Funding opportunities

Directed differentiation of MSCs by a novel biologic to promote cartilage repair

Funding Type: 
Disease Team Research I
Grant Number: 
Funds requested: 
$20 000 003
Funding Recommendations: 
Not recommended
Grant approved: 
Public Abstract: 
The ability to direct the differentiation of resident mesenchymal stem cells (MSCs) towards the cartilage lineage offers considerable promise in regenerative medicine of articular cartilage after traumatic joint injury or aging-related osteoarthritis (OA). MSCs can be stimulated in vitro to form new functional cartilage. In the OA-affected joint, the repair is insufficient, leaving a damaged matrix suggesting key factors are missing to properly direct the regenerative process. Molecules that activate this potential of cartilage stem cells potentially can prevent further cartilage destruction and stimulate repair of cartilage lesions. Currently there are no disease-modifying therapeutics available for the 40 million Americans suffering from OA. Therapeutic options are limited to oral and intra-articularly injected pain medications and joint replacement surgery. The primary objective of this project is to develop a non-invasive, universal therapeutic for the regeneration of cartilage at any stage of OA. This new therapy will target the resident MSCs in the joint, stimulate production of new cartilage matrix, promote repair and thus limit additional joint damage and improve joint pain and function. From cell-based screens of a unique library of secreted proteins, novel candidates enhancing the formation of articular cartilage (chondrogenesis) from MSCs in vitro were identified. In secondary assays, proteins were assessed for protection of the existing cartilage against induced tissue damage. Through these approaches, the proposed biologic therapeutic OTX-75 was identified to potently promote cartilage differentiation and protect cartilage from inflammatory mediators. Following intra-articular injection in mouse and rat knees, OTX-75 localized to the pericellular matrix, thus reaching the cells in the joint cartilage. OTX-75 did not cause any unwarranted effects in joint tissues or immune responses after 4 weeks. We determined that the chondrogenic activity localizes to the C-terminal domain and subsequently solved its crystal structure. Here we aim to demonstrate the ability of OTX-75 to repair cartilage in vivo in experimental OA in rat, and 2 large animal models. We will characterize the biological activities and identify the binding partners of OTX-75 and its C-terminus as a potential back-up strategy to minimize off-target effects or systemic toxicity. This protein will be developed to meet therapeutic production standards for use in humans and verified for the lack of adverse events. The development of specific biomarkers will allow monitoring of mechanism of action-based efficacy in vivo. These data and reagents will allow the filing of an Investigational New Drug application by the end of the funding period. Successful completion of the program has the potential to lead to the first effective disease-modifying therapy for the approximate 7% of the US population suffering from osteoarthritis.
Statement of Benefit to California: 
Osteoarthritis (OA) is the most prevalent musculoskeletal disease and globally the 4th leading cause of Years Lost to Disease (YLD). OA affects over 40 million Americans and the magnitude of the problem is predicted to increase even further with the obesity epidemic and aging of the baby boomer generation. It is estimated that 80% of the population will have radiographic evidence of OA by age 65 years. The annual economic impact of arthritis in the U.S. is estimated at over $100 billion, representing more than 2% of the gross domestic product. It accounts for 25% of visits to primary care physicians. In 2004 OA patients received 650,000 knee and hip replacements at a cost of $26 billion. Without change in treatment options 1.8 million joint replacements will be performed in 2015. OA is a painful, degenerative type of arthritis; physical activity and working can become difficult or impossible. Some patients with osteoarthritis are forced to stop working because their condition becomes so severe and limiting. OA can interfere with a patient's ability to even perform routine daily activities, resulting in a decrease in quality of life. The goals of osteoarthritis treatment are to relieve pain and other symptoms, preserve or improve joint function, and reduce physical disability. Current therapeutic options are limited to pain medications and joint replacement for patients with advanced disease. No disease-modifying OA drugs are approved for clinical use. The OA problem is thus unparalleled with its clinical and socioeconomic impact and a complete absence of effective therapies. This proposal is aimed at advancing a novel disease-modifying OA drug to the clinic within 4 years. The candidate therapeutic mitigates the underlying cause of OA – specifically joint destruction from abnormal activation and differentiation of cartilage cells. This therapeutic has been developed to act on the resident stem cells, already present in the joint of both normal and diseased joint cartilage, and stimulate the regeneration of cartilage – leading to the improvement of joint function. The development of the novel therapeutic that improves the symptoms and underlying causes of OA would have a significant impact on the well-being of patients and reduce the economic impact resulting from this highly prevalent disease.
Review Summary: 
The goal of this proposal is to develop a novel protein therapeutic for treating osteoarthritis (OA) by promoting regeneration of damaged cartilage in affected joints. This new therapy would target the resident mesenchymal stem cells (MSCs) in the damaged area and direct their differentiation towards lineages that stimulate the production of new cartilage matrix. To bring this drug to the clinic, the applicants have proposed a series of tasks and milestones that would culminate in the filing of an Investigational New Drug application (IND). Initial efforts would be directed towards demonstrating efficacy in preclinical models of OA and characterizing the biological activity and toxicity of the lead candidate. The applicants would then focus on deriving the cell lines to be used for manufacture of the clinical product and completing single dose toxicology studies. In the third year, GMP production of the therapeutic would begin. The final year would be dedicated to obtaining the IND and preparing for a Phase I/Phase II clinical trial. Beyond these primary goals, the applicants propose a series of aims to create reagents, define biomarkers and identify the biological target of the therapeutic. Despite an intriguing rationale and a strong team, the reviewers were not convinced that the proposed therapy is sufficiently mature to warrant clinical translation under the terms of this award. While the development plan addressed the necessary elements for an IND filing, a number of open questions remained regarding the identity and efficacy of the candidate as well as the suitability of the preclinical models. Reviewers also deemed several of the proposed activities extraneous to obtaining an IND and felt the milestones were suboptimal. As a result, the reviewers doubted the overall feasibility of this effort did not recommend this proposal for funding. In general, reviewers appreciated the rationale for use of a protein therapeutic to mobilize endogenous stem cells for regenerative purposes in an arthritic joint. However, there was some uncertainty as to the extent that the proposed biologic, OTX-75, would exert its effects through such a mechanism. For example, one reviewer noted that in addition to stimulation of resident stem cells, OTX-75 might contribute to cartilage synthesis indirectly through an anti-inflammatory process. Regardless of the precise mechanism, the reviewers agreed that the clinical and practical significance of such a therapy would be substantial. There is a strong unmet need for better treatment of OA, the most common musculoskeletal disorder and one that significantly impacts the quality of life. As there are currently no disease-modifying drugs on the market that specifically target OA, the majority of its sufferers must resort to surgery or palliative care. From a clinical perspective, the reviewers highlighted several advantages the proposed approach may offer over competing methodologies. First, direct injection of OTX-75 into an affected joint could allow more efficient targeting of the therapeutic than would be afforded by an oral route. Second, this approach is well suited to administration in a primary care setting and in a cost-effective manner, two considerations that are important to the patients that are targeted for this treatment. Finally, OTX-75 does not appear to promote osteogenic activity, thereby lessening the risk of calcification or other unwanted effects. While there are several other candidates in clinical testing or preclinical development, OTX-75 may offer advantages in one or more of these key areas. The reviewers expressed significant concerns about the feasibility and maturity of the preclinical research and development plan. First, most of the preliminary data were obtained using the mouse OTX-75 and not the human molecule that is the actual drug candidate. More troubling, however, was the lack of data demonstrating efficacy in a disease model of osteoarthritis. Thus, despite data suggesting that OTX-75 is retained in the joint following intra-articular administration, it was not clear whether such levels would be efficacious or even available to the targeted cell population. The reviewers were also left to wonder whether the environment of a chronically damaged joint could potentially impede the functional organization of cartilage, or whether forcing differentiation of resident MSCs might compromise their ability to mediate other functions. While these concerns were considerable, the reviewers appreciated the elegant studies that led to the identification of OTX-75 and felt that the evidence that OTX-75 can drive chondrogenesis in vitro was compelling. Nonetheless, some reviewers desired stronger evidence that this mechanism is effected through MSCs, for example through a comprehensive analysis of gene expression changes that occur in response to OTX-75. They also recommended a thorough histological characterization of the OTX-75-treated tissues in order to more convincingly exclude the presence of osteogenic precursors that could potentially lead to a fibrogenic phenotype. The reviewers felt the applicants addressed all of the critical elements that would be required to obtain an IND in the appropriate time frame. Nonetheless, several risks were identified that compromised this approach. First, the final identity of the therapeutic remains to be determined, as multiple forms of the protein will be assessed. Moreover, reviewers expressed dissatisfaction with the preclinical models upon which the development plan depends. For example, the proposed meniscal tear models do not necessarily reflect the idiopathic disease of the clinical target and complicate distinction of the effects of OTX-75 from the indirect effects of meniscal healing. The reviewers were also disturbed by the lack of concrete plans to obtain critical FDA feedback from the earliest stages of this effort, especially as the IND may require inclusion of efficacy data obtained with species-specific, rather than human protein. The FDA could also provide advice regarding immunogenicity studies that may prove necessary, particularly if the selected culture system contributes novel epitopes or glycosyl profiles to the candidate. Beyond these concerns, the reviewers identified several experiments and activities that they considered outside the scope of this RFA. First, the efforts aimed at developing truncated and mutated forms of OTX-75 were viewed as drug discovery approaches that should be eliminated or refocused towards developing only the most mature and promising lead(s). Second, the proposed identification of biomarkers, although potentially of interest for early studies, were of uncertain value for clinical use and were therefore not viewed as germane. Finally, the plan to identify the molecular targets of OTX-75 was viewed as pure discovery research. In the end, reviewers found these activities to be distractions that could dilute the focus of the investigators and thereby undermine the feasibility of this effort. The reviewers expressed mixed feelings about the proposed milestones and timelines. While most appeared reasonable with appropriate no/go decisions, the overall strategy for prioritization was questioned. Rather than devoting initial efforts to the mouse protein, reviewers felt that the true go/no decision should revolve solely around demonstrating efficacy of either of the two forms of human OTX-75. Furthermore, efforts towards validating and selecting the lead human candidate should advance to the earliest stages of this project. Prior to initiating the lengthier, more risky and expensive studies in the OA models, reviewers suggested that the applicants verify candidate protein activity in vitro using the appropriate animal cells. Finally, the milestones relating to target and biomarker identification were deemed nonessential. In their stead, some reviewers suggested a histological exploration of treated joints would be useful, particularly as this analysis could inform the development of relevant clinical end-points. The reviewers uniformly praised the qualifications and expertise of the research team. The principal investigator (PI) has established a worldwide reputation and solid publication record in osteoarthritis research. Each co-PI was found to bring unique qualifications to the team with clearly defined roles and laudable levels of commitment. In terms of the leadership plan, the reviewers were generally satisfied that all elements were in place to ensure coordination of activities across the team, enable strategic decisions to be implemented and to resolve any potential conflicts that should arise. However, they emphasized that the applicants should engage regulatory consultants both earlier in the program and more frequently, rather than relegating this potentially critical input to its later stages. From the leadership plan, it was not clear who would drive this interaction. A second concern was the budget. Although the expenses were deemed appropriate for the activities as proposed, several reviewers objected to the allocation of funds for the discovery-based research that they considered out of bounds for this RFA. The reviewers unanimously agreed that the resources available to this Disease Team are outstanding. Both collaborating institutions are integral to proposed work and provide key ingredients such as administrative support, necessary infrastructure and pertinent experience with translational projects. The contract research organizations that would provide the preclinical modeling and protein manufacture were both judged to be excellent. While strong letters of collaboration were in place, some reviewers desired a more explicit accounting of the processes for technology transfer to the contractors for clinical development. Nonetheless, the reviewers felt these combined assets added tangible strength to the quality of this application. Overall, this proposal represents an intriguing and practical approach for addressing an important and unmet medical need. Despite a strong team and logical development plan, the reviewers felt that the project lacked the necessary maturity and feasibility to ensure timely clinical translation.
  • Darin Weber

© 2013 California Institute for Regenerative Medicine