A Study to Determine the Safety and Efficacy of TG-C in Subjects With Kellgren and Lawrence Grade 2 or 3 OA of the Knee

This protocol is designed to assess the safety and efficacy of TG-C in treating symptoms of osteoarthritis of the knee and determining disease modifying effects of TG-C. This study is intended for the treatment of patients with KL Grade 2 and 3 osteoarthritis and OARSI JSN Grade 1 and 2. Assessments will be made on both the symptomatic effects of pain (VAS), function (WOMAC), and Quality of Life (SF-12) as well as the physical effects (JSW, MRI evaluations of whole knee joint organ tissues and structure) and biochemical biomarkers. This is a placebo-controlled study, TG-C will be compared to normal saline as a control. Additionally, this protocol is designed to evaluate the safety of TG-C. Safety will be evaluated by observation of the injection site for irritation or other effects, the incidence and severity of adverse events, and changes in physical examination findings, radiographic criteria, and laboratory tests. Patients will be followed for 24 months for both safety and efficacy with annual cancer surveillance questionnaires through 15 years post dosing for subjects who do not enroll in the Long Term Safety study.

• TG-C (Biological), also known as TissueGene-C: 2 mL injection of non-transduced human chondrocytes and irradiated transduced human GP2-293 cells expressing TGF-B1.
• Placebo Control (Biological), also known as Normal Saline: 2 mL normal saline injection

Primary outcomes

• Change in Knee Function as Assessed by the Western Ontario and McMaster Universities Index (WOMAC) [12 months]: Assessment of change from baseline in target knee function using the WOMAC Osteoarthritis Index. The WOMAC is a proprietary set of standardized questionnaires used by health professionals to evaluate the condition of patients with osteoarthritis of the knee including pain, stiffness, and physical functioning of the joints. The response to the questions is in the form of a checked box associated with the response; None, Mild, Moderate, Severe and Extreme.
• Change in Knee Pain as Assessed by VAS [12 months]: Assessment of change from baseline in target knee pain using the Visual Analog Scale (VAS). The VAS is a method for the assessment of the intensity of pain. The VAS is a horizontal line, 100 mm in length and anchored by word descriptors at each end (no pain, very severe pain). The patient marks on the line at the point that represents their current state. The VAS score is determined by measuring in millimeters from the left hand end to the point of the mark. The score ranges from "0" or no pain to "100" very severe pain.

Secondary outcomes

• MRI Assessment of Target Knee [12 months]: Evaluation of the features of OA, as determined by structural changes of the knee joint, assessed by MRI
• PCS of the SF-12 Questionnaire [12 months]: Evaluation the Health-Related Quality of Life (HRQoL) as measured by the physical component score (PCS) of the 12-Item Short-Form Health Survey version 2 (SF-12v2®) questionnaire
• WOMAC Total Score [24 months]: Evaluation of the efficacy of TG-C with regard to knee function via WOMAC total score
• Health Assessment Questionnaire Disability Index [12 months]: Evaluation of the HRQoL as measured by the Health Assessment Questionnaire - Disability Index (HAQ-DI)

Other outcomes

• Radiography for Structural Change in Knee Joint [Through 24 months]: Evaluate structural changes of the knee joint as determined by radiography (X-ray)
• Efficacy of TG-C with Regard to Knee Function via WOMAC Total Score [At Months 3, 6, 9 and 18]: Evaluation of the efficacy of TG-C with regard to knee function via WOMAC total score
• Efficacy of TG-C with Regard to Knee Function via WOMAC Pain, Function, and Stiffness Scores [Through 24 months]: Evaluate the efficacy of TG-C with regard to knee function via WOMAC® pain, function, and stiffness scores
• Efficacy of TG-C with Regard to Knee Function via VAS Pain Score [At Day 1, Week 1, and Months 1, 3, 6, 9, 18 and 24]: Evaluation of the efficacy of TG-C with regard to knee function via VAS pain score at time points other than Month 12
• OMERACT-OARSI Responder Analysis [12 and 24 months]: Analysis of response using the Outcomes Measures in Rheumatoid Arthritis Clinical Trials (OMERACT)-OARSI responder criteria

Sex: All, ages: 40 Years to any

Inclusion Criteria:

* Aged 40 or older
* BMI between 18.5 and 40
* KL Grade 2 or 3 knee OA
* OARSI Grade 1 or 2 medial JSN
* Pain >= 40 on VAS scale
* Written informed consent
* Using birth control

Exclusion Criteria:

* Knee symptoms that result in difficulty or inability to walk
* Knee effusion >2+
* Has Grade 3 OARSI JSN
* Has a score of 0 or >=5 on the cartilage feature of the WORMS at Screening
* MRI exam indicates fracture or tumor
* Has a positive result on RCR testing at Screening
* Has taken NSAIDS with 14 days of baseline
* Has taken steroidal anti-inflammatory medication within 2 months of baseline
* Chronic (>21 days) narcotic use
* Recent history (within 1 year) of drug or alcohol abuse
* Pregnant or lactating
* Has received injection to target knee within 2 months prior to study entry
* History of various disorders of the knee including but not limited to rheumatoid arthritis, psoriatic arthritis, autoimmune disorder, chondrocalcinosis, gout, hemochromatosis, villonodular synovitis, or synovial chondromatosis
* Severe hip osteoarthritis ipsilateral to the target knee
* Ongoing infectious disease including but not limited to HIV, HTLV-1, VSV-G, HBV, or HCV.
* Clinically significant congestive heart failure, hepatic disease, kidney disease, adrenal insufficiency, acromegaly, uncontrolled hyper- or hypothyroidism, or non-specified uncontrolled endocrine disorder.
* Uncontrolled diabetes based on a HbA1c > 8% at screening.
* Documented active malignancy within the last 5 years except for basal cell carcinoma, squamous cell carcinoma, and benign pigmented nevi.

• Results publication: Mehta S, He T, Bajpayee AG. Recent advances in targeted drug delivery for treatment of osteoarthritis. Curr Opin Rheumatol. 2021 Jan;33(1):94-109. doi: 10.1097/BOR.0000000000000761. PMID 33229973

• Moon Jong Noh, PhD, Study chair, Kolon TissueGene, Inc.