Disease Team Therapy Development III
$13 277 369
Recommended if funds allow
The goal is to bring a safe and effective therapy to adult patients with critical narrowing of the upper windpipe (trachea) and lower voicebox (larynx). Our intent is to implement all of the necessary steps for a successful new stem/progenitor cell-derived airway transplant for later stage clinical trials and/or commercialization within 4 years. Our team builds on first-in-human surgical successes with stem cell-based tissue engineered airway implants in compassionate use cases in adults and children. To this end, we will perform the necessary preclinical studies to support a successful IND application within 2 years, followed by a Phase I trial in 10 patients with 1 year of follow-up. We propose to use stem/progenitor cells from the patients themselves to treat an extraordinarily difficult to manage health problem, namely large airway stenosis. This causes severe airway obstruction, which severely limits quality of life, exercise tolerance, communication, and social and employment opportunities. Occasionally, the stenosis may also be life threatening. It occurs in approximately 200 individuals in California each year. Treatment costs for these patients are very high, and the personal and societal investments are substantially higher, although outcomes are consistently poor. The endpoint desired is normal airway and lung function and an improved quality of life. Our team aims to eliminate the need for repeated surgical interventions and/or the use of stents (metal or plastic tube implants), which are not necessarily successful, yet presently the standard of care for such patients. In 2008/2010, we used stem cell-based, engineered tracheal implants to successfully save a young woman's and a child's life. Both are very well at 5 and 3 years post-implantation. These first-in-human studies emphasize that our goal is realistic, but also highlighted the gaps in our knowledge. Specifically, there is a need for preclinical studies to address questions of safety and long-term maintenance of airway, as well as to determine the fate of the implanted cells; secondly, if supported by these preclinical safety studies, there is a need for a formal clinical trial in patients of our candidate airway implant. Stem/progenitor cell-derived airway transplants that use the patients' own cells have the clinical advantage of not requiring anti-rejection medications. Our experience, to date, indicates such medication is not needed and this finding represents a scientific and clinical breakthrough in organ transplantation. While medical benefit was demonstrated in these two preliminary patients, there is substantial work to be done before such transplants can be considered routine for patients. We address this challenge with our team approach and emphasize the synergism that occurs when linking team members from California and a partner institution, with expertise in a variety of scientific and medical disciplines to address this critical need.
Statement of Benefit to California:
The citizens of California have generously invested in stem cell research and a return on their investment will include breakthroughs in medical treatments for diseases where there are currently limited options. Tissue-engineered stem/progenitor cell-derived airway transplantation is a leading example of translational research in regenerative medicine that can be used for a host of diseases. Through this team effort scientists and physicians will lead the early promise of airway transplantation to clinical trials in California and beyond. This research team proposes to use tissue-engineered airway scaffolds with stem and progenitor cells to cure an extraordinarily difficult to manage and life-threatening health problem. Severe airway obstruction occurs in approximately 200 adults in California each year. The morbidity associated with this disease is very high, and it can be fatal for some. The knowledge gained from the tissue engineering and preclinical studies proposed will provide a new technology that can be applied to these and other disorders in California. We foresee that our stem cell-derived airway transplant could also be extended to treat an important subpopulation of children with severe subglottic and tracheal stenosis, malacia, or agenesis that have proven refractory to standard surgical interventions, and adult patients with debilitating laryngeal scarring. A further exciting possibility is that stem cell-derived airway transplants or bioengineered stents could also be applied to treat an important subpopulation of adults with severe chronic obstructive pulmonary disease (COPD). Given that the prevalence rate of COPD for California citizens greater than 65 years of age approaches 10%, if even 0.1% of COPD patients in California were candidates, specifically those with associated tracheobronchomalacia, then greater than 3,000 patients might benefit from this treatment. The methods and technology developed from this project can also be used as the basis for other similar health needs including esophageal, bladder, and bowel replacements for disorders where present treatments are very limited and impair quality of life.
EXECUTIVE SUMMARY The applicants propose to use an engineered replacement trachea to treat large airway stenosis, a highly morbid condition that causes severe obstruction of the airway. The intended approach will use stem cells from the patients themselves combined with a biologic scaffolding to create the engineered trachea. The therapeutic approach has already been used in first-in-human studies for individual cases, and this proposal builds on that clinical experience to conduct the preclinical development activities and a clinical trial required to make this procedure accessible to more patients. This project proposes to complete the necessary preclinical studies to file an Investigational New Drug (IND) application with the Food and Drug Administration (FDA) and complete an early phase clinical trial within the award period. Significance and Impact - The proposed approaches address a clear unmet medical need. There are currently no good options for the replacement of large sections of airway. - While the number of cases of tracheal stenosis is small, this approach could offer a unique and life-saving therapy for patients with the condition. - Reviewers agreed that this proposal was highly responsive to the RFA and that it presents a unique opportunity to bring a world-leading regenerative medicine technology to California. It was also noted that this project is unlikely to be funded by other agencies. Scientific Rationale and Risk/Benefit - Engineered tracheas similar to the proposed development candidate have already been used in humans as well as in animal models, providing preliminary safety data and rationale to support advancing to a clinical trial. - Failure of the therapy could be fatal, but given the nature of the condition, the reviewers considered the risk/benefit ratio acceptable. Therapeutic Development Readiness - Reviewers agreed that having already treated human patients using this approach is strong proof of concept. Proof of concept has also been tested using clinically relevant preclinical models, although a significant amount of IND-enabling preclinical work remains to be conducted. - Comparability to the tracheal constructs used in prior human cases has not been shown. If that can be demonstrated to leverage the existing clinical experience with patients, the team may be able to reduce the number of clinically relevant preclinical studies required prior to seeking regulatory approval for the proposed clinical trial. - The manufacturing and testing methods were not well described in the proposal. Additional focus on these activities is likely needed and reviewers noted that the UK-based collaborators will clearly play an important role in helping to establish the manufacturing process. Design and Feasibility - The studies are well designed with appropriate milestones and go/no-go decision points and the clinical trial design is feasible with appropriate safety and efficacy outcome measures. -The proposed preclinical development and clinical trial are an appropriate and logical next step based on the prior clinical experience with the approach. - There was concern regarding the feasibility of the timeline to complete both the remaining preclinical work and the proposed clinical study. The timeline should be reconsidered, given the number of preclinical studies that must be conducted before the IND filing. -The feasibility of the timeline to enroll and complete the proposed clinical trial was also questioned by reviewers Principal Investigator (PI), Development Team and Leadership Plan - The PI and team were viewed as world-leading in this functional tissue engineering approach with the appropriate experience and expertise to complete the proposed studies. -It was suggested to consider adding an independent clinical monitoring function, under the supervision of a clinical operations manager, and an independent safety and pharmacovigilance program. Budget - Reviewers were concerned that the budget proposed may be inadequate to complete all of the remaining preclinical studies. Some additional activities that must be conducted may not have been budgeted for. - The budget for the proposed clinical study was viewed as high for a small Phase I study. Collaborations, Assets, Resources and Environment - Reviewers were unclear on the relationship between the California- and UK-based team members and whether the relationship and efforts were collaborative or duplicative. Once clarified, however, reviewers noted that the collaboration is a valuable resource to provide access to the technology under development.
- Andrew Balber