Treatment and prevention of osteoarthritis with an intra-articular disease-modifying regenerative therapy

Abstract Nearly one in every ten Americans, and one in every three over the age of 65 years, suffers from osteoarthritis (OA), a degenerative joint disorder that causes progressive cartilage loss. Current therapeutic options include physical and occupational therapy, acupuncture, medication, intraarticular injection, and surgery. As total joint surgery (arthroplasty) is costly and has a maximum lifetime of 15 years before requiring even more expensive and risky revision surgery, OA intervention strategies generally retain patients on the least invasive methods for as long as possible to delay the need for arthroplasty. However, the limited relief offered by palliative therapeutic options such as exercise, anti-inflammatory medications (ibuprofen, glucocorticoids), narcotics (opioids), and injections (hyaluronic acid, corticosteroids) impose a drawn-out period of suffering for OA patients to endure chronic pain from cartilage destruction, inflammation, and other pathological damages associated with the disease. Such approaches provide only symptomatic pain relief, and are not disease-modifying interventions. Although the pathogenesis of OA remains incompletely understood, we have discovered that adenosine, acting at its A2a receptor (A2aR), is a critical autocrine homeostatic factor that maintains chondrocyte and cartilage balance. Regenosine is developing Lipo-Ade, a first-in-class liposomal adenosine product in a proprietary, novel formulation for effective, prolonged treatment and for regenerating cartilage in joints in patients with established OA. We have demonstrated that use of liposomes as a mechanism to encapsulate the short-lived adenosine and its delivery into the intraarticular space enables the bioactive compound to promote cartilage regeneration, stop the progression and reverse the pathology of OA. For this Direct to Phase II project, Regenosine will continue to develop and test Lipo-Ade as an optimal OA treatment formulation in preparation for initiating our clinical trials by undertaking four specific aims: 1) conducting studies to define release kinetics and measure primary metabolites in synovial fluid and plasma, 2) performing a large animal proof-of-principal/bridge study to evaluate the safety and efficacy of Lipo-Ade in pain and joint structural change in dogs with OA, 3) characterizing an optimal, stable formulation, determining the chemistry, manufacturing, and controls (CMC) of liposomes, and undertaking the manufacturing of a pilot scale batch, and 4) conducting Investigational New Drug (IND) enabling pharmacokinetic and toxicology studies of the Lipo-Ade to satisfy requirements set by the US FDA. These assessments will validate the safety, efficacy, and feasibility of Lipo-Ade to usher the technology towards commercial application. Quality control standards such as shelf-life, sterility, batch-to-batch variation, etc. in the manufacturing process will be addressed, and more importantly the ability of Lipo-Ade to reduce pain and regenerate cartilage will be determined. As a set, these Specific Aims will address the remaining gaps in Regenosine's non-clinical development that must be filled for a successful Investigational New Drug (IND) submission, which will pave the way for a first-in-human clinical study.