Disclaimer: CME certification for these activities has expired. All information is pertinent to the timeframe in which it was released.
Ahead of the Curve: Emerging CF Therapies
To provide community clinicians involved in the treatment of patients with cystic fibrosis (CF) with up-to-date information on potential therapeutic targets, current research, and methods for managing patients with CF.
This activity is designed for community clinicians involved in the treatment of patients with cystic fibrosis. No prerequisites required.
At the conclusion of this activity, the participant should be able to:
- Describe the most current understanding of the pathophysiology underlying cystic fibrosis (CF).
- Identify the potential therapeutic targets of current clinical research.
- Summarize the known data regarding ongoing research into CF transmembrane conductance regulator modulation.
- Recognize the current research regarding salt transport/correcting ion transport, P2Y2 agonists, epithelial sodium channel antagonists, et al.
- Integrate information about these emerging therapies into current clinical practice strategies for managing patient expectations.
The Johns Hopkins University School of Medicine and The Institute for Johns Hopkins Nursing take responsibility for the content, quality, and scientific integrity of this CME/CNE activity.
This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of The Johns Hopkins University School of Medicine and The Institute for Johns Hopkins Nursing. The Johns Hopkins University School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.
The Institute for Johns Hopkins Nursing is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation.
CREDIT DESIGNATION STATEMENT
The Johns Hopkins University School of Medicine designates this educational activity for a maximum of 2 AMA PRA Category I Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.
This 1.55 contact hour educational activity is provided by The Institute for Johns Hopkins Nursing. Claim only those contact hours actually spent in the activity. Contact hours will be awarded for this educational activity until March 15, 2012.
The estimated time to complete this educational activity: 2 hours.
Release date: March 15, 2010. Expiration date: March 15, 2012.
HOW TO RECEIVE CREDIT OR CONTACT HOURS
After reading this monograph, participants may receive credit or contact hours by completing the CME/CNE test, evaluation, and receiving a score of 70% or higher. See page 29 for additional CME/CNE certificate processing information.
THE INSTITUTE FOR JOHNS HOPKINS NURSING MISSION STATEMENT
The mission of The Institute for Johns Hopkins Nursing is to share the innovations of Johns Hopkins Nursing in practice, education, and research—locally, nationally, and globally.
Our goal in continuing nursing education is to bring you activities that reflect the expertise and creativity of Johns Hopkins Nursing. Our service values are quality, integrity, flexibility, and personal attentiveness. We appreciate your thoughts and welcome your concerns. Please feel free to e-mail us: IJHN@son.jhmi.edu.
This educational activity is supported by an educational grant from Vertex Pharmaceuticals, Inc.
Full Disclosure Policy Affecting CME Activities:
As a provider accredited by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of The Johns Hopkins University School of Medicine to require the disclosure of the existence of any relevant financial interest or any other relationship a faculty member or a sponsor has with the manufacturer(s) of any commercial product(s) discussed in an educational presentation.
Policy on Faculty and Provider Disclosure
It is the policy of The Institute for Johns Hopkins Nursing to require our continuing nursing education faculty and planning committee members to disclose any financial relationships with companies providing program funding or manufacturers of any commercial products discussed in the educational activity. The Course Directors and Participating Faculty reported the following:
Peter Mogayzel, Jr, MD, PhD
Associate Professor of Pediatrics
Director, Cystic Fibrosis Center
Medical Director, Pediatric Specialty Clinic
Johns Hopkins Cystic Fibrosis Center
• Dr Mogayzel reports having no relationships with commercial interests related to this activity.
Meghan Ramsay, MS, CRNP
Clinical Coordinator, Adults
Johns Hopkins Adult Cystic Fibrosis Program
• Ms Ramsay reports having no relationships with commercial interests related to this activity
John Paul Clancy, MD
Professor, Director, and Raymond K.
Lyrene Chair in Pediatric Pulmonology
Department of Pediatrics
University of Alabama at Birmingham
Children’s Hospital of Alabama
• Dr Clancy reports receiving grants/research support from Cystic Fibrosis Foundation Therapeutics, Inc, Inspire Pharmaceuticals, Transave Inhalational Therapeutics, and Vertex Pharmaceuticals, Inc; and serving as a consultant for Transave Inhalational Therapeutics and Vertex Pharmaceuticals, Inc.
Christopher H. Goss, MD, MS, FCCP
Associate Professor of Medicine
Adjunct Associate Professor of Pediatrics,
Pulmonary and Critical Care Medicine
University of Washington Medical Center
• Dr Goss reports receiving grants/research support from Transave, Inc; and receiving honoraria from Bayer.
Richard B. Moss, MD
Professor of Pediatrics – Pulmonary Medicine
Co-Director, Cystic Fibrosis Center
Center of Excellence in Pulmonary Biology
Palo Alto, California
• Dr Moss reports receiving grants/research support from Gilead, GlaxoSmithKline, Inspire Pharmaceuticals, PTC Therapeutics, Inc, and Vertex Pharmaceuticals, Inc; serving as a consultant for Aridis Pharmaceuticals, Arriva Pharmaceuticals, Inc, Genentech, Inc, Inspire Pharmaceuticals, Johnson & Johnson, Lantibio, Inc/AOP Orphan Pharmaceuticals AG, MPEX Pharmaceuticals, Novartis Pharmaceuticals, PTC Therapeutics, Inc, and Vertex Pharmaceuticals, Inc; holding stock in Genentech, Inc and Gilead; and serving on the speakers’ bureau for Genentech, Inc and Novartis Pharmaceuticals.
Pamela L. Zeitlin, MD, PhD
Professor of Pediatrics
Director, Pediatric Pulmonary
The Johns Hopkins University School of
• Dr Zeitlin reports receiving grants/research support from Inspire Pharmaceuticals, Pharmaxis, PTC Therapeutics, Inc, and Vertex Pharmaceuticals, Inc; holding stock in Sucampo Pharmaceuticals, Inc; and serving on the speakers’ bureau for France Foundation.
Grants to investigators at The Johns Hopkins University are negotiated and administered by the institution that receives the grants, typically through the Office of Research Administration. Individual investigators who participate in the sponsored project(s) are not directly compensated by the sponsor, but may receive salary or other support from the institution to support their effort on the project(s).
Off-Label Product Discussion: The following members of the faculty have indicated that they intend to discuss off-label or investigational use of products in their articles:
Dr Moss—azithromycin, colistin, denufosol, hypertonic saline, mannitol, PTC124, Tobi, VX-770, and VX-809.
Dr Zeitlin—amiloride, bronchitol, cobiprostone, denufosol, lubiprostone, mannitol, and MOLI1901.
All other faculty have indicated that they have not referenced unlabeled/unapproved uses of drugs or devices.
The opinions and recommendations expressed by faculty and other experts whose input is included in this program are their own. This enduring material is produced for educational purposes only. Use of The Johns Hopkins University School of Medicine and The Institute for Johns Hopkins Nursing names implies review of educational format, design, and approach. Please review the complete prescribing information of specific drugs or combinations of drugs, including indications, contraindications, warnings, and adverse effects, before administering pharmacologic therapy to patients.
Non-Endorsement of Products
The Institute for Johns Hopkins Nursing does not endorse the use of any commercial products discussed or displayed in conjunction with this educational activity.
AHEAD OF THE CURVE: EMERGING CF THERAPIES
Peter Mogayzel, Jr, MD, PhD* and Meghan Ramsay, MS, CRNP†
Twenty years have passed since the discovery of the gene for cystic fibrosis (CF), and although medical advances have increased survival to the median age of 37 years, a cure for this fatal disease remains out of reach. More than 1000 new cases of CF are diagnosed each year, and approximately 90% are diagnosed in children before the age of 3. An autosomal recessive disease, CF most commonly afflicts individuals of European background, with carrier numbers of 1 in 25. Mortality rates have dramatically improved since the 1960s, when the mean life expectancy was only 14 years. As a result of newly introduced therapies (eg, inhaled antibiotics) and aggressive management of CF lung disease, today’s patients can be expected to live well into adulthood and have an improved quality of life.
Cystic fibrosis is essentially caused by a mutation in the CF transmembrane conductance regulator (CFTR), a chloride channel that is expressed on the surface of epithelial cells in the intestine, respiratory system, pancreas, and sweat glands. The presence of the deficient CFTR protein leads to an accelerated rate of sodium absorption, inefficient chloride secretion, airway surface liquid depletion, and defective mucociliary clearance. Although the resultant thick mucus secretions affect the pancreas, lungs, and reproductive organs, they are most devastating in the lungs, where they block the airways and cause chronic bacterial infection and degeneration of lung tissue.
Because lung disease accounts for more than 85% of mortality in CF, pulmonary care is clearly the main focus of current therapy, with inhaled treatments broadly recommended in current CF pulmonary therapy guidelines.1 Specifically, antimicrobials targeting Pseudomonas aeruginosa (inhaled tobramycin) and agents that aid in mucociliary clearance (dornase alfa) are mainstays in the management of CF lung disease, and are backed by “good” quality of evidence substantiating benefits in moderate to severe disease.1 Still, patient deaths are commonly due to lung destruction caused by recurrent antibiotic-resistant lung infections, and therefore, research into new treatment strategies and therapeutic targets is critical.
Fortunately, the confirmation of CFTR as a chloride channel that is critical to the normal functioning of airways has guided research efforts to the identification of more than 1000 CFTR-related mutations and development of CFTR-modulating drugs that may ultimately preserve lung function by restoring some level of activity to the defective protein. Depending on the CFTR mutation being targeted, these investigational agents may optimize production of the full-length CFTR protein, activate mutant CFTR proteins that are at the plasma membrane, or address a defect that prevents a mutant CFTR from reaching the cell membrane. Other therapeutic strategies under development involve potentiating or inhibiting alternative ion channels, or increasing hydration of surface liquid. Various phase II/III trials are currently examining these agents and are open to patient enrollment. As such, healthcare providers may encounter the drugs in their dealings with patients participating in clinical trials, and potentially, in day-to-day practice should they become US Food and Drug Administration approved. Thus, it is critical to become familiar with the science behind these emerging treatments and their role in therapy.
This issue of Johns Hopkins Advanced Studies in Medicine is based on a recent seminar at The 23rd Annual North American Cystic Fibrosis Conference, which was held in Minneapolis, Minnesota, on October 16, 2009. It is dedicated to providing community clinicians involved in the treatment of patients with CF with an update on the latest research and therapeutic targets in CF. Richard B. Moss, MD, offers an overview of CF pathophysiology and an introduction to the current drug discovery efforts, which include development of new therapeutic agents to treat or replace the underlying defective CFTR protein, development of new therapies to treat secondary consequences of dysfunctional CFTR, and identification of approved therapies that may be of benefit in CF. Dr Moss explores the challenges that researchers face in using traditional outcome measures to validate efficacy of new drugs and discusses emerging therapeutic targets, particularly those that focus on abnormal CFTR protein production, altered ion transport/abnormal mucus secretion, and infection/inflammation.
Next, John Paul Clancy, MD, reviews current CFTR modulators in development, including suppressor agents that optimize production of the full-length CFTR protein, potentiator agents that activate mutant CFTR proteins at the plasma membrane, and corrector agents that address the primary folding defect in the F508del mutation. In his discussion on CFTR, Dr Clancy describes the pathway involved in normal synthesis and function of CFTR, and the type of abnormalities within CFTR synthesis and function that the major identified mutations produce.
In exploring ongoing research into emerging therapies that may aid in the transport of chloride through CFTR-independent channels, Pamela L. Zeitlin, MD, PhD, focuses on alternative chloride channel agonists, sodium channel blockers, and osmotic agents. Dr Zeitlin underscores the critical balance required to maintain hydration of airways by offering a detailed comparison of ion channel activity within normal versus CF airways.
Finally, Christopher H. Goss, MD, MS, FCCP, explores the many research challenges that investigators face in meeting patient enrollment requirements, evaluating impact of therapy on critical patient outcomes (eg, survival), and extrapolating the available evidence. In illustrating the various issues that arise among patients participating in clinical research, Dr Goss presents 2 brief case studies (each followed by audience discussion) of patients under consideration for investigational therapy.
1. Flume PA, O’Sullivan BP, Robinson KA, et al. Cystic Fibrosis Pulmonary Guidelines: chronic medications for maintenance of lung health. Am J Respir Crit Care Med. 2007;176:957-969.
*Associate Professor of Pediatrics, Director, Cystic Fibrosis Center, Medical Director, Pediatric Specialty Clinic, Johns Hopkins Cystic Fibrosis Center, Baltimore, Maryland.
†Clinical Coordinator, Adults, Johns Hopkins Adult Cystic Fibrosis Program, Baltimore, Maryland.
Address correspondence to: Peter Mogayzel, Jr, MD, PhD, Associate Professor of Pediatrics, Director, Cystic Fibrosis Center, Medical Director, Pediatric Specialty Clinic, 200 North Wolfe Street, Suite 3053, Baltimore, MD 21287. E-mail: email@example.com.
The content in this monograph was developed with the assistance of a medical writer. The authors made substantial contributions to the intellectual content of the articles by conceiving and designing the original presentations, researching references and studies, drafting the manuscripts, reviewing and revising the manuscripts, and/or providing supervision.