A Phase 2, Open Label, Pharmacokinetic (PK) Study of TLC599 in Subjects With Osteoarthritis of the Knee

This Phase 2, open-label, 1 period, parallel study will enroll

1. approximately 90 subjects to receive a single dose of TLC599 or DSP via intra-articular (IA) injection, followed by a PK evaluation period up to 24 weeks and an additional follow-up period of 1 to 5 weeks. Additional subjects may be recruited as needed to achieve at least 10 subjects completing the 1-week blood collection period for each treatment.
2. approximately 12 healthy subjects to receive a single dose of DSP via IV injection, followed by a PK evaluation period up to 1 week and an additional follow-up period of 1 week. Additional subjects may be recruited as needed to achieve at least 12 subjects completing the 48-hour blood collection period for IV DSP.

• TLC599 (Drug), also known as TLC599 Injection: TLC599 is manufactured with the proprietary lipid formulation in lyophilized form (BioSeizer) for the reconstitution with the aqueous DSP (active ingredient).
• DSP (Drug), also known as Dexamethasone Sodium Phosphate: Dexamethasone sodium phosphate (DSP) is a glucocorticoid widely used in the treatment of joint pain such as gout, osteoarthritis and rheumatoid arthritis via IA injection.

Primary outcomes

• Area under the Curve [AUC] [Baseline till 24 weeks post investigational product (IP) administration]: Area under the concentration-time curve
• Cmax: maximum concentration [Baseline till 24 weeks post IP administration]: Maximum concentration
• Tmax: time to peak concentration [Baseline till 24 weeks post IP administration]: Time to peak concentration

Secondary outcomes

• Number of adverse events (AEs), including serious adverse event (SAE) and treatment-emergent AE [Screening till 25 weeks post IP administration]: Number of AEs, including SAE and treatment-emergent AE
• Cortisol concentration [baseline till 24 weeks post IP administration]: Cortisol concentration

Sex: All, ages: 18 Years to any, accepts healthy volunteers

Study Criteria for Patients with OA of the Knee (Cohort G1-G9)

Inclusion Criteria:

* Age 45 or older, non or moderate smokers, body mass index (BMI) ≤ 40.0 kg/m2.
* Knee OA symptoms with confirmed mild to moderate OA.
* Study knee OA severity grade 1-3 (Kellgren-Lawrence).
* Agree to use contraception

Exclusion Criteria:

* Clinically significant (CS) abnormalities (physical, lab, hepatitis B/C, HIV, electrocardiogram \[ECG\], vital sign or unstable illness).
* Positive urine drug screen, tuberculosis (TB) test; significant alcohol/drug abuse
* Allergic reactions to TLC599, its components, related drugs or cosyntropin.
* History of autoimmune disease, immunodeficiency diseases, treated malignancy, CS opportunistic infection, tuberculosis, infective arthritis or concurrent knee infection
* Intra-articular bleeding in study knee.
* Skin issues at injection site or hindrance to knee joint penetration.
* Blood coagulation disorders.
* Stroke or myocardial infarction
* Poorly controlled hypertension or vital sign abnormalities.
* Interfering conditions with dosing, visits, or compliance or refusal of synovial fluid collection.
* Medication: Strong/moderate Cytochrome P450 (CYP) 3A/3A4 inhibitors/inducers, prescription meds, over-the-counter (OTC)/natural health products, meds affecting platelet function, depot injection/implant, IA corticosteroid, hyaluronic acid, or other injection in study knee, impact on endogenous steroid levels, systemic corticosteroids, live attenuated vaccine, chemotherapeutic/immunosuppressant use for inflammatory diseases.
* Plasma donation or significant blood loss.
* Pregnancy, breastfeeding, or planning to be pregnant/breastfeed
* Serious local/systemic infection or symptomatic viral/bacterial infection
* Severe OA (grade 4) in non-study knee (Kellgren-Lawrence).
* Recent surgery, scheduled knee replacement or lower limb amputation.
* Known/adrenal insufficiency risk.
* Recent participation in other study research

Study Criteria for Healthy Subjects (Cohort G10)

Inclusion Criteria:

* Age 18-45, non-smokers, BMI 18.5-25 kg/m2, body weight ≥ 50.0 kg (males) or ≥ 45.0 kg (females).
* Healthy with no CS illness/surgery within 4 weeks or CS medical history.
* Agree to use contraception
* No new tattoos/body piercings at the injection site until the study ends.

Exclusion Criteria:

* CS abnormal physical, ECG or vital sign findings.
* Known/adrenal insufficiency risk.
* Abnormal lab results (HBV, HCV, HIV, TB).
* Positive pregnancy test or lactating; positive urine drug screen or cotinine test.
* Significant alcohol/drug abuse or positive alcohol test.
* Significant drug allergies or allergic reactions to DSP, dexamethasone, cosyntropin, natural adrenocorticotropic hormone (ACTH), or other related drugs.
* History/presence of conditions including CS opportunistic infection, serious local/systemic infection, autoimmune, blood, heart, vascular, respiratory, lung, skin, liver, gallbladder, retinopathy, neuromuscular, cancer, kidney, diabetes, severe allergic reactions, or others that would preclude participation.
* Fever
* Active/latent tuberculosis or symptomatic viral/bacterial infection
* Medication: Depot injection/implant, vaccine, drug known to induce or inhibit CYP3A4 metabolism, prescription meds, OTC/natural health products.
* Consumption of specified fruits.
* Recent participation in other study research
* Plasma donation or significant blood loss.
* Reasons preventing study participation

• Terry Tai, MD, Study director, Taiwan Liposome Company