Bone or Cartilage Disease

Coding Dimension ID: 
279
Coding Dimension path name: 
Bone or Cartilage Disease

Increasing the endogenous mesenchymal stem cells to the bone surface to treat osteoporosis

Funding Type: 
Disease Team Therapy Planning I
Grant Number: 
DR2-05302
ICOC Funds Committed: 
$110 000
Disease Focus: 
Bone or Cartilage Disease
oldStatus: 
Closed
Public Abstract: 
Although most individuals are aware that osteoporosis is disease of increased bone fragility that results from estrogen deficiency and aging, most are unaware of the high risk and cost of the disorder. It is estimated that close to 30% of the fractures that occur in the United States each year are due to osteoporosis (Schwartz & Kagan (2002). California, with one of the largest over-age-65 populations, is expected to double the fracture rate from 1995 to 2015 (Schwartz & Kagan 2002). One study places the cost per year in osteoporotic fractures at 2.4 billion dollars (Schwartz & Kagan 2002), establishing it as one of the highest health care costs for older individuals. The prevalence of osteoporosis is projected to increase with increasing lifespan globally both from age related bone loss and from secondary causes of bone loss including inflammatory diseases and cancer. In additional, medications used for the treatment of cancer and inflammatory diseases can also induce bone loss. Current treatment of osteoporosis is focused on agents that prevent further bone loss such as the bisphosphonates or selective estrogen modulators. The only bone growing agent that is approved by FDA is the protein, hPTH 1-34, which requires two years of daily injections and is only effective in about 60% of treated individuals. We have developed a small molecule, LLP2A-Alendronate that augments the homing of endogenous mesenchymal stem cells (MSCs), the cells that have the potential to grow bone tissue, to the bone surface and form new bone. Therefore, we plan to file IND in the next sin months and we will perform two clinical trials to test its safety and efficacy in two clinical trials in the next fours years. Yrs. 1-2: Phase I clinical trial. To determine if LLP2A-Ale is safe when used in patients with osteoporosis. After this phase I study, our research group will decide on two or three doses of LLP2A-Ale and two dosing regimens and will perform a phase II clinical trial. Yrs. 3-4: Our phase II clinical trials will evaluate the efficacy of LLP2A-Ale in patients with osteoporosis The primary endpoint will be bone mineral density measured by DEXA of the lumbar spine and hip and biochemical markers of bone turnover, also calciotrophic hormones of bone metabolism (Vitamin D, FGF23, Sclerostin, IGF-1,and sclerostin,etc). Secondary clinical study endpoints will include a detailed assessment of the quantity of new bone formed and its distribution throughout the skeleton with XtremeCT, a new high-resolution 3 dimensional bone scan that allows regular follow-up measurements with software that automatically matches cortical and trabecular bone regions (SCANCO Medical microCT Systems) at 3 month intervals and bone biopsies performed at the iliac crest after treatment is completed. All the patients in the trials will be followed at 3 month intervals for 2 years.
Statement of Benefit to California: 
Osteoporosis is a disease of the elderly that results from a process of age related bone loss that renders the bone fragile such that it breaks with very little force. Current osteoporosis treatments have relatively good efficacy in improving bone strength and reducing incident fractures, however these agents ( anti-resorptive agents or the anabolic agent rhPTH (1-34) only reduce the risk of hip fractures by 40%, and require years of treatment to be effective. The goal of this project is to increase bone homing of the endogenous MSCs with a novel compound to form new bone as a novel treatment for osteoporosis. A compound that could cure osteoporosis with only 3-4 injections of an agent that mobilized MSCs to build bone would be highly competitive in this market as the efficacy of increasing bone mass and bone strength would be high and the risks in a very acceptable range. This agent would be effective in patients with primary osteoporosis defined by very low bone mass or low trauma fractures, in patients with secondary osteoporosis due to long term glucocorticoid treatment or after chemotherapy in both men and women and to augment peak bone mass in adolescents. The market potential for bone tissue regeneration is large, an estimated two million fractures and $19 billion in costs annually. By 2025, experts predict that osteoporosis will be responsible for approximately three million fractures and $25.3 billion in costs each year (publication from National Osteoporosis Function). The osteoporotic patients spend about $10 a month for the generic version of Fosamax, at the lower end, to about $80 a month for brand-name Fosamax or Actonel to $900 or more a month for Forteo (huPTH (1-34).A compound that could cure osteoporosis with only 3-4 injections of an agent that mobilized MSCs to build bone would be highly competitive in this market as the efficacy of increasing bone mass and bone strength would be high and the risks in a very acceptable range. Once validated in osteoporosis patients, this form of tissue regeneration will be useful for children in whom current osteoporosis medications is contraindicated, individuals who have had radiation to their skeletons, and to augment fracture healing in the elderly. The market potential for bone tissue regeneration is large as it is estimated that close to 1/3 of fractures that occur in the US each year are due to osteoporosis (Schwartz & Kagan (2002). California, with one of the largest over-age-65 populations, is expected to double the fracture rate from 1995 to 2015 (Schwartz & Kagan 2002). One study places the cost per year in osteoporotic fractures at 2.4 billion dollars (Schwartz & Kagan 2002), establishing it as one of the highest health care costs for older individuals. The prevalence of osteoporosis is projected to increase with increasing lifespan globally both from age related bone loss and from secondary causes of bone loss including inflammatory diseases and cancer.
Progress Report: 
  • The purpose of our Disease Team planning grant was to develop a solid Clinical development program for our compound, LLP2A- Ale that directs mesenchymal stem cells to the bone marrow and stimulates new bone formation.
  • We published our scientific findings in the Journal Nature Medicine (2012 March issue). Our research team developed a clinical development program that included producing compound, performing toxicity studies, and a clinical development plan for a Phase I study. We also submitted an IND for the FDA, the FDA responded to our clinical development program and questions we raised, and we had a teleconference with the FDA CDER group on January 31st, 2012.
  • We have obtained sufficient information from the FDA on our IND to begin producing our compound for toxicity studies. In addition, we participated in a Stem Cell Awareness Public Forum at UC Davis in which we displayed our work with the mesenchymal stem cells to build new bone.

Clinical Development of an osteoinductive therapy to prevent osteoporosis-related fractures

Funding Type: 
Disease Team Therapy Planning I
Grant Number: 
DR2-05368
Investigator: 
ICOC Funds Committed: 
$99 110
Disease Focus: 
Bone or Cartilage Disease
oldStatus: 
Closed
Public Abstract: 
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.
Statement of Benefit to California: 
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.
Progress Report: 
  • This project is working to advance a first-in-class, small molecule Wnt pathway activator through IND-enabling and Phase I/II clinical studies for treatment of osteoporotic hip fractures. During this reporting period, quotes were solicited from drug manufacturing companies for the manufacture of the drug compound, a manufacturer was selected and the drug is presently in the GMP manufacturing process. In addition, international thought leaders were identified to act as clinical consultants and with their input the outline of a Phase I/II clinical trial plan was drafted and submitted to the FDA for comment. Beyond that, a pre-IND briefing document was prepared that described the clinical product’s known pharmacology, pharmacokinetic, toxicology and chemical characteristics. After preparing and submitting the clinical plan outline and pre-IND briefing document to the FDA, the team had a successful pre-IND meeting on January 30, 2012. IND filing is proposed for the first half of 2013. Currently, quotes have been requested for contract research organizations (CROs) who offer appropriate preclinical fracture model studies and a decision on the most suitable vendor for the study will be determined shortly.
  • In addition, the CIRM disease team application detailing known properties of the drug, along with a 4 year development plan and associated budget was drafted and completed during the reporting period.

Genetically Engineered Mesenchymal Stem Cells for the Treatment of Vertebral Compression Fractures.

Funding Type: 
Disease Team Therapy Planning I
Grant Number: 
DR2-05288
ICOC Funds Committed: 
$109 743
Disease Focus: 
Bone or Cartilage Disease
oldStatus: 
Closed
Public Abstract: 
Osteoporosis is an unsolved and highly prevalent health care problem: 10 million Americans suffer from the disease, and an additional 34 million have low bone mass. Roughly half of all women and a fourth of all men older than 50 years will sustain an osteoporosis-related fracture at some time in their lives, and when such a fracture occurs, the chances of death within 12 months are about 1 in 5. Osteoporotic fractures can take several forms, but VCFs (vertebral compression fractures) occur at a rate of 700,000 per year—twice the rate of hip fractures. The economic burden of osteoporotic fractures is tremendous. In 2001, there were approximately 1.5 million osteoporosis-related fractures in the US at a cost of $17 billion, or approximately $47 million per day. Currently, treatment is focused primarily on prevention. When fractures occur in patients with osteoporosis, treatment options are limited because open surgery with implants often fails. Recently, new therapies involving injection of cement into the vertebral body were developed. Unfortunately, these procedures do not regenerate bone tissue, but do incur risks of leakage and emboli. Moreover,recent publications in leading scientific journal question the effectiveness of those procedures. Hence, we need new biological treatment that will promote repair of such fractures in a safe and efficient manner. We propose to develop a therapy that exploits MSCs (mesenchymal stem cells) that are genetically engineered to express a bone-inducing gene, bone morphogenetic protein-2 (BMP-2). Those cells have been shown to induce bone formation and fracture repair in numerous studies in animal models. Specifically, we intend to use allogeneic ("off the shelf") human MSCs. These cells will be genetically engineered with a BMP-2 gene using a technology based on short electric pulses. BMP-2 engineered MSCs have an advantage in bone repair since they become bone cells by themselves and recruit additional cells from the environment. This synergistic effect leads to accelerated and robust bone formation, which could be an attractive therapy for a variety of clinical conditions involving bone lose. An image-guided injection of BMP-2 engineered MSCs to a fractured vertebra could be an attractive treatment that would lead to rapid fracture repair and shortening of hospitalization time. We propose to use off-the-shelf MSCs that do not require the patient to undergo additional medical procedure such as bone marrow aspiration. In addition, the use of allogeneic cells is not limited by cell number, as could be the case for autologous cells, that are taken from the patient. If successful, this therapeutic strategy could revolutionize the treatment in osteoporsis patients, offering a minimal-invasive, biological solution. We plan to analyze aspects of efficiency and safety of the proposed therapy in a pre-clinical model, that will enable us to submit an approvable IND to the FDA by the end of the 4-year project.
Statement of Benefit to California: 
Approximately 10 million people in the United States are diagnosed as osteoporotic, while an additional 34 million are classified as having low bone mass. 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. Vertebral compression fractures (VCFs) are the most common fragility fractures in the United States, accounting for approximately 700,000 injuries per year, twice the rate of hip fractures. Approximately 70,000 VCFs result in hospitalization each year with an average hospital stay per patient of 8 days. Fragility fractures due to osteoporosis also place a severe financial strain upon the health care industry. Estimates show there were approximately 1.5 million osteoporosis-related fractures in the United States in 2001, the care of which cost about $17 billion. Moreover, as the number of individuals over the age of fifty continues to increase, costs are predicted to rise to an estimated $60 billion a year by the year 2030. VCFs have previously received limited attention from the spine care community. This oversight may be a result of the perception that VCFs are benign, self-limited problems or that treatment options are limited. However, it has become clear that VCFs are associated with significant physiologic and functional impairment, even in patients not presenting for medical evaluation at the time of fracture. Current treatment of osteoporotic patients is mostly focused on prevention of VCFs. There are a few options of treatment when VCFs actually occur. Since open surgery involves morbidity and implant failure in the osteoporotic patient population, nonoperative management, including medications and bracing, is usually recommended for the vast majority of patients. Unfortunately, large numbers of patients report intractable pain and inability to return to activities. Currently there is no efficient biological solution for the treatment of VCFs. The proposed study will further develop a biological therapeutic solution that will accelerate repair of VCFs. The treatment will rely upon adult stem cell that are genetically engineered to overexpress an osteogenic gene, BMP-2, using a non-viral technique that is currently in clinical trials. It will also involve an injection of the cells into the fracture site, instead of a percutaneous injection of a polymer, which does not restore lost bone tissue. Data generated form this study could potentially revolutionize the treatment of vertebral fractures and other complex fractures in patients suffering from osteoporosis, and so 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 VCFs.
Progress Report: 
  • Approximately 10 million people in the United States are diagnosed as osteoporotic, while an additional 34 million are classified as having low bone mass. The lifetime incidence of fragility fractures secondary to osteoporosis in females over the age of fifty years of age is approximately 1 in 2, and in males over the age of fifty, is 1 in 4. Vertebral compression fractures (VCFs) are the most common fragility fractures in the United States, accounting for approximately 700,000 injuries per year, twice the rate of hip fractures. Approximately 70,000 VCFs result in hospitalization each year with an average hospital stay per patient of 8 days. There are limited options of treatment when VCFs occur. New, non-biological, methods have been developed to regain the biomechanical properties of a fractured vertebral body. These methods include the minimally invasive procedures of vertebroplasty and balloon tamp reduction. Both procedures involve injection of synthetic nonbiological material that does not resorb and instead remains a permanent foreign-body fixture in the spine. Ultimately, a biological solution that would promote rapid fracture healing and stimulate normal bone production would be the best for osteoporotic patients with vertebral column injuries. Our goal is to develop a novel therapy for VCFs, which will be based on adult stem cells, isolated from bone marrow samples. These cells will be "triggered" to form bone by the activation of a specific gene and then injected into the fractured vertebra leading to fast fracture repair. The funding from the planning award allowed us to establish a highly experienced team, from the academy and industry, that would be able to bring the proposed therapy to clinical use. In addition, we assembled a comprehensive development plan that described in detail the studies and steps required to obtain an approval from the FDA in order to begin clinical trials. Furthermore, we have negotiated and obtained commitment from several biotech companies, which will provide the necessary materials and facilities to perform the studies described in the development plan. Our proposal for a Disease Team Therapy Development Award was submitted in January 2012. If awarded, we will be beginning the pre - clinical studies in August 2012.

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