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). Current treatment of osteoporosis is focused on anti-resorptive agents that prevent further bone loss. These agents and are effective in reducing new vertebral fractures but less effective for the prevention of hip fractures, and the duration of use of one anti-resorptive class, the bisphosphonates, is limited due to a concern about weakening of the cortical bone with longterm use. The only bone growing agent that is approved by FDA is the protein, hPTH 1-34, which requires two years of daily injections, is only approved by the FDA for one course of treatment, is only effective in about 60% of treated individuals for reduction of vertebral fractures, and has not been shown to be effective in reducing new hip fractures. This leaves an unmet medical need for an anabolic or agent that stimulates bone formation for millions of elderly Californians that suffer or will suffer from this disease.
We have developed a small molecule, LLP2A-Ale that directs endogenous mesenchymal stem cells (MSCs), the cells that have the potential to grow bone tissue, to the bone surface to form new bone. We propose a development plan for this small molecule, LLP2A-Ale for the treatment of osteoporosis in both postmenopausal women and men.
Yrs. 1-2: These 2 years will be spent with optimizing the manufacturing and packaging of the small molecule, obtaining information about the efficacy and toxicity in preclinical models, and preparing documents for an FDA meeting when the preclinical studies are completed to provide comment on the proposed Phase I clinical trials.
Yrs. 3-4. We plan perform a Phase I study with two parts. Part I will study postmenopausal women with osteopenia and a fracture risk (3% for hip fracture and 20% for major nonvertebral fractures over the next 10 years). After the initial Phase I study in postmenopausal women we will perform Part 2 and study both postmenopausal women and men with similar inclusion and exclusion criteria. The primary endpoint of these studies will be change in biochemical markers of bone turnover (PINP, BSAP, osteocalcin), and secondary endpoints will be bone mineral density of the lumbar spine measured by DXA and trabecular bone volume measured by QCT. The Phase I trials will also include required pharmacokinetic and pharmacodynamic measures to obtain information about the action of this small molecule and to inform us for Phase II clinical studies in the future.
Osteoporosis is a disease of the elderly that results from a process of age related bone loss that renders the bone fragile. Current osteoporosis treatments have relatively good efficacy in reducing incident fractures. However these agents (anti-resorptive agents or the anabolic agent rhPTH (1-34) only reduce the risk of vertebral fractures about 60%, and hip fractures only 40%, and these agents require years of treatment to be effective. The goal of this project is to increase bone homing of the endogenous MSCs with a small molecule (LLP2A-Ale) to form new bone as a novel treatment for osteoporosis that could cure osteoporosis with only 3-4 injections by mobilizing the endogenous MSCs to build bone. Our molecule 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.
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. The market potential for bone tissue regeneration is large, an estimated 2 million fractures and $19 billion in costs annually. By 2025, experts predict that osteoporosis will be responsible for approximately 3 million fractures and $25.3 billion in costs each year (publication from National Osteoporosis Foundation). 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 (rhPTH (1-34).
Therefore, once validated in osteoporosis patients, this form of tissue regeneration would be effective in patients with primary osteoporosis, 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 children in whom current osteoporosis medications are contraindicated, in individuals who have had radiation to their skeletons in whom rhPTH (1-34) is contraindicated and to augment fracture healing in the elderly. Our agent would have the potential to save the State of California millions of dollars in health care and would allow these osteoporotic individuals to live longer and be independent longer.
This application proposes to develop a small molecule that promotes new bone growth for the treatment of osteoporosis through the clinical proof of concept. The molecule, LLP2A-Ale, is designed to direct endogenous mesenchymal stem cells (MSC) to the bone surface and promote their differentiation into bone forming cells (osteoblasts). Osteoporosis affects over 75 million people worldwide, and in the US 40% of women over 50 and 13% of men will experience an osteoporotic fracture in their lifetime. The applicants plan to develop assays, perform preclinical safety and efficacy studies in relevant animal models, perform the IND-enabling studies required by the FDA, complete scale up of cGMP manufacturing of drug substance, and initiate and complete Phase I/II clinical studies in osteoporotic subjects.
SIGNIFICANCE AND IMPACT
-It is currently estimated that the number of Americans with osteoporosis is predicted to increase to 61.4 million by the year 2020. This growing burden to patients, their families and the economy is only partially addressed with available therapies.
-There are several approved therapeutics for osteoporosis that increase bone mass by reducing bone turnover, but these do not stimulate bone remodeling or form new bone. The only currently approved treatment that actually increases bone formation requires costly, inconvenient daily subcutaneous injections for 2 years and is limited to one course of therapy. If successfully developed, the proposed therapeutic would build bone, only require occasional intravenous dosing and thereby have a huge positive impact upon both disease and quality of life.
-Reviewers appreciated that this novel small molecule drug was specifically designed to mobilize endogenous MSCs to the bone surface and to direct their differentiation to osteoblasts which will promote new bone growth.
-Reviewers agreed with the applicants’ rationale for clinical development of the proposed therapeutic in osteoporotic subjects and found it to be strongly supported by peer reviewed publications as well as numerous in vitro and in vivo studies.
THERAPEUTIC DEVELOPMENT READINESS
-This team has conducted preliminary discussions with the FDA and have incorporated the regulators’ suggestions into their development plan.
-Reviewers found in vivo data showing increased bone mass in a mouse model of osteoporosis to be compelling and supportive of the program's readiness.
-The panel also appreciated strong, in vitro data showing that LLP2A-Ale increased MSC migration and osteoblastic differentiation, consistent with the proposed mechanism of action.
-The milestones were well described, and the majority of the reviewers agreed that a 4-year timeframe is reasonable for completion of the study.
-The team has identified potential toxicities and has appropriately addressed these issues in their preclinical models and trial monitoring plans.
FEASIBILITY OF THE PROJECT PLAN
-The fact this team has already had positive discussions with the FDA buoyed reviewer confidence that this project was feasible in the 4 year time frame.
-Reviewers appreciated the completeness of the applicants’ preclinical plans (well defined toxicology models, relevant preclinical model for dose ranging, etc) to support a successful IND filing.
-The group noted that significant work remains to be done to enable successful IND submission including characterization of raw material purity, assay development and scale up of LPP2-Ale production.
PRINCIPAL INVESTIGATOR AND DEVELOPMENT TEAM
-PI is a renowned leader in the field and has extensive research and clinical experience in osteoporosis; however, the PI’s experience in leading a small molecule drug development program appears limited.
-The Co-PI has extensive experience and publications in preclinical animal models of bone disease/injury. However, reviewers expressed concern about whether the Co-PI had sufficient development experience to supervise the GMP manufacturing and non-GLP pivotal safety studies. The panel further noted that the team would benefit from a professional project manager with product development experience.
COLLABORATIONS, RESOURCES AND ENVIRONMENT
-This molecular entity was discovered by the PI and team; intellectual property is held by the applicant institution.
-The research team has selected a successful, experienced consulting agency to provide input on technical support and management of the IND-enabling studies. Additionally, they using a toxicology lab that has specific expertise in bone toxicology.
-Additionally, the team has identified appropriate resources for production and analysis of custom cGMP grade peptides.
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 major issues raised.
- David Pepperl
- Joy Cavagnaro