Disease Team Therapy Development III
$13 277 369
Recommended if funds allow
There are no satisfactory conventional solutions for thousands of Californians with acquired severe airway stenosis, which is a narrowing of the airway. Airway stenosis has profound impact on quality of life, limiting the ability to breathe and communicate. Reconstructive surgery using currently available tissue flaps or grafts has failed to deliver satisfactory results, and for many, the only option is to use medical devices like tracheotomy tubes or stents, both of which can lead to infection and pain, and possible complications of erosion, blockage, bleeding, and death. Thus, overall quality of life of afflicted individuals is limited and the cost to the healthcare system, the patient, and their caregivers is disproportionately high. A solution that permits effective breathing and speaking while avoiding prosthetic airway support is highly desirable. Our team has performed a series of compassionate use tissue-engineered, stem cell based tracheal implants in adults and children with life-threatening airway stenosis. Three lives were saved and one received effective treatment of symptoms. Although ground-breaking, these procedures have left many questions unanswered, thus further investigation is required before definitive conclusions can be drawn regarding the safety and efficacy of this approach. Although compassionate use surgeries have met with initial clinical success and have garnered notable attention, there remain significant scientific gaps that must be addressed in clinically relevant preclinical studies before this technology is ready for widespread use. This project and the associated uniquely qualified team are ready to rigorously address these unanswered questions and move this new therapy to more widespread human clinical application.
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