Disease Team Therapy Planning I
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.
EXECUTIVE SUMMARY Project synopsis This proposal targets the treatment of osteoporosis by enhancing bone formation. The proposed therapeutic candidate consists of a synthetic molecule, LLP2A-Ale, which has been designed to enhance homing of endogenous mesenchymal stem cells (MSCs) from the bone marrow to the bone surface. Since MSCs have the ability to differentiate into bone forming (osteogenic) cells, they are then hoped to form new bone, thereby overcoming bone fragility that occurs due to bone loss. The applicant plans to conduct a Phase I and a Phase II trial during the Research Award period with osteoporotic post-menopausal women as study subjects. Significance and Impact - Due to the prevalence of osteoporosis over the age of 50 and the associated health care costs, the development of a new and efficacious product warrants consideration. - Although the proposed product is not expected to be more potent than existing products in the restoration of bone mineral density in osteoporosis patients, it does have a real market potential. - LLP2A-Ale appears to have the potential to provide a cost advantage over standard of care treatments, although this is hard to predict this early in the development process. - The proposed product would only require a few injections rather than repeated daily dosing, thus ensuring compliance. This would be a significant advantage over existing treatments. - The proposed product could potentially be extended for use in children, which is not possible with existing therapies. - The Target Product Profile (TPP) is reasonably well articulated, the targeted patient population is appropriate, and clinical study parameters have been defined. - A single therapeutic candidate that meets the RFA’s criterion as an eligible therapeutic approach is proposed. A reviewer pointed out, though, that although LLP2A-Ale is thought to mobilize endogenous osteogenic stem cells to the bone-forming surface, this has not been demonstrated experimentally, and thus it remains unknown whether the mechanism of action involves endogenous stem cells. Project Rationale and Feasibility - The theoretical rationale for this therapeutic intervention is strong, and the concept underlying the molecule’s design is very innovative. - Preliminary in-vitro and in-vivo data is impressive. The efficacy of LLP2A-Ale has been demonstrated in mice, making a reasonably convincing case that the compound could be efficacious in the treatment of post-menopausal osteoporosis. The in vitro data for enhanced osteogenesis of MSC are convincing, but important data on the claimed absence of a chondrogenic effect were not included. - Preliminary data on human (rather than only mouse) MSC expressing the relevant LLP2A-binding surface protein and responding to LLP2A-Ale with increased osteogenic differentiation and maturation would have strengthened this proposal. Because of conflicting reports in the literature, evidence of relevant surface protein expression in human MSC will be critical for the Research Award application. - The proposed human dosing regimen is based on studies in mice only. The acquisition of pharmacokinetic and -dynamic data in the ongoing non-rodent studies is essential for establishing first in human dose. - It was not clear to reviewers whether clinical trial material stability has been determined. - No adverse effects on relevant organs and other parameters were observed with LLP2A-Ale in mice and critical safety studies using a non-rodent animal model are in progress. - It is unknown whether homing of MSC by LLP2A-Ale would be directed specifically to areas of bone loss. Non-specific targeting of the MSC to healthy bone surfaces and other tissues may result in significant adverse effects. - Reviewers noted that data from on-going efficacy, specificity and toxicity studies as proposed can be available in support of a timely Investigational New Drug (IND) application filing, though the applicant does not clearly indicate when these studies will be completed and the IND filed. - It was recommend that a pre-IND meeting with the Food and Drug Administration (FDA) be conducted prior to initiation of Good Laboratory Practic (GLP) toxicology studies or, if these studies have already commenced, prior to filing of the IND. - The applicant did not provide a clear plan to meet the Phase I objective of demonstrating safety of 6 monthly injections and a sufficiently detailed Phase I timeline was absent. Reviewers expect that the Phase I study might take longer than proposed and recommended to plan a Phase I study only should a full application be submitted. - The potential immunogenicity and tumorigenicity of the candidate molecule has not been discussed. A reviewer expressed the opinion that these issues can be easily worked out in the ongoing studies. Principal Investigator (PI) and Planning Leader - The Principal Investigator (PI) is an experienced physician and an internationally recognized expert in musculoskeletal diseases with extensive experience in preclinical models for osteoporosis and osteoarthritis, in translational research and in clinical trials, and is well qualified to lead this project. - The Planning Leader (PL) has a strong scientific background in musculoskeletal research. Although the PL appears to be well capable of performing translational studies, experience with designing IND-enabling studies is not apparent. The PL does not have much supervisorial experience. - Reviewer suggestion: It may be important to recruit a qualified, industry experienced project manager to work with the PL, or as the PL, to move the project on to milestone driven, go/no go stages.