Evaluation of Intra-articular CX-011 to Treat Moderate to Severe Pain From Knee Osteoarthritis

The primary objective of the study is to assess the safety and tolerability of three escalating doses of CX-011 (100, 300, and 1000 μg) following a single intra-articular administration. Safety assessments will include the incidence and severity of local and systemic adverse events, procedure- and product-related serious adverse events, physical examinations, index knee evaluations, vital signs, electrocardiograms, and safety laboratory tests. Dose-limiting toxicities and the maximum tolerated dose will be determined based on these assessments.

Secondary objectives focus on evaluating the preliminary efficacy of CX-011 for the treatment of knee osteoarthritis pain and function, as well as further characterization of its safety profile. Efficacy endpoints include changes from baseline in pain intensity measured by the Visual Analog Scale (VAS) at 4, 12, and 24 weeks post-injection, as well as percentage improvements in the pain and function subscales of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at the same time points.

Up to 72 patients will participate in this study (in one study center). The expected length of participation in the study is about 28 weeks including the screening period.

Inclusion criteria

• Written consent to participate in the study.
• Males or females 40 years of age or less than 75 years old.
• Diagnosis OA of the index knee by a combination of clinical and radiographic findings wherein the index knee is self-identified by the subject as the more severe knee (if both knees qualified) and symptoms have persisted for >3 months.
• Radiographic evidence of OA in the tibiofemoral compartment of the index knee (Kellgren-Lawrence grades II or III) within 6 months prior to Screening or during the Screening period
• Index knee pain on most days (>15 days) over the last month
• Subjects who have failed to adequately respond for at least 6 months within the previous 12 months to at least three osteoarthritis therapies that include at least two pharmacological treatments such as simple analgesics (e.g., acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS)), corticosteroid injection, extended-release steroid use within 4 months, Viscosupplement (e.g., hyaluronic acid) injection, platelet-rich plasma injection, bone marrow aspiration concentrate, placental-derived tissue/cells, adipose tissue, or any other autologous or allogeneic product. Conservative, non-pharmacological therapy includes: avoidance of activities that cause joint pain; exercise; weight loss; physical therapy; and removal of excess fluid from the knee.
• VAS Pain score of 4-8 on a 0 - 10 scale.
• Overall index knee pain score of 11 or more in the index knee using the 0 - 20 WOMAC Pain scale.
• hsCRP ≥ 2 mg/L
• Body mass index < 40 kg/m2
• If female, must not be pregnant or nursing and willing to refrain from becoming pregnant during the study.
• Willing to agree not to use illicit drugs during the study, including cannabinoids, and to have illicit drug testing at screening and at later time points if illicit drug use is suspected during the study.
• Able to comply with study requirements and complete the full sequence of protocol-related procedures and evaluations.
• Subjects shall agree to refrain from taking NSAIDS, opioids, intra-articular steroids and hyaluronic acid (viscosupplementation), electrotherapy and acupuncture during the study.
• Subjects receiving glucagon-like peptide-1 receptor agonists (GLP-1RAs), including semaglutide, liraglutide, dulaglutide, or tirzepatide, may be enrolled only if they have been on a stable maintenance dose for at least 12 weeks prior to screening, with no dose adjustments, and are not undergoing dose titration or escalation.
• Subjects shall agree to refrain from using topical pain therapies including capsaicin, lidocaine patches, heat patches, CBD oil and topical NSAIDs.
• Subjects shall agree to refrain from any additional pain medication for 24 h prior to all study visits, excluding screening visit.
• Male or female subjects with reproductive potential agree to comply with a highly effective contraceptive method from the first Screening visit through 90 days after last study drug administration. A highly effective method of contraception is defined as one that has no higher than a 1% failure rate. In this study, the only acceptable methods of contraception are as follows:

i. Hormonal contraception and male condom. ii. Placement of intrauterine system and male condom. iii. Female subject's partner vasectomized for ≥6 months prior to Screening and subject's verbal confirmation that absence of sperm in the ejaculate was confirmed.

iv. Female subject or male subject's partner with bilateral tubal ligation ≥6 months prior to Screening.

v. Sexual abstinence when in relation to the preferred and usual lifestyle of the subject.

Contraception requirements do not apply for subjects in an exclusively same-sex relationship. Subjects with reproductive potential who are not currently sexually active must agree to use acceptable contraception as specified above if they become sexually active during the study period and for 90 days after the last dose of study drug. Subjects with reproductive potential must agree not to donate sperm or eggs during the study and for 90 days after the last dose of study drug.

Subjects are considered of non-reproductive potential if any of the following apply:

i. Post-menopausal female with ≥12 consecutive months of spontaneous amenorrhea with follicle stimulating hormone (FSH) >30 mIU/mL at Screening.

ii. Surgically sterile female and at least 6 weeks post-sterilization (i.e., bilateral oophorectomy or hysterectomy).

iii. Sterilized male ≥6 months post vasectomy and subject's verbal confirmation that absence of sperm in the ejaculate was confirmed.

Inclusion criteria

on Day of Injection

• Prior to dosing on Day 1, subjects must meet the following criteria:

i. BP systolic between 90-160 mmHg and diastolic between 60-100 mmHg ii. Pulse between 60-100 bpm iii. Respiratory Rate between 12-20 per minute iv. Afebrile

Exclusion criteria

• Daily use of assistive devices (e.g. cane or walker) or presence of comorbidities that would limit the subject's ability to walk.
• History of Reiter's syndrome, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, arthritis associated with inflammatory bowel disease, sarcoidosis or amyloidosis.
• Unstable joint (such as a torn anterior cruciate ligament)
• Inability to undergo Magnetic Resonance Imaging (MRI) due to presence of surgical hardware or other foreign body in the index knee, or because of subject's claustrophobia or other MRI contraindication, including intolerance of or allergic reaction to IV contrast
• Regular daily use of anticoagulants
• VAS Pain score of ≥4 on a 0 - 10 scale in the contralateral knee
• Symptoms of locking, intermittent block to range of motion, or loose body sensation that could indicate meniscal displacement or an IA loose body; knee ligament instability at the index knee.
• Major dysplasia or congenital abnormalities
• Corticosteroid injection into the index knee within 3 months prior to screening; extended-release steroid use within 4 months prior to screening.
• Viscosupplement (e.g., hyaluronic acid [HA] injection, platelet-rich plasma injection, bone marrow aspirate or bone marrow aspiration concentrate, placental-derived tissue/cells, adipose tissue, or any other autologous or allogeneic product) into the index knee within 3 months prior to screening.
• Knee surgery or procedure on the index knee within 12 months prior to screening and/or planned knee surgery during the study including cold or radiofrequency nerve ablation.
• Knee surgery or procedure on the contralateral knee within 6 months prior to screening and/or planned knee surgery during the study including cold or radiofrequency nerve ablation.
• Acute index knee trauma within 3 months prior to screening.
• Knee joint infections, skin diseases or infections in the area of the injection site.
• Current therapy with any immunosuppressive therapy, including corticosteroids (> 5 mg/day of prednisone) or subjects with conditions that would likely include treatment with immunosuppressive therapy (including corticosteroids) during the study period.
• HbA1c ≥ 8% and/or insulin-dependent diabetes
• Initiation of GLP-1RA therapy, dose titration or escalation, switching between GLP-1RA agents or discontinuation of GLP-1RA therapy within 12 weeks prior to screening or planned during the study period.
• Known intention to start any anti-obesity pharmacotherapy (including GLP-1RAs) during the study period.
• Moderate to severe renal impairment
• Moderate to severe hepatic impairment
• Active use of moderate to strong inhibitors or inducers of major P450s
• Systolic BP > 160 mmHg or diastolic BP > 100 mmHg or on > 3 blood pressure medications at screening.
• Clinically significant findings on physical examination or screening tests (e.g. laboratory and radiographic) that are not specific to OA of the knee and may interfere with study conduct or interpretation of data or increase subject risk.
• Clinically significant intercurrent illness, medical condition, non-knee pain, or medical history (including neurological or mental illness, human immunodeficiency virus, autoimmune diseases or connective tissue disorder, fibromyalgia, complex regional pain syndrome, clinical anxiety, clinical depression, any active infection including hepatitis B or C) that would jeopardize subject safety, limit participation, or compromise interpretation of data derived from the subject.
• Participation in another clinical trial within the previous 30 days before screening or planned participation in another clinical trial during the study.
• X-ray showing any exclusionary criteria such as subchondral insufficiency fracture, tumor, osteonecrosis, fragmentation or collapse of part of the joint, infiltration of the bone marrow, stress fracture or reaction.
• History of active malignancy, with the exception of resected basal cell carcinoma, squamous cell carcinoma of the skin, or resected cervical atypia or carcinoma in situ within 5 years.
• Known active or quiescent tuberculosis infection of the respiratory tract; untreated systemic fungal, bacterial, viral or parasitic infections, or ocular herpes simplex.
• Any infection requiring intravenous antibiotics within 4 weeks of Screening, infection requiring oral antibiotics within 2 weeks of Screening, history of chronic infection, or a history of osteomyelitis.
• Screening 12-lead electrocardiogram (ECG) consistently demonstrating heart rate corrected QT intervals (QTc) >450 msec in male subjects and >470 msec in female subjects or any clinically significant ECG abnormality as judged by the Investigator.
• Active psychiatric disorder including psychosis and major depressive disorder.
• History of or active Cushing's syndrome
• Any other clinically significant acute or chronic medical conditions (e.g., uncontrolled diabetes) that, in the judgment of the Investigator, would preclude the use of CX-011 or that could compromise subject safety, limit the subject's ability to complete the study, and/or compromise the objectives of the study.
• Positive drug or alcohol screen.