derived cell therapy, administered by intramuscular injection in subjects with peripheral arterial disease (PAD) and diabetic foot ulcers (DFU). This was a multicenter, open-label, 3+3 dose-escalation study. Subjects received PDA-002 administered intramuscularly on Study Days 1 and 8 at 1 of 4 planned dose levels ranging from 3 × 10^6 to 100 × 10^6 cells. Dose escalation proceeded after review of safety data from previously enrolled subjects. Subjects were followed for safety assessments for up to 24 months.

Inclusion criteria

• Subjects must satisfy the following criteria to be enrolled in the study:

• Males and females, 18 to 80 years of age at the time of signing the informed consent document.
• Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures are conducted.
• Able to adhere to the study visit schedule and other protocol requirements.
• Diabetes mellitus type 1 or 2
• Ischemic or neuro-ischemic diabetic foot ulcer with severity of Grade 1 (full thickness only) or Grade 2 on the Wagner Grading Scale (Appendix A) of greater than one month duration which has not adequately responded to conventional ulcer therapy.
• Peripheral arterial disease with ankle-brachial index > 0.5 and ≤ 0.9 or toe-brachial index > 0.35 and ≤ 0.7.
• No planned revascularization or amputation over the next 3 months after Screening visit, in the opinion of the Investigator.
• Screening should not begin until at least 2 weeks after a failed reperfusion intervention and at least 2 months after a successful mechanical intervention.
• Subject can have stable angina, (Canadian Cardiovascular Society (CCS) Class I-II angina (Appendix H).
• Subjects should be receiving appropriate medical therapy for hypertension and diabetes.
• A female of childbearing potential [FCBP] must have a negative serum pregnancy test at Screening and a negative urine pregnancy test prior to treatment with study therapy. In addition, sexually active FCBP must agree to use 2 of the following adequate forms of contraception methods simultaneously such as: oral, injectable, or implantable hormonal contraception; tubal ligation; intrauterine device [IUD]; barrier contraceptive with spermicide or vasectomized partner for the duration of the study and the follow-up period.
• Males (including those who have had a vasectomy) must agree to use barrier contraception (latex condoms) when engaging in reproductive sexual activity with FCBP for the duration of the study and the follow-up period.

Exclusion criteria

• The presence of any of the following will exclude a subject from enrollment:

• Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
• Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he or she were to participate in the study.
• Any condition that confounds the ability to interpret data from the study.
• Subjects whom, in the judgment of the Investigator, are at elevated risk for the development of a malignancy. This judgment may be based on family history, history of industrial exposures, smoking history or other cancer risk factors.
• Known to be positive for human immunodeficiency virus.
• Pregnant or lactating females.
• Subjects with a body mass index > 40 at Screening.
• Aspartate transaminase (AST) or Alanine transaminase (ALT) > 2.5 x the upper limit of normal (ULN) at Screening.
• Estimated Glomerular Filtration Rate (eGFR) < 45 mL/min/1.73 m2 at Screening calculated using the Modification of Diet in Renal Disease Study equation (Levey, 2006) or history of eGFR decline > 15 mL/min/1.73 m2 in the past year.
• Alkaline phosphatase > 2.5 x the ULN at Screening.
• Bilirubin level > 2 mg/dL (unless subject has known Gilbert's disease) at Screening.
• Untreated chronic infection or treatment of any infection with systemic antibiotics, including the ulcer site, within 4 weeks prior to dosing with investigational product [IP].
• Known osteomyelitis.
• Ulcer that has decreased or increased in size by ≥ 50% during the screening period.
• Uncontrolled hypertension (defined as diastolic blood pressure > 100 mmHg or systolic blood pressure > 180 mmHg during Screening at 2 independent measurements taken while subject is sitting and resting for at least 5 minutes).
• Poorly controlled diabetes mellitus (hemoglobin A1c > 9%).
• Untreated proliferative retinopathy.
• History of malignant ventricular arrhythmia, CCS Class III-IV angina pectoris, myocardial infarction/PCI (percutaneous coronary intervention)/CABG (coronary artery bypass graft) in the preceding 6 months, pending coronary revascularization in the following 2 months, transient ischemic attack/cerebrovascular accident in the preceding 6 months, and/or New York Heart Association [NYHA] Stage III or IV congestive heart failure, (Appendix C).
• Abnormal ECG: new bundle branch block (BBB) ≥ 120 msec in the preceding 3 months; QTcB and/or QTcF > 480 msec or QTcB and/or QTcF ≥ 500 msec with old BBB. Patients with a potential risk for Torsades des Pointes should not be enrolled.
• Uncontrolled hypercoagulation.
• Life expectancy less than 2 years due to concomitant illnesses.
• In the opinion of the Investigator, the subject is unsuitable for cellular therapy.
• History of malignancy within 5 years except basal cell or squamous cell carcinoma of the skin or remote history of cancer now considered cured or positive Pap smear with subsequent negative follow-up.
• History of hypersensitivity to any of the components of the product formulation (including bovine or porcine products, dextran 40, and dimethyl sulfoxide [DMSO]).
• Disorders or allergies precluding the use of radiographic contrast or renal insufficiency severe enough to contraindicate the use of radiographic contrast.
• Subject has received an investigational agent -an agent or device not approved by the US Food and Drug Administration (FDA) for marketed use in any indication- within 90 days (or 5 half-lives, whichever is longer) prior to treatment with study therapy or planned participation in another therapeutic study prior to the completion of this study.
• Subject has received previous gene or cell therapy.