We propose the development of a stem cell-targeted drug therapy to improve and accelerate bone healing in patients with osteoporotic hip fractures. Hip fractures are a devastating consequence of osteoporosis striking 1.5 million Americans and 180,000 Californians annually. Among these patients, approximately 375,000 patients in the US and 45,000 patients in California die within one year of their injury. This debilitating and potentially deadly disease-related injury currently has no effective treatment. Current treatment is typically orthopedic surgery to attempt to join the bones, 1-2 weeks of hospitalization followed by extensive rehabilitation and commonly, admission to a nursing home. Current treatment is painful, does nothing to stimulate bone regeneration, often fails, and incurs significant risks of mortality and morbidity. Standard of care leaves large numbers of hip fracture patients in intractable pain, unable to return to normal activities and at significant risk for recurrent fractures. If fracture union is not achieved, the patient may suffer long-term disability. The unmet clinical need for the population of osteoporosis patients with debilitating fracture is enormous and growing with our aging demographics.
Bone is often thought of as a permanent substance that does not change after childhood. However, bone is alive, dynamic and constantly being renewed though a process of the breakdown of old bone and the formation of new bone. As we age, more bone is lost than generated which can lead to osteoporosis, a disease of the bone that greatly increases the bone's fragility. Upon successful development of this project, the drug will drive the patient’s own stem cells at the site of the injury to change into bone forming cells that will build and strengthen the affected bone to speed the healing process and reduce the risk of future fractures.
This project will take an already identified compound that is currently under manufacture, through non-clinical and clinical safety studies as well as preliminary efficacy studies as required by the Food and Drug Administration (FDA). This includes supporting data for filing an investigational new drug (IND) application to enter clinical studies and Phase I/II safety and efficacy clinical trials in patients within this grant’s time frame of four years. The goal of this project is to significantly advance development of a medication that will be administered when a patient has incurred a fracture and is undergoing the current standard of care, orthopedic surgery. Utilizing the body’s own cellular machinery, by inducing stem cells to build localized bone at the point of fracture, is a therapeutic strategy with a high likelihood of success with a low probability of side effects. This proposal offers a therapy that will significantly improve hip fracture patient’s post-surgical prognosis, revolutionizing the treatment of hip fractures.
Statement of Benefit to California:
The aim of this project is to advance the clinical development of a stem cell targeted therapy to improve and accelerate bone healing in osteoporotic hip fracture patients through Phase I/II clinical trials. Osteoporosis is a disease of the bone that increases bone fragility and the possibility of fracture. Hip fractures are a devastating consequence of osteoporosis striking approximately 180,000 Californians annually at an estimated cost of approximately $2 billion. Of these patients, an estimated 45,000 Californians die within one year of their injury. There is no approved drug to treat this scourge of California's aging population.
Current hip fracture treatment is typically orthopedic surgery to attempt to join the bones, 1-2 weeks of hospitalization followed by extensive rehabilitation and commonly, admission to a nursing home. Current treatment is painful, does nothing to stimulate bone regeneration, often fails, and incurs significant risks of mortality and morbidity. Standard of care leaves large numbers of hip fracture patients in intractable pain, unable to return to normal activities and at significant risk for recurrent fractures. If fracture union is not achieved, the patient may suffer long-term disability. The clinical unmet need for the population of California’s osteoporosis patients with debilitating fracture is enormous and growing with the aging demographics of our society.
This project will advance development of a compound that is already identified and currently under manufacture, through non-clinical and clinical safety studies as well as preliminary efficacy studies as required by the Food and Drug Administration (FDA). The drug will be administered at the time of fracture when a patient is undergoing the current standard of care, orthopedic surgery. Successful development of this therapy will revolutionize the treatment of osteoporotic hip fractures; not only saving lives, but also significantly improving thousands of Californian’s lives every year after sustaining a hip fracture. This therapy will also contribute to a substantial cost savings for the State of California’s healthcare budget.
The goal of this proposal is to advance a small molecule drug for accelerating bone repair following osteoporotic hip fracture. The proposed therapy would be administered at the same time as a patient undergoes standard-of-care orthopedic surgery. The applicant claims that the treatment would drive the patient’s own stem cells to become bone-forming cells, thereby speeding the healing process and potentially preventing future fractures. The applicant proposes to complete Investigational New Drug (IND)-enabling studies and conduct a Phase I/II trial within four years.
Significance and Impact
- Reviewers agreed that there is a clinical need for bone regenerative strategies, particularly for patients with osteoporosis. However, they were not convinced that this approach would have major impact, as there are currently other treatment options available for hip fracture, and outcomes are significantly improving with time.
- Reviewers found the Target Product Profile (TPP) to be somewhat lacking in details, particularly those relating to optimal indication and specifics of the biologic activity. With so little information provided regarding the identity of the compound and therefore mode of action, reviewers found it difficult to assess the competitiveness of this approach against other drugs/biologics that promote bone formation, such as parathyroid hormone and various bone morphogenetic proteins (BMPs).
- Only circumstantial evidence was provided to indicate that the proposed therapeutic specifically targets an endogenous human stem cell, as required in the RFA. Most reviewers found the proposal to be technically responsive, however, as the targeted pathway is a well-known player in stem cell biology and osteogenesis.
- The scientific rationale for the project is strong. The proposed therapeutic targets a pathway that is well- known to be involved in bone repair and remodeling.
- Although extensive preliminary data were provided to document the in vitro and in vivo effects of the proposed therapeutic using rodent cells, there were no data provided to confirm that similar effects would be observed with human bone progenitor cells.
- Preliminary data indicate that the proposed therapeutic performs comparably, but not better, than a clinically approved bone growth factor.
- The potential for off-target effects of the therapeutic was not adequately considered in the application. Even with minimal systemic exposure, reviewers questioned whether the gastrointestinal tract and other organ systems might be particularly vulnerable.
- No evidence of an in vivo dose response was provided.
Therapeutic Development Readiness
-The applicant provided a well-defined set of milestones.
- Reviewers expressed concern at the premature status of the toxicology studies, noting that many therapeutic candidates fail in development due to poor toxicology results. No GLP study data were provided, and it was not clear from the application whether all of the necessary studies had been considered.
- Reviewers disagreed about whether the preclinical data provided were compelling. While preclinical efficacy data were viewed as a strength of the application, some reviewers were concerned that key preclinical large animal studies simulating the human disease had not been completed.
- The in vitro studies performed to characterize the proposed drug delivery approach are not likely to reflect the clinical scenario. While some in vivo data were provided, reviewers believed that a more thorough analysis would be necessary.
Feasibility of the Project Plan
-Some reviewers found their ability to fully assess the project plan feasibility was limited by lack of information about the therapeutic molecule itself and possible safety considerations that might arise.
- Reviewers strongly questioned the feasibility of the proposed timeline, especially when considering the additional preclinical studies requested by the regulatory agency.
- The project plan does not account for dose ranging studies or allow sufficient time for the overall nonclinical program, which usually takes approximately 1 year to complete prior to IND preparation and submission.
- The technical and regulatory challenges associated with the proposed localized delivery method were not adequately addressed or discussed.
Principal Investigator (PI) and Development Team
- Reviewers did not feel this was a strong team. In particular, they noted that many key hires were not yet made and individuals to fill those positions had not been identified.
- The apparent view of the applicants that they could have multiple pre-IND meetings with the regulatory agency suggests a relative lack of experience with the regulatory process.
- Concern was expressed that the applicants may not have the requisite nonclinical expertise on hand to fully anticipate the needs of the nonclinical program or assess the regulatory requirements for IND-enabling studies in this indication.
-Based on the information provided, it was not clear whether the project would be sufficiently staffed and with the appropriate expertise to manage the proposed clinical trial.
Collaborations, Resources and Environment
- Reviewers were concerned that many of the potential clinical sites identified are not affiliated with a university or research institution.
-Little information on collaborators was provided, so reviewers could not adequately determine whether these collaborators would play a significant role and whether they were appropriately qualified.
- Intellectual property position appears reasonable.
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.)
- Reviewers commented that the overall budget needs refining, particularly after revising project plans in accordance with regulatory advice.
- Reviewers believed the costs of the toxicology studies are likely underestimated, whereas the costs for the proposed bone defect study were viewed as excessive.
- Reviewers noted that the matching funds offered by the applicant did not meet the suggested minimum that was defined in the RFA.