Current and Future Research Needs in the Era of Highly Effective Modulator Therapies for Cystic Fibrosis

Workshop Overview

On June 2 and 3, 2022 the National Heart, Lung, and Blood Institute (NHLBI) Division of Lung Diseases, the National Institute of Allergy and Infectious Diseases (NIAID) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH), in planning collaboration with the Cystic Fibrosis Foundation (CFF), hosted a virtual workshop with the objective to bring together experts in Cystic Fibrosis (CF) clinical-translational research to address critical questions and inform the field of the future research needs in the era of highly effective modulator therapies (HEMT) for the treatment of CF. The workshop highlighted challenges and opportunities for research in the context of rapidly shifting treatment options. This workshop brought together experts from various fields (research, clinical care, community stakeholder groups, pharma, and government) to share their insights, begin partnerships, foster collaborations, and provide ideas for the future research needs in these topics.

Sessions focused on the current research landscape for CF in the era of HEMT, including (1) animal model systems to study HEMTs, (2) late-stage CF lung disease pathophysiology and processes, (3) concerns and questions about people with CF and early lung disease, (4) considerations for modulator use in special populations, and (5) advancing clinical care and outcomes for people with CF in the post modulator era. Community member perspectives were also shared from persons with CF and their caregivers. The format consisted of short talks in each session followed by moderated Q&A with panelists. Each day also hosted three concurrent breakout sessions followed by a panel discussion to discuss gaps and opportunities for future research and programming.  The workshop took place over two days and gathered more than 400 attendees daily.

The event was archived for future viewing: 

Current and Future Research Needs in the Era of Highly Effective Modulator Therapies for Cystic Fibrosis - Day 1

Current and Future Research Needs in the Era of Highly Effective Modulator Therapies for Cystic Fibrosis - Day 2

Discussions

The workshop presentations and discussions centered around the following key topic areas:

Plenary: Cystic Fibrosis Research Landscape in the Era of High Effective Modulator Therapies

This session set the stage for the meeting with an overview of the current CF research landscape and the development pipeline of CFTR-based therapies for all including novel modulators, genetic-based therapies, and readthrough agents. This session addressed how outcomes and future research needs of those on HEMT will critically inform the research needed when disease modifying therapies are available and accessible to all individuals with CF.

Session 1: Animal Model Systems to Study High Effective Modulator Therapies

This session introduced current animal models to study HEMT, discussing their capabilities and limitations. The goal was to educate the audience of some of the available CF animal models that can enhance understanding of the CF human condition and inform clinical studies.

Session 2: Late-stage Cystic Fibrosis Lung Disease Pathophysiology and Processes

The session discussed what aspects of lung pathology in CF could be reversible in people with chronic and established lung disease, including structural changes and chronic infection. Cross-talk between endocrine systems, nutrition, and metabolism was addressed and how changes in these systems link to lung disease progression. The goal was to define clinical challenges for CF patients on HEMT with chronic lung disease.

Session 3: Concerns and Questions About People with Cystic Fibrosis and Early Lung Disease

This session defined clinical challenges for CF patients on HEMT without chronic lung disease. Topics included: additive therapies for children on HEMT, when to start or stop?; dDisease monitoring in children starting HEMT, including use of bronchoscopy, imaging, LCI, pathogen monitoring, CFRD screening, and non-invasive biomarkers; effects of HEMT on host-pathogen interactions and extrapulmonary organ systems—multiorgan interactions on the evolution of CF lung disease; and potential use of HEMT in utero and early models to predict disease course.

Session 4: Considerations for Modulator use in Special Populations 

This session addressed modulator use and needs during pregnancy, post-transplant, in patients with ultra-rare mutations, and as patients age with risk of age-related co-morbidities (cancer, renal failure, etc.). This session also addressed racial disparities in CF, including access to medication, representation in clinical trials, and known healthcare disparities pre-modulators as a primer for a path forward to high-quality clinical care for all patients with CF.

Session 5: Advancing Clinical Care and Outcomes for Patients with CF in the Post Modulator Era 

This session highlighted challenges in measuring health outcomes and meaningful endpoints for research in the post-modulator era. Topics included discussion of novel imaging, pathogen detection, and remote data capture tools for monitoring lung disease progression in CF, as well as defining and treating acute pulmonary exacerbations.

Research Gaps and Opportunities:

Speakers identified research gaps opportunities in their domains of scientific expertise in the Program Book. The workshop participants identified a number of additional knowledge gaps and research opportunities. Many of these are specific to the mission areas of NHLBI and the Division of Lung Diseases, but also represent cross-cutting topics of high priority to the field and workshop planning partners (CFF, NIDDK, NIAID). 

Specific Research Gaps:

In vitro, ex vivo, and Animal Models

• Should standardized methods and practices be developed by the community for in vitro/in vivo models to allow for comparisons across laboratories? 
• Is it necessary to evaluate multiple tissue types/models or are findings from one tissue/model relevant to all organs?
• How can in vitro/ex vivo/animal models be better leveraged in preclinical studies?
• Cystic Fibrosis affects multiple organs.  What models recapitulate relevant, new disease phenotypes related to aging in CF which will begin to manifest as persons with CF live longer (male fertility, CVD, cancers, etc.)? 
• Is there value comparing disease phenotypes between different animal models, even when not all reproduce the human phenotypes?

Disease Monitoring and Clinical Endpoints 

• As more patients utilize HEMT, there is a decrease in sputum expectoration used for pathogen and biomarker detection. Should we consider bronchoscopy or improve our understanding of the current value of the oropharyngeal (OP) swab?
• What health outcomes are now inadequate? For example, should we be finding ceiling effects for FEV1pp, PEx, CFQ-R, sputum for lower airway microbiology (not producing anymore)?
• FEV1 does not capture small, incremental changes in lung status and is not that sensitive. What are the best clinical endpoint(s) to monitor lung health in the era of HEMT (i.e. MRI, LCI, etc.)?
• In the era of ‘omics technologies, should we be more agnostic about disease monitoring and clinical endpoint(s) for CF?
• Is sweat chloride a useful biomarker to track optimal HEMT dosage and/or adherence? 

Initiation/Stopping HEMT and/or Other Therapies 

• As HEMT becomes more available to younger, healthier persons with CF, when should mucolytic therapy (e.g., hypertonic saline and dornase alfa) be started? Or when can these type of therapies be stopped for those with mild disease? Could implementation of case-control studies of people who stop and start modulator therapies inform this?
• What are the risks of delaying HEMT therapy for people with minimal/no evidence of lung disease?
• If HEMT initiation is delayed, what clinical markers are most useful in determining a need to start treatment (e.g., lung function, exacerbations, structural disease on imaging)?

Long-term Safety for HEMT and Future Considerations 

• What are the long-term risks for use of HEMT?
• Can patient registries be updated to collect adverse events and/or off-target effects of HEMT? Can patient-reported adverse events be included as well?
• What clinical information is needed to establish an individual’s optimal dosage of HEMT?
• What can we learn from non-CF bronchiectasis (NCFB)? What overlap with CF bronchiectasis and NCBF can inform phenotypes, symptoms, and potential for exacerbations? 
• Is bronchiectasis permanent or can we help epithelial cells reverse/remodel into a more functional airway? 
• Will age-related disease and comorbid conditions differ in CF from those in the general population?
• How do age-related disease progression and comorbidities impact family planning? The future of lung transplantation? 
• What is the impact of HEMT on neurodevelopment? 
• What research is needed to understand and prevent racial and ethnic disparities in CF morbidity and mortality?

Research Opportunities:

• Develop more complex and high-throughput in vitro/ex vivo models that incorporate state-of-the-art bioengineering, flow and inflammation to better reflect the in vivo situation.
• Advance personalized medicine through increased utilization of clinical models (nasal, bronchial, rectal tissues) with various CFTR mutations for therapeutic lead discovery.
• Develop relevant endpoints/readouts from in vitro studies beyond cell swelling and CFTR function.
• Expand use of animal models to understand non-epithelial pathology in CF (immune, smooth muscle, bone, etc.) and to expand our understanding of crosstalk between organ systems.
• Utilize animal models to better understand effects of HEMT in pregnancy and during postnatal care of infants (both CF and non-CF) born on HEMT.
• High costs to maintain and care for specialized disease animal models restricts widespread use; infrastructure should be created to facilitate their use in the larger CF research and development community.
• Generation of new animal models may be needed to understand the future course of CF disease in the era of HEMT, particularly in informing biomarker discovery of new disease states.
• Incorporate screenings for conditions or complications of aging into CF clinical care by bringing in expertise in these domains (CVD, hypertension, obesity, diabetes, CKD, cancer, etc.).
• Expand/build a surveillance database for risk and prevalence of comorbid conditions and conditions or complications of aging, including risk for long-term HEMT use.
• Develop studies and research programs that will help inform CF disease progression across the lifespan, starting with early-stage lung disease and including adults/late stage disease.
• Optimize FEV1 and sputum measures in parallel with development of novel biomarkers for disease monitoring and phenotyping.
• Support infrastructure that will continue and/or expand banking biospecimens from CF research studies; including expanding sampling from various regions of the airway, other tissues, and DNA.
• Promote biobanking as often as possible in CF research for future, longitudinal studies which also optimizes collaboration within the community and promotes ancillary studies.
• Promote/increase utilization of data/banked specimens from other CF research studies which are likely being underutilized because of lack of awareness/centralization.
• Understand the heterogeneity in response to HEMT; why some people respond to one modulator therapy and not to another or not as expected based on genotype.
• Identify new CF phenotypes based on the genome, i.e. genetic modifiers; identify transcriptomic and epigenetic changes in CF.
• Define the role of the CFTR defect in immune cells in disease onset and progression.
• Expand clinical data collection across centers and different clinics to understand how CF and HEMT affects the whole person (e.g. data on pregnancy, lactation, mental health, etc.).
• Evaluate how clinicians treating CF need to be trained in the era of HEMT.
• Develop new infant/preschool guidelines for persons with CF on HEMT, while maintaining guidelines for those not on HEMT.
• Expand research in fertility, pregnancy, and lactation for persons with CF in the post-modulator era as much remains unknown.
• Harmonize efforts between NIH and CFF in Path to a Cure.
• Explore opportunities to continue developing better modulators, developing new drugs, or even advancing gene-based therapies to help those who are not currently eligible for, or can’t take modulators, by expanding availability of disease-modifying therapies for all persons with CF.
• Make CF research and trial findings inclusive and broadly applicable by inclusion of all populations in trials.
• Continue to build trust in the CF research community through increased diversity in research teams, diversity and inclusion training for providers and research staff members, and removal/amelioration of barriers such as transportation, language/cultural differences, and health literacy issues that impede individual participation in clinical research.

Workshop Planning Committee:

Dr. Marrah Lachowicz-Scroggins, Ph.D., Program Director, Division of Lung Diseases, NHLBI, Planning Committee Lead
Dr. Tom Eggerman, MD, Ph.D., Program Director, Division of Diabetes, Endocrinology, and Metabolic Diseases, NIDDK 
Dr. Xin-Xing Gu, MD, Program Director, Respiratory Diseases Branch, NIAID 
Dr. JP Clancy, MD, Vice President of Clinical Research, Cystic Fibrosis Foundation 
Dr. John Engelhardt, PhD, University of Iowa,  Workshop Co-chair 
Dr. Susan Birket, PharmD, PhD, University of Alabama Birmingham, Workshop Co-chair  
Dr. Nicole Mayer Hamblett, PhD, Seattle Children’s Hospital,  Workshop Co-chair 
Dr. Katie Hisert, MD, PhD, National Jewish Health, Workshop Co-chair 

Additional Members from Cystic Fibrosis Foundation:

Dara Riva, M.S., Director of Clinical Research Awards 
Dr. Elizabeth Yu, PhD, Director of Physician Scientist Training Programs 
Dr. Katherine Tuggle, PhD, Sr. Director of Research 
Dr. Patrick Thibodeau, PhD, Vice President of Basic Research, Cystic Fibrosis Foundation 

Session Chairs and Speakers

Dr. JP Clancy, MD, Vice President of Clinical Research, Cystic Fibrosis Foundation
Dr. Steven Rowe, MD, Chief Scientific Officer, Cystic Fibrosis Foundation
Dr. Deepika Polineni, MD, MPH, Washington University in St. Louis
Ms. Melanie Lawrence, Community Member Perspective
Dr. Craig Hodges, PhD, Case Western Reserve University
Dr. Susan Birket, PharmD, PhD, University of Alabama Birmingham
Dr. John Engelhardt, PhD, University of Iowa
Dr. Sarah Ernst, PhD, University of Iowa
Dr. Irina Polejaeva, PhD, MS, USTAR, Utah State University
Dr. Ann Harris, PhD, Case Western Reserve University
Dr. Katie Hisert, MD, PhD, National Jewish Health
Dr. Frank McKeon, PhD, University of Houston
Dr. Eszter Vladar, PhD, University of Colorado Anschutz Medical Campus
Dr. Pradeep Singh, MD, University of Washington
Dr. Andrea Kelly, MD, MSCE, Children’s Hospital of Philadelphia
Dr. Jessica Alvarez, PhD, RD, Emory University
Ms. Lisa Hamburger, Community Member Perspective
Dr. Terri Laguna, MD, Northwestern University
Dr. Felix Ratjen, MD, FRCP(C), The Hospital for Sick Children
Dr. Jennifer Bomberger, PhD, University of Pittsburgh
Dr. Christopher Fortner, MD, PhD, Upstate Medical University
Dr. Gerry Cutting, MD, John Hopkins University
Dr. Jennifer Taylor-Cousar, MD, MSCS, National Jewish Health
Dr. Kathy Ramos, MD, MS, University of Washington
Dr. Christopher Goss, MD, MS, FCCP, University of Washington
Dr. John Brewington, MD, Cincinnati Children’s Hospital Medical Center
Dr. Megan McGarry, MD, MS, University of California San Francisco
Dr. Nicole Mayer Hamblett, PhD, Seattle Children’s Hospital
Dr. Zachary Cleveland, PhD, Cincinnati Children’s Hospital Medical Center
Dr. Heather Bean, Arizona State University
Dr. Natalie Elliott West, MD, MHS, John Hopkins University
Dr. Margaret Rosenfeld, MD, MPH, Seattle Children’s Hospital
Ms. Jennifer Kyle, Community Member Perspective
Mr. Kade Hammes, Community Member Perspective

Breakout Moderators and Discussants 

Dr. Martina Gentzsch, PhD, University of North Carolina Chapel Hill
Dr. Anjaparavanda “AP” Naren, PhD, Cedars-Sinai Medical Center
Dr. Amy Ryan, PhD, University of Iowa
Dr. Susan Reynolds, PhD, Nationwide Children’s Hospital
Dr. Bruce Stanton, PhD, Dartmouth College
Dr. John Engelhardt, PhD, University of Iowa
Dr. Lindsay Caverly, MD, University of Michigan Health
Dr. Manu Jain, MD, Northwestern University 
Dr. Gina Hong, MD, MHS, University of Pennsylvania 
Dr. Ron Rubenstein, PhD, Washington University in St. Louis
Dr. Edith Zemanick, MD, University of Colorado School of Medicine
Dr. Jessica Pittman, MD, MPH, Washington University in St. Louis
Dr. Bonnie Ramsey, MD, University of Washington
Dr. Rhonda Szczesniak, PhD, Cincinnati Children’s Hospital Medical Center
Dr. Timothy Corcoran, PhD, University of Pittsburgh
Dr. Kathryn Oliver, PhD, Emory University
Dr. Gabriela Oates, PhD, University of Alabama Birmingham
Dr. Traci Kazmerski, MD, MS, University of Pittsburgh

Workshop Documents

Program Book and Agenda Current and Future Research Needs in the Era of Highly Effective Modulator Therapies for Cystic Fibrosis

Contact

For programmatic questions, contact Marrah Lachowicz-Scroggins at marrah.lachowicz-scroggins@nih.gov. For logistical questions, contact NHLBI Workshop Support at NHLBIWorkshopSupport@nih.gov.