Nearly 4,000 researchers and health care professionals gathered in Salt Lake City, Oct. 17–19, for the 27th North American Cystic Fibrosis Conference (NACFC), sponsored by the Cystic Fibrosis Foundation.
The annual meeting brings together scientists, clinicians and caregivers from around the world to discuss and share ideas on the latest advances in CF research, care and drug development.
For the first time, the conference’s three plenary sessions were available for live viewing online for those not at the conference, including people with CF and their families and the general public.
The plenaries featured presentations by leading CF researchers and clinicians on such topics as emerging therapies that target the underlying cause of CF, current research to address all CF gene mutations and treat the symptoms of the disease, and early detection and treatment of CF-related diabetes.
Scroll down to read summaries and watch videos of the NACFC 2013 plenary sessions.
Note: You must register to watch the plenary sessions.
Plenary Session 1: Restoring CFTR Function: Roadmap to a Cure (Part 1)
Speaker: Scott H. Donaldson, M.D.
Scott H. Donaldson, M.D., associate professor of medicine and associate director of the adult CF center at the University of North Carolina at Chapel Hill, gave an overview of the progress of research efforts to treat the underlying cause of CF — a defective protein, called CFTR, caused by mutations in the CF gene.
Reviewing current understanding of the role of CFTR in regulating the flow of salt and fluids across the cell membrane, Donaldson described how different classes of CF mutations cause the CFTR protein to malfunction in distinct ways, requiring different therapeutic approaches to treat effectively.
The first drug to successfully target — or “modulate” — the faulty CFTR protein, ivacaftor (Kalydeco™), was approved in 2012 for people with the G551D mutation of CF ages 6 and older and is now being studied in more CF patient groups, as well as in combination with other potential drugs in people with two copies of the most common mutation of CF, Delta F508. These early studies of CFTR modulators, said Donaldson, offer a roadmap that could speed development of new breakthrough therapies for all people with CF, including those with rare mutations.
First, said Donaldson, it is important to focus on the essential functions of the CFTR protein in different parts of the body — in particular the pancreas, intestines and lungs — to determine how much CFTR activity is necessary to restore the health of a person with CF. Donaldson also emphasized the need for new ways to measure CFTR function and demonstrate that therapies targeting CFTR actually improve key symptoms of CF by “turning on” the defective protein.
Research in the lab and clinic is already providing valuable information that could help move research forward. Donaldson described findings from the ongoing multicenter G551D Observational (GOAL) Study, which is collecting clinical data and samples from people with the G551D mutation who are now taking ivacaftor. Several GOAL substudies are using novel testing methods to identify and measure health outcomes that are closely tied to CFTR function in different organ systems.
Results from the GOAL Study show that those taking ivacaftor have reduced gastrointestinal symptoms, significantly improved mucociliary clearance and a reduction in lung infections caused by the bacteria Pseudomonas aeruginosa.
The GOAL findings also confirm the dramatic improvement in lung function seen in Phase 3 and open-label trials of the drug. However, said Donaldson, even with these improvements, sustained for many months, people with the G551D mutation who are on ivacaftor still have persistent CF disease.
Donaldson outlined next steps, some already underway, to maximize the potential of ivacaftor and other therapies now in development. Moving forward, said Donaldson, it will be important to treat people with CFTR modulators earlier; treat both CF mutations in an individual to increase restoration of CFTR function; and use new screening technologies to identify and develop more and better therapies to benefit all people with CF.
Plenary Session 2: Roadmap to a Cure (Part 2): Clinical Research Pathway to Ensure That All Patients with CF Benefit from Novel Therapies
Speaker: Bonnie W. Ramsey, M.D.
Bonnie W. Ramsey, M.D., CF endowed professor of pediatrics at the University of Washington School of Medicine and director of the CF Foundation’s Therapeutics Development Network Coordinating Center, expanded the focus of the first plenary on the clinical pathway set by the approval and success of ivacaftor in people with the G551D mutation of CF ages 6 and older.
With more than 1,000 known CF mutations, which are associated with varying symptoms and severity of the disease, identifying the best approaches to treat different mutations remains challenging. A first step, said Ramsey, is determining which additional patient groups could benefit from ivacaftor as a single therapy.
Phase 3 studies are now evaluating ivacaftor in people who have other “gating mutations” besides G551D (the most common gating mutation) and in those with the R117H mutation, as well as in young children with G551D.
Ramsey gave an update on the Phase 3 clinical trials of ivacaftor in combination with another potential oral therapy, VX-809, in people with two copies of the Delta F508 mutation (about 50 percent of the CF population). These important studies, which enrolled over 1,000 participants around the world in record time, are moving forward, with results expected in summer 2014.
Treating the Delta F508 mutation is a complex and multistep process, said Ramsey, and will likely require two drugs or more. In addition, earlier studies showed that the combined ivacaftor and VX-809 treatment had much less effect in those with only one copy of Delta F508. Using lessons learned from studies of these “first-generation” efforts to treat the defective CFTR protein, the CF Foundation is collaborating with seven pharmaceutical companies, and has also established its own research lab, to help find new and more effective therapies for people with the Delta F508 mutation, as well as those with rare mutations.
Ramsey discussed current research to develop treatments for the 10 percent of people with CF who have what are known as nonsense mutations, which interrupt the production of a full-length CFTR protein. This work includes a new Phase 3 trial of the potential drug ataluren, planned to begin in 2014 in people with nonsense mutations who are not receiving inhaled aminoglycocides (a group of inhaled antibiotics that includes TOBI®). An earlier Phase 3 trial showed that the use of aminoglycocides may have reduced the response to ataluren.
In addition, said Ramsey, academic and industry researchers are using cutting-edge technologies to potentially address the underlying cause of CF regardless of an individual's mutations. Among these are programs to replace or repair the defective CF gene or to replace the CFTR protein.
While amazing progress has been made, Ramsey reminded the audience that new therapies are still needed to treat the symptoms of CF. CFTR modulators such as ivacaftor cannot reverse the organ damage caused by CF. Preventing that damage is critical until lifesaving drugs that treat the underlying cause of CF are available to 100 percent of people with the disease beginning in infancy.
Referring to the CF Foundation’s therapeutics pipeline, Ramsey focused on current studies that are advancing antibiotic and anti-inflammatory treatments to combat lung infection and damage, and paid tribute to the clinical trials networks around the world that have helped create the wealth of research opportunities the CF community has today.
Plenary Session 3: CFRD: From Bench to Bedside & Back Again
Speakers: Andrea Kelly, M.D., M.S.C.E., and John F. Engelhardt, Ph.D.
In the final plenary session, Andrea Kelly, M.D., M.S.C.E., assistant professor in the division of pediatric endocrinology and diabetes at the Children's Hospital of Philadelphia, gave an overview of current research on and care of cystic fibrosis-related diabetes (CFRD). CFRD is one of the most common complications of CF, occurring in more than 30 percent of people with CF ages 18 and older.
In people with CFRD, the pancreas does not make enough insulin, a hormone that helps the body get the nutrients it needs from food to gain and maintain weight. This insulin deficiency causes high blood glucose levels (the amount of sugar in the blood), which if not treated with insulin can lead to a decline in lung function and nutrition and cause other serious health complications. Managing CFRD adds to the already considerable daily treatment burden of a person with CF.
Kelly described how CFRD has been largely understood to arise from scarring on the pancreas caused by CF over time. However, said Kelly, insulin deficiency can be present in childhood, even when blood glucose levels are normal and before CFRD is diagnosed. Earlier onset insulin defects are associated with a greater likelihood of lung transplant and worse survival among people with CF. Kelly reviewed recent studies on the underlying mechanisms of insulin deficiency that could help advance development of interventions to interrupt the progression of CFRD.
One research avenue is exploring what factors other than damage to the pancreas might contribute to the decreased ability of beta cells—the cells in the pancreas that make and secrete insulin—to do their job. Researchers are also investigating whether an inherent genetic defect limits beta cell function. This works includes research to determine the relationship between CFTR, the key protein in CF, and insulin secretion.
Following Kelly’s presentation, John F. Engelhardt, Ph.D., professor and chairman in the department of anatomy and cell biology at the University of Iowa, presented findings from basic research on the mechanisms of CFRD that affect insulin and glucose regulation in the different parts of the body that depend on the CFTR protein.
Lessons learned in the laboratory, said Engelhardt, could lead to a better understanding of the early stages of CFRD and eventually new therapies to treat it. Early diagnosis and prompt treatment of CFRD can help people with CF improve their lung function, nutrition and overall health.
Engelhardt discussed results from a clinical trial of children with CF ages 3 months to 5 years, which showed that early abnormalities in glucose tolerance were due not to a lack of insulin but to poor regulation of insulin and the other hormones that control insulin. Studies such as these may help improve early diagnosis of CFRD and lead to earlier interventions, including nutritional therapies, that could slow the progress of CFRD in people with CF.