Clinical Development of a Small Molecule Drug Targeting Endogenous Stem Cells to Restore Cartilage and Relieve Pain in Osteoarthritis Patients
Strategic Partnership I
We propose to develop the first drug therapy to reverse the damage of osteoarthritis (OA) in joints. OA is a serious disease that involves the degeneration of joint cartilage and the underlying bone resulting in joint pain, stiffness and immobility. OA is the leading cause of disability and chronic pain in the world and its impact on patients and its economic burden are rapidly increasing with our aging demographics. The statistics for OA are staggering: 27 million Americans and 3.25 million Californians have moderate to severe OA, 25% of OA patients cannot perform their major daily activities of life and 80% have limitations in movement. Ultimately, the pain and disability caused by OA is so severe that 1 million patients annually opt for painful, and for certain patients life-threatening, joint replacement surgery. Our proposed therapy is a small molecule drug that will be delivered as a single injection into the affected knee. Once injected, the drug activates the patient’s own stem cells that are already in the knee, causing them to change into cells that produce the cartilage tissue that is lacking in OA joints. It’s this lack of joint cartilage that leads to most of the debilitating symptoms associated with OA, including joint swelling, pain and immobility. By recruiting the patient’s own stem cells and natural repair machinery to fix the cause of OA, our drug can repair the diseased joint and allow the patient the opportunity to return to a normal productive, active lifestyle. The drug itself is only present at appreciable levels in the joint and nowhere else in the body, making it extraordinarily safe. This drug has proven safe and active in regenerating cartilage tissue in all preclinical models to date and we expect it to begin the clinical trial required by the US Food and Drug Administration in the first quarter of 2013. Depending on the results of those trials, the drug could be broadly available as early as 2017.
Statement of Benefit to California:
The proposed research comprises the clinical development to demonstrate safety and efficacy of an interventional drug to treat Osteoarthritis (“OA”) and restore patients to a normal active lifestyle. OA is a serious degenerative disease involving joint cartilage and the underlying bone. It affects 3 million Californians and prevents an estimated 750 thousand Californians from performing their major daily activities of life, and its impact is growing fast with our aging population. Our drug candidate offers the potential to regenerate cartilage tissue, repair the affected joint and relieve the patient of debilitating pain, thereby restoring many of these patients back to a state of well being, permitting them to return to their normal productive daily activities. Additionally, the economic cost of OA to the state of California is substantial, approximately $7-11 billion per year including direct medical, drug and work loss costs. Due to the medical impact of OA on patients and its economic burden on our health care system, an approved drug for this disease would be valued highly across the nation and globally and could bring countless new jobs and tax revenue to the citizens and State of California. Furthermore, an early success in regenerative medicine in California would likely generate additional excitement and investment in the stem cell field, generating more jobs and helping to ensure California’s leadership in this important new industry.
Executive Summary This application proposes to submit an IND, and to conduct and complete both a Phase 1 and Phase 2 clinical trial in osteoarthritis (OA) within the four year project period. Osteoarthritis is a chronic debilitating disease that involves the degeneration of the joint cartilage and bone that leads to disability and chronic pain afflicting over 27 million patients in the US. Standard of care therapy for OA may reduce pain and inflammation but do not affect cartilage and bone destruction. The intended therapy is a small molecule drug that activates a signaling pathway important for healthy bone and tissue maintenance, and will be delivered locally into affected joints. This approach is based on the applicant’s premise that the drug stimulates the patient’s endogenous stem cells to produce cartilage and thus repairs the joint damage. Significance and Impact - Reviewers agreed that there is a significant unmet medical need for treatment of OA. Current treatment options are limited to reduction of pain and inflammation, and ultimately joint replacement. A disease-modifying product for treating OA of the knee would have a large impact on health and quality of life. - The Target Product Profile (TPP) lacked appropriate detail for the proposed stage of development. The target population, efficacy endpoints, dosing regimen and safety section are all inadequately specified. The safety section was judged to be inadequate. Risk/Benefit - Reviewers were intrigued by the therapeutic concept to deliver a small molecule locally that could stimulate chondrogenesis. - The preclinical data presented to support the rationale of using the candidate in OA was judged to be weak; and to date, limited in vivo data support the premise that mobilization of the endogenous stem cells is a primary mechanism of action. - Although an increase in chondrocytes could lead to symptom relief in patients with knee OA, reviewers cautioned it is possible that this might lead to increased symptoms if there is induction of inflammation or too much cartilage or bone production in the knee. - Another concern was raised regarding the overstimulation of this target and potential tumorigenesis. The panel recommended long term toxicology studies to determine the risk for oncogenic transformation. Design and Feasibility - Reviewers judged the timeline to be unrealistic, based on their assessment of additional necessary preclinical work. - The in vitro preclinical proof-of-concept (POC) efficacy data was judged to be inadequate for a proposed project at this stage of development. - Reviewers suggested further studies for functional outcome be conducted in large animal models with surgically induced cartilage damage to better understand the impact of the therapeutic on cartilage in weight-bearing conditions. Additionally large animal models were recommended to study the impact of dose and regimen on the balance of cartilage repair versus potential overgrowth. - Reviewers agreed the amount of preclinical work (including additional necessary studies) and the proposed Phase 1 study was feasible to complete in the 4 year time frame. However the proposed Phase 2 study timeline was not realistic due to the large number of subjects to be enrolled and the longer duration of the study compared to the Phase 1. Principal Investigator (PI), Development Team and Leadership Plan - The team could benefit from an advisor with small molecule development experience, and regulatory expertise familiar with the CDER division. Collaborations, Assets, Resources and Environment - Reviewers found the list of collaborations comprehensive but would have liked more detailed description of selection of the Contract Research Organizations. Budget (Assessment of the budget was conducted separately from the overall scientific evaluation and points or concerns raised in this section did not contribute to the scientific score. This section highlights items that must be addressed should the application be approved for funding.) No relevant budget concerns were highlighted by reviewers.
- Joy Cavagnaro