Unprecedented Trans-NCATS Collaboration Enables Rapid Advancement of Rare Lung Disease Therapy to Human Trials

Translational Science Highlights

  • NCATS helped shepherd a potential new drug for a deadly lung disease through many steps of the translational science process and provided a bridge moving this therapeutic from preclinical to clinical research.
  • Academic and industry researchers collaborated with NCATS Therapeutics for Rare and Neglected Diseases scientists on preclinical testing.
  • Clinical and Translational Science Awards Program support enabled researchers to begin an early study of the experimental drug in patients.

Bruce Trapnell, M.D., was frustrated. As a pulmonologist and professor of medicine and pediatrics at Cincinnati Children’s Hospital and University of Cincinnati Medical Centers, he suspected that an inhaled medication could help treat patients with autoimmune pulmonary alveolar proteinosis (aPAP), a rare, potentially deadly lung disease. But for several years, a series of financial and logistical obstacles stood in the way of proving his theory. Seeking collaborative support, Trapnell reached out to NCATS, which helped shepherd the potential therapy through several steps of the drug development process, ultimately enabling a clinical trial in aPAP patients.


Finding a Better Treatment for aPAP

By all accounts, aPAP is a difficult condition to live with and to treat. It is marked by a build-up of lipids and proteins (called a surfactant) in the tiny gas exchange pockets of the lung that leads to respiratory failure. The body’s immune system attacks a protein called granulocyte/macrophage colony-stimulating factor (GM-CSF), which is critical for proper clearance of the surfactant. The condition affects an estimated 40,000 to 50,000 people worldwide.

Studies suggest that therapies to supplement GM-CSF could stimulate aPAP patients’ own immune cells to properly clear the lungs.

In the U.S., GM-CSF is approved for intravenous use in other conditions and is currently owned by Sanofi Genzyme, a Cambridge, Massachusetts-based biotechnology company. However, both animal and human studies suggested that GM-CSF, delivered in inhaled form, could be an effective therapy for aPAP patients. It was also promising that a 2010 Japanese study indicated that inhaled GM-CSF was safe and effective for aPAP patients. Still, in order for Trapnell to further study the drug in humans in the U.S., the Food and Drug Administration (FDA) required preclinical studies in animals to demonstrate the inhaled drug’s safety.

Autoimmune PAP shown next to healthy personTrapnell had been studying aPAP in humans for more than a decade in his role as principal investigator of the Rare Lung Diseases Consortium (RLDC), part of the NCATS-supported Rare Diseases Clinical Research Network. But the RLDC was not funded to conduct animal studies, and Trapnell couldn’t find financial support for the FDA-required study or attract a commercial partner with interest in further developing the inhaled drug.

Meanwhile, aPAP patients continued to undergo the standard but invasive procedure to treat their condition. Developed in the 1960s and mostly unchanged since then, the treatment, called whole-lung lavage, involves periodic internal washing of the lungs and must be repeated throughout the patient’s entire life. During the procedure, patients must undergo general anesthesia. Clinicians keep one lung working via mechanical ventilation while they fill the other lung with saline, repeatedly pound on the chest to loosen the built-up surfactant, and drain the contents of the lung. The process is then repeated on the other lung. Some patients must undergo this procedure every six months.

“In terms of patient safety, quality of life and cost, an inhaled treatment would be a major improvement over standard care,” Trapnell said.

New Hope for an Inhaled Therapy

Trapnell successfully applied to NCATS’ Therapeutics for Rare and Neglected Diseases (TRND) program, through which outside investigators partner with NCATS researchers, with the goal of moving promising therapeutics into human clinical trials. External partners benefit from the rare and neglected disease drug development capabilities, clinical resources and regulatory expertise provided by TRND researchers and project managers in a highly collaborative environment. The aim is to produce data to support successful investigational new drug (IND) applications to the FDA. If approved, an IND application enables researchers to launch a human drug study. Potential therapies that reach the IND stage may be attractive to biotechnology and pharmaceutical companies to invest in and advance for clinical development.

Soon after starting work with TRND experts, the team entered into a collaboration with Sanofi Genzyme that provided the essential clinical-grade GM-CSF product to conduct the necessary preclinical studies.

“The research partnership with NCATS’ TRND experts added a level of legitimacy to the project that enabled us to strike up a collaboration with Sanofi Genzyme,” said Trapnell.

To facilitate the partnership process among industry, academia and NCATS scientists, NCATS’ Office of Strategic Alliances staff arranged a formal, three-way materials-sharing agreement between Trapnell, TRND scientists and Sanofi Genzyme. The negotiations helped convince the company that Trapnell’s research might lead to a new use for the drug. The agreement provided all three partners with research flexibility, while protecting Sanofi Genzyme’s commercial interests. The company provided the drug free of charge, resulting in large cost savings for the project.

With the drug available from Sanofi Genzyme, preclinical safety studies were completed, demonstrating the safety of inhaled GM-CSF in animals. Trapnell used these data in his IND application, which the FDA cleared in 2016.

A Bump in the Road

But then Trapnell hit another roadblock: Although he had the green light from the FDA to start testing the safety and initial measures of effectiveness of inhaled GM-CSF in aPAP patients, he lacked the funding to do so. Again, the effort stalled.

Soon, however, Trapnell saw an opportunity to launch a human clinical trial through another NCATS initiative: the Clinical and Translational Science Awards (CTSA) Program. The CTSA Program supports a national network of medical research institutions — called hubs ― that work together to improve the translational research process. The University of Cincinnati, where Trapnell practices and conducts research, is home to a CTSA Program hub. The University of Cincinnati hub is a collaborative partnership among the University of Cincinnati, Cincinnati Children’s Hospital and a number of other local clinical research institutions.

Trapnell realized that his project aligned with CTSA Program goals, and he successfully applied for a supplemental grant.

Light at the End of the Tunnel

The CTSA Program supplement provided the financial support necessary for a preliminary clinical study of inhaled GM-CSF at two program hubs: Cincinnati Children’s Hospital and the University of California, Los Angeles. During the Phase I clinical trial, which is expected to begin in January 2017, researchers will test the safety and proper dosage of inhaled GM-CSF in 10 aPAP patients.

The study also serves as a pilot project of the CTSA Program’s newly implemented single institutional review board (IRB) reliance platform for multisite clinical studies: the NCATS Streamlined, Multisite, Accelerated Resources for Trials (SMART) IRB Reliance Platform. IRBs review and approve human study protocols to ensure that the research meets ethical guidelines. Through the NCATS SMART IRB Reliance Platform, all sites participating in a multisite clinical study rely on the ethical review of a single IRB as a way to streamline the IRB review process and provide more consistent, high-quality reviews.

Trapnell expects the study to last about six months. At that point, researchers hope to move into a Phase II trial to test the drug’s effectiveness in a larger group of aPAP patients. Trapnell is optimistic that a potentially life-changing treatment is one step closer to benefitting patients.

“Dr. Trapnell’s broadly collaborative efforts with NCATS’ preclinical and clinical programs have advanced this important potential therapy to patients, and it has demonstrated general principles that NCATS and the research community can apply to other diseases,” said NCATS Director Christopher P. Austin, M.D. “This approach exemplifies the Center’s team approach to developing, demonstrating and disseminating translational science improvements that get more treatments to more patients more quickly.”

April 2018 Update

The outlook continues to improve for an inhaled GM-CSF therapy to become the first noninvasive treatment available for aPAP patients. Enrollment is now complete for the first group of participants in the Phase I trial at Cincinnati Children’s Hospital and the University of California, Los Angeles. The focus of this trial is to evaluate the safety and tolerability of an inhaled GM-CSF called sargramostim at two different doses. In addition, researchers are analyzing results of two other aPAP trials of inhaled GM-CSF; these trials were conducted in Japan and Italy, respectively.

Private-sector interest in this new therapeutic approach for aPAP has continued to grow. Savara Pharmaceuticals is currently sponsoring a Phase III trial to test the safety and effectiveness of molgramostim, another form of inhaled GM-CSF. This trial is taking place at 32 locations across the globe, including at Cincinnati Children’s Hospital.


Posted January 2017