There are over 1.5 million osteoporotic fractures annually in the USA alone, at a cost of approximately $15 billion each year. The majority of these fractures occur in the spine, followed by the hip and wrist. Incidence varies according to age; vertebral fracture rates increase rapidly by the sixth decade of life, whereas the risk of hip fracture rises markedly by the eighth decade and beyond.
Current treatment is focused on prevention using osteoclast inhibitors, hormone therapy, diet and exercise. When a fracture occurs current therapies involve injection of cement into the vertebral body and/or open surgery with implants. Unfortunately, these procedures do not regenerate bone tissue, often fail and incur risks of leakage and emboli. The clinical and economic impact associated with these fractures is substantial. Following a fragility fracture, significant pain, disability, and deformity can ensue. If fracture union is not achieved, the patient may suffer long-term disability. This is exacerbated because there is a five-fold increase in the risk for sustaining a subsequent vertebral fracture and the odds that a neighboring vertebrae will fail within one year is >20%. We propose to add a noninvasive anabolic option to the treatment and prevention of osteoporotic fractures. This therapy utilizes a novel small molecule Wnt pathway activator that drives the endogenous stem cells in the bone compartment to differentiate into bone forming osteoblasts thereby increasing bone mass and reducing the risk of fracture. This therapy will be administered 1-2X/year by injection, eliminating the concerns over patient compliance and revolutionizing the treatment of vertebral and hip fractures in patients suffering from osteoporosis.
There are over 25 million osteoporosis patients in the US alone, leading to 1.5 million osteoporotic fractures annually at a cost of approximately $17 billion per year. The lifetime incidence of fragility fractures secondary to osteoporosis in females over fifty years of age is approximately 1 in 2, and in males over the age of fifty, is 1 in 4. Osteoporosis-related vertebral compression fractures are the most common fragility fractures in the United States, accounting for more than 79% of the total. Approximately 70,000 OVCFs result in hospitalization each year with an average hospital stay per patient of 8 days. Current treatment is focused on prevention using osteoclast inhibitors, hormone therapy, diet and exercise. When a fracture occurs, current therapies involve injection of cement into the vertebral body and/or open surgery with implants. Unfortunately, these procedures do not regenerate bone tissue, often fail, incur risks of leakage and emboli, and suffer significant side effects. The clinical and economic impact associated with these fractures is substantial. Following a fragility fracture, significant pain, disability, and deformity can ensue. If fracture union is not achieved, the patient may suffer long-term disability. This is exacerbated because there is a five-fold increase in the risk for sustaining a subsequent vertebral fracture after the first fracture, and the odds that an adjacent vertebrae will fail within one year is >20%. We propose to add a noninvasive anabolic option to the treatment and prevention of osteoporotic fractures, with minimal to no side effects or systemic safety concerns. This therapy utilizes a novel small molecule Wnt pathway activator that drives the endogenous stem cells in the bone compartment to differentiate into bone forming cells, thereby increasing bone mass and reducing the risk of fracture. This therapy will be administered 1-4 times per year by injection, eliminating the concerns over patient compliance and revolutionizing the treatment of vertebral and hip fractures in patients suffering from osteoporosis. This will benefit the citizens of California by reducing hospitalization periods, operative costs and loss of workdays, and by improving quality of life for Californians with osteoporosis that are at risk for OVCFs.
The applicant proposes to prophylactically treat vertebral bones at risk for fracture in osteoporotic patients. The therapeutic candidate is a small molecule Wnt pathway agonist formulated for sustained release at an injection site adjacent to susceptible vertebrae. The agonist is intended to promote bone formation by inducing endogenous stem cell differentiation into osteoblasts, i.e. bone forming progenitor cells. The team proposes to complete investigational new drug (IND)-enabling studies, file an IND application with the Food and Drug Administration (FDA), and conduct a Phase I/II trial.
Significance and Impact
- Prevention of vertebral compression fractures, a common occurrence in osteoporosis patients, presents a major clinical need. Varying successes and side effects of existing treatments suggest that a new bone anabolic is likely to have a major impact.
- The proposed approach requires only occasional dosing of the target product; this is an attractive feature as that increases the likelihood of patient compliance.
- Although reviewers appreciated potential advantages of the proposed product over rPTH, a standard of care bone anabolic agent, this was not sufficiently discussed in the application. Reviewers considered the lack of direct comparison between the two compounds in the preclinical data a weakness.
- The applicant proposes to develop a single therapeutic candidate that is designed to promote the differentiation of endogenous stem cells and thus falls within the scope of this RFA. However, no data were shown that this compound selectively acts on human or mouse stem cells, and thus it is unclear whether its mechanism of action involves endogenous stem cells.
Project Rationale and Feasibility
- There is a strong scientific rationale for the proposed intervention. Bone marrow stem cell numbers and their capacity to undergo differentiation to osteoblasts is impaired in ageing and osteoporosis. Therefore, methods of promoting differentiation of these cells as they accumulate in osteoporotic bone sites have a good chance of improving the therapeutic choices for these patients.
- The discovery of the candidate molecule was based on a logical screening approach, and the proposed treatment approach is novel.
- The in vivo efficacy data demonstrating enhanced osteogenesis by the proposed product are convincing, but cannot predict whether or not the fracture rate can be reduced. Collectively, however, the in vitro and in vivo efficacy data, knowledge of mechanism and provisional safety data provide very strong support to justify the therapeutic rationale.
- The preliminary data were derived without use of the sustained release methodology, but this is not a major concern for the molecule’s efficacy. It is expected that slow release will alter pharmacokinetics and not pharmacodynamics, and pivotal efficacy studies with the validated formulation are planned in a mouse model.
- Reviewers expressed concern about the number of vertebrae that may have to be treated prophylactically, given the need for local administration. This issue should be addressed in the research award application.
- If the target product indeed acts on stem cells and induces their differentiation, there is a concern that it may deplete the stem cell pool. This will require careful testing.
- For the planned safety studies, a key outcome measure is inflammation at the site of injection. However, reviewers expressed strong concern about the possible oncogenic effects of a Wnt pathway activator, as the candidate molecule is very potent. The potential for off target effects is enormous, and the FDA will pay close attention to that. The applicant argues that available data show very low systemic exposure of the locally delivered product, but reviewers cautioned that release rates of the drug from the polymer and potential exposure to the blood circulation after injection have yet to be considered. Reviewers advised that the release rate of the drug from the polymer be investigated, and strongly recommended that oncogenic effects of the candidate molecule be interrogated in the toxicity studies. They did acknowledge the difficulty of identifying the appropriate animal model for those studies.
- The targeted patient population is appropriate.
- The data provided support the project status on the therapeutic scorecard, and there is compelling evidence to progress to IND-enabling studies.
- Scale-up of compound production has been completed, however the good manufacturing practice (GMP) process must still be developed and validated. This may slow the progression to IND application and clinical trial.
- Reviewers differed in their assessment of the proposed clinical end points; some felt there was a need to more clearly define them, whereas others were convinced they will, as proposed, provide important data to support the design of a Phase III trial.
- It is not clear that the proposed activities can be achieved in four years; many of the development activities have not yet been completed, and it is unrealistic to accomplish the planned IND-enabling studies in the proposed time frame.
Principal Investigator (PI) and Planning Leader
- The Principal Investigator (PI) has relevant experience, is a member of the team that has developed the proposed therapeutic approach and is well placed to lead this project. The PI has led several clinical investigations through IND application and into clinical trials.
- The Planning Leader is a medicinal chemist with industrial experience and some experience in leading projects through IND-enabling studies but does not have clinical research experience.
- Programmatic Review
- A motion was made to move this application into Tier 1, Recommended for Funding. The panel reiterated the possible safety issues associated with a very potent Wnt pathway agonist, but also acknowledged that the overall environment and expertise at the applicant institution provides some confidence that this issue will be appropriately addressed. Panelists further cautioned that injections into the spine may not be embraced by patients who have less invasive options. However, from a surgical perspective, the proposed treatment should be considered feasible and relatively safe. The treatment of compression fractures presents an enormous unmet need and the proposed approach is an exciting one. The motion carried.