Early Translational II
Local bone formation can be mediated by a number of adult stem cell populations, such as mesenchymal stem cells (MSCs), osteoprogenitors and osteoblasts, and proliferation of these cell populations can contribute to improved bone formation. Adult stem cells are naturally-occurring cells found in almost all tissues or organs in the body and are primarily responsible for maintaining and repairing their native tissue. For example, mesenchymal stem cells are multipotent cells that can differentiate into a variety of cell types, including osteoblasts, chondrocytes, myocytes and adipocytes, which go on to form bone, cartilage, muscle and fat. The promotion of bone formation by growth factors has been well researched but has only yielded one approved biologic therapeutic that is limited in use due to cost and safety issues. Our research into specific stem cell pathways and small molecule compounds that can induce MSC differentiation to mature, bone-forming osteoblasts offers a new mechanism of intervention, which may be applied to treat a number of bone injuries and conditions, including non-union fractures, fractures-at-risk and spinal fusions. These conditions represent more than 36 million procedures that could be improved with a cost-effective, safe small molecule to reduce time to healing and overall medical costs. While many current medications aimed at addressing bone deficiencies work by preventing further decay or are expensive biologics, new osteogenic small molecule medicines would be designed to stimulate positive bone growth and offer an improved course of action in orthopedic medicine ranging from bone fractures to osteoporosis. In initial proof of concept experiments, we have already identified a collection of promising small molecule hits based on novel chemistry and the ability to stimulate MSCs to osteoblasts through known pathways in vitro and improve bone formation and repair in vivo, which will be the preclinical efficacy endpoints. The objective of this proposal will be to validate from our collection of hits a lead drug candidate in mechanism of action studies and in vivo animal models and perform initial pilot studies of dose and safety to be ready for preclinical development and rapidly move into clinical testing. We plan to optimize local delivery and extend the molecule’s half-life. Outside of the local environment, the molecule is quickly degraded indicating safety risks will most likely be small. This project leverages more than a decade of essential stem cell research and has the potential to translate stem cell research into much needed medicines to improve standard-of-care to reduce pain and decrease medical costs.
Statement of Benefit to California:
New small molecule osteoregenerative therapeutics would provide an alternative to expensive biologics and offer an improved course of action and treatment paradigm in orthopedic medicine. Osteoregeneration is needed in a number of conditions of the bone, including non-union fractures, fractures-at-risk and spinal fusions, where improvements in therapeutic options have been minimal. Current treatments include bone growth factors, which have proven to be successful at addressing a billion dollar market in non-union fractures and lumbar cervical spinal fusion, which represents approximately 350,000 procedures, but bone growth factors are actually limited in use in the other indications due to safety and expense. Treating fractures accounts for nearly half of the $56 billion annual expenditure for trauma medicine. As a cost-effective, safe small molecule, the proposed drug candidate could begin to address the 36 million procedures in the U.S. and 3.4 million in California that represent non-union fractures, fractures-at-risk and spinal fusions, to improve time to healing and reduce pain and costs. Non-union bone fractures cannot heal without further intervention, and the oft-used treatment is to take a bone graft from the patient's pelvis. However, this increases pain, medical procedures and costs, hospital time and the risk of potential complications, such as donor site wound infection, bleeding and numbness. The only FDA-approved product on the market is a bone growth factor that reduces to a small extent the use of bone grafts, but the product is expensive, does not reduce time to healing and cannot be used in some procedures because of safety issues. Being able to use a small molecule therapeutic to stimulate bone formation in cases where the currently approved biologic is not used because of safety or expense would reduce need for secondary intervention, accelerate healing and provide the patient a faster return to normal function. Advancing cost-effective small molecule drug to provide quicker healing times and reduce unnecessary medical procedures would reduce pain and suffering for patients and decrease healthcare costs for California and the nation.
This application for a Development Candidate Award focuses on a small molecule therapeutic for bone repair, including the treatment of non-union fractures, fractures-at-risk and spinal fusions. The applicant has identified a small molecule that stimulates the differentiation of mesenchymal stem cells (MSCs) to bone-forming osteoblasts and promotes bone formation and repair in vivo. The applicant proposes a series of studies to advance this compound toward clinical translation: (1) determination of its cellular and molecular targets; (2) identification of backup lead compounds; (3) testing of compounds in animal models of bone repair; and (4) IDE-enabling pharmacodynamic, biodistribution, toxicology and tumorigenicity studies. Reviewers were not convinced that this proposal would have a significant impact on the treatment of bone injuries. They noted that an FDA-approved product similar to that envisioned in this proposal is currently in clinical use, and the need for improvement is not clearly justified. The applicant refers to cost advantages, but it is not obvious that a product containing a small molecule will be less expensive than a comparable product with a recombinant growth factor. The applicant also mentions safety issues with existing products and other growth factors, but it is not clear that a small molecule would be superior and the research plan does not address this question. In terms of scientific rationale, reviewers were concerned that a therapeutic target has not yet been identified. In addition, the lead compound is presented as a promoter of cell differentiation, but in the target patient population it may be cell numbers that are limiting rather than differentiation capacity. Reviewers also noted that the IDE-enabling studies proposed for Year 3 are explicitly outside the scope of this RFA. While reviewers appreciated the impressive preliminary data presented for the lead compound, they did not find the research plan to be focused on reaching IDE-enabling studies at the end of three years. They noted that the investigation of the cell based assays to determine the mechanism of action is important to understand what cells are being recruited for bone formation. However, the extensive experiments designed to identify the molecular targets are scientifically interesting, but represent basic research and do not lie along the critical path toward defining and validating a development candidate. Reviewers noted that the SAR plan and its specific goals are not clearly presented. In addition, quantitative go/no-go milestones and success criteria are not well described. Reviewers also would have appreciated greater discussion of the delivery device development and selection and potential issues associated with it, such as ectopic bone formation. The reviewers described the research team as well qualified to carry out the proposed research. They noted that the principal investigator (PI) has an excellent track record and extensive experience with the BMPs and their receptors, as well as the biology of mesenchymal stem cells. Reviewers found other team members to be appropriately qualified and praised the strong investigators collaborating on the project. They described the research environment as excellent for drug discovery and development. Overall, while reviewers appreciated the strong preliminary data and research team, they raised questions about the potential impact of the proposed therapeutic. Reviewers did not find the research plan to be focused toward IDE-enabling studies and were not convinced that it would reach this goal by the end of three years.
- Joy Cavagnaro
- Darin Weber