Overview of Study of Highly Effective CFTR Modulator Therapy for Cystic Fibrosis

Background on CFTR modulator drug therapy research

Highly effective CFTR modulator drug therapy targets certain mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR modulators have been found to improve important health outcomes and quality of life for people with cystic fibrosis (CF).

A large, multidisciplinary research study called PROMISE is investigating the effects of the highly effective triple combination CFTR modulator therapy, elexacaftor/tezacaftor/ivacaftor (ETI), across a broad spectrum of organ systems and disease manifestations in people ages 6 years and older. The study seeks to better understand the clinical impacts of ETI therapy and to identify therapeutic and research priorities for those treated with ETI.

Methods of PROMISE study

The study is being conducted at 56 CF research sites across the nation. Two Children’s Hospital Colorado researchers are the co-principal investigators of PROMISE. They are Michael Narkewicz, MD, pediatric hepatologist in the Digestive Health Institute and pediatric pulmonologist Scott Sagel, MD, PhD, director of the Mike McMorris Cystic Fibrosis Research and Care Center.

PROMISE includes biospecimen collection and storage for future investigations. Sites are focusing on shared assessments plus additional targeted outcomes, aligned with organ system sub-studies.

At the time the research review manuscript was published:

• More than 500 participants were enrolled; 98% successfully started ETI.
• Approximately 50% of participants are homozygous for the F508del mutation; most having transitioned from a two-drug CFTR modulator combination to ETI.
• Most of the remaining participants have one copy of the F508del mutation and have not previously been treated with CFTR modulator therapy.

When ETI therapy was approved for use down to 6 years of age in June 2021, a large pediatric sub-study was initiated to include children 6 to 11 years of age. In addition, a separate study called BEGIN will enroll infants and young children up to 5 years of age to evaluate the natural history of CF prior to modulator use in anticipation that ETI will eventually be approved beginning in early infancy.

Organ systems evaluated in PROMISE

Core assessments of PROMISE

Mucus biology and mucociliary clearance (MCC)

Understanding how restoration of CFTR improves MCC could drive future drug development decisions. The PROMISE Mucus/MCC sub-study will:

• Measure MCC in those who have mild to moderate pulmonary disease
• Evaluate effects of ETI on mucus hydration
• Measure pH

Airway microbiology

To better answer questions about the effects of modulators on chronic lung infections, the microbiology sub-study is:

• Collecting induced sputum in subgroup of approximately 250 participants with collection at 1, 3, 6, 12 and 24-month time points and address decrements in sputum production after modulator treatment
  • Measuring quantitative qPCR of targeted species and 16S rRNA gene sequence to obtain broader composition of microbial DNA reflective of lower and upper airway components in sputum
  • Conducting genome sequencing studies to determine if pathogen strains present at pretreatment persist

Effects of ETI on pulmonary and systemic inflammation

To determine the effects of restoration of CFTR function on airway and systemic inflammation, critical downstream consequences of impaired CFTR function, this component of the study, led by Dr. Sagel, is:

• Collecting induced sputum and blood from approximately 250 participants to assess for changes from baseline in airway and circulating measures of inflammation
• Examining relationships between changes in airway inflammation and airway infection, and changes in inflammation with clinical outcomes (lung and nutritional)

Gastrointestinal disease and symptoms

To understand ETI’s impact on GI ailments, particularly correlations between symptoms, motility and luminal pH, the study is:

• Assessing participants’ symptoms and quality of life, and testing subgroups for inflammation, non-pancreatic malabsorption, exocrine pancreatic function, intestinal pH and dysmotility
• Measuring inflammation, exocrine pancreatic function and microbiome changes

CF-related liver disease

Hepatic fibrosis is a potential therapeutic target when studying the clinical impact of ETI. This component of the study, led by Dr. Narkewicz, is:

• Evaluating markers of fibrosis, rate of increase in liver stiffness and changes in liver classification/disease
• Conducting standard phenotypic characterization of CF liver involvement with phenotypic classification
• Evaluating novel biomarkers of liver function

Endocrine-related disorders

To understand how ETI will impact insulin requirements in people with CFRD and those progressing to CFRD, the study will:

• Collect data on insulin requirements and hypoglycemia, and perform extended, multi-sample oral glucose tolerance tests at baseline, 12 and 24 months to examine glucose tolerance or excursion, insulin secretory rates, hepatic insulin clearance and incretin and glucagon secretion
• Collect dual-energy X-ray absorptiometry (DXA) for bone mineral density and body composition annually
• Determine and compare age, gender and pubertal status specific growth velocity Z-scores with baseline growth velocity and to normative data
• Assess lean body mass (LBM) and fat mass changes in the context of BMI
• Evaluate endocrine growth factors throughout study

Advancing personal outcome measures

The PROMISE study aims to better understand the relationship between CFTR rescue and mucociliary clearance and test correlations of groups defined by genetic mutations, including:

• Proving in vitro measures collected from participants will support human nasal epithelial cells as a useful model system for clinical response to ETI
• Establishing a tissue biorepository for future investigations

Pediatric populations

The PROMISE Peds sub-study will help determine if ETI will modify the natural history of younger age groups and control CF disease progression. It is:

• Evaluating longitudinal outcomes associated with ETI initiation in children 6-11 years old, for two years, including:
  • Measuring short and long-term impact of ETI on lung function, microbiology, nutritional status and sweat chloride
  • Collect patient-reported outcomes
  • Measuring lung clearance index (LCI) measured by nitrogen multiple breath washout (MBW)
  • Performing spirometry
  • Obtaining induced sputum and oropharyngeal samples for microbiologic analysis
  • Measuring changes in respiratory microbiota
  • Exploring associations between changes in lung function, airway microbiology and markers of airway inflammation
  • Collecting and banking respiratory samples
  • Capturing effects of modulator therapy on nutritional status and gastrointestinal health through longitudinal changes in BMI and GI-related patient-reported outcome measures

Research review conclusion: a new paradigm of care for CF patients

Collective efforts among these studies will provide a comprehensive understanding of the use of ETI, which authors believe represents a key milestone in the treatment of CF. It also expands research to include younger patients across the world.