Cystic Fibrosis Transmembrane Conductance Regulator Modulators Research Articles

Cystic fibrosis

Cystic fibrosis (CF) is an autosomal recessive genetic disease caused by variants in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. CFTR dysfunction results in abnormal chloride and bicarbonate transport in epithelial cells, leading to a multiorgan disease dominated by respiratory and digestive manifestations. The respiratory disease, which is characterized by airway mucus plugging, chronic bacterial infection and progressive development of bronchiectasis, may lead to chronic respiratory failure, which is the main cause of premature death in people with CF. Over the past 50 years, major progress has been obtained by implementing multidisciplinary care, including nutritional support, airway clearance techniques and antibiotics in specialized CF centers. The past 10 years have further seen the progressive development of oral medications, called CFTR modulators, that partially restore ion transport and lead to a major improvement in clinical manifestations and lung function, presumably resulting in longer survival. Although an increasing proportion of people with CF are being treated with CFTR modulators, challenges remain regarding access to CFTR modulators due to their high cost, and their lack of marketing approval and/or effectiveness in people with rare CFTR variants. The anticipated increase in the number of adults with CF and their aging also challenge the current organization of CF care. The purpose of this review article is to describe current status and future perspective of CF disease and care.

Comparative effects of CFTR modulators on phagocytic, metabolic and inflammatory profiles of CF and nonCF macrophages

Macrophage dysfunction has been well-described in Cystic Fibrosis (CF) and may contribute to bacterial persistence in the lung. Whether CF macrophage dysfunction is related directly to Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) in macrophages or an indirect consequence of chronic inflammation and mucostasis is a subject of ongoing debate. CFTR modulators that restore CFTR function in epithelial cells improve global CF monocyte inflammatory responses but their direct effects on macrophages are less well understood. To address this knowledge gap, we measured phagocytosis, metabolism, and cytokine expression in response to a classical CF pathogen, Pseudomonas aeruginosa in monocyte-derived macrophages (MDM) isolated from CF F508del homozygous subjects and nonCF controls. Unexpectedly, we found that CFTR modulators enhanced phagocytosis in both CF and nonCF cohorts. CFTR triple modulators also inhibited MDM mitochondrial function, consistent with MDM activation. In contrast to studies in humans where CFTR modulators decreased serum inflammatory cytokine levels, modulators did not alter cytokine secretion in our system. Our studies therefore suggest modulator induced metabolic effects may promote bacterial clearance in both CF and nonCF monocyte-derived macrophages.

Lung Transplantation in a New Era in the Field of Cystic Fibrosis.

Lung transplantation for people with cystic fibrosis (PwCF) is a critical therapeutic option, in a disease without a cure to this day, and its overall success in this population is evident. The medical advancements in knowledge, treatment, and clinical care in the field of cystic fibrosis (CF) rapidly expanded and improved over the last several decades, starting from early pathology reports of CF organ involvement in 1938, to the identification of the CF gene in 1989. Lung transplantation for CF has been performed since 1983, and CF now accounts for about 17% of pre-transplantation diagnoses in lung transplantation recipients. Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have been the latest new therapeutic modality addressing the underlying CF protein defect with the first modulator, ivacaftor, approved in 2012. Fast forward to today, and we now have a growing CF population. More than half of PwCF are now adults, and younger patients face a better life expectancy than they ever did before. Unfortunately, CFTR modulator therapy is not effective in all patients, and efficacy varies among patients; it is not a cure, and CF remains a progressive disease that leads predominantly to respiratory failure. Lung transplantation remains a lifesaving treatment for this disease. Here, we reviewed the current knowledge of lung transplantation in PwCF, the challenges associated with its implementation, and the ongoing changes to the field as we enter a new era in the care of PwCF. Improved life expectancy in PwCF will surely influence the role of transplantation in patient care and may even lead to a change in the demographics of which people benefit most from transplantation.

Emulated trial investigating effects of multiple treatments: estimating combined effects of mucoactive nebulisers in cystic fibrosis using registry data

IntroductionPeople with cystic fibrosis (CF) are often on multiple long-term treatments, including mucoactive nebulisers. In the UK, the most common mucoactive nebuliser is dornase alfa (DNase). A common therapeutic approach...

The Effects of Elexacaftor, Tezacaftor, and Ivacaftor (ETI) on Blood Glucose in Patients With Cystic Fibrosis: A Systematic Review.

Cystic fibrosis (CF) is an autosomal recessive genetic disorder resulting from defects in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which in turn results in a multi-systemic disorder. There are numerous known CF alleles associated with different mutations of the CFTR gene, with the most common CF allele being a three-base-pair deletion known as ΔF508. One common manifestation of CF is glycemic dysregulation associated with decreased insulin secretion, often progressing into a distinct form of diabetes known as cystic fibrosis-related diabetes (CFRD). In the past decade, a class of drugs known as CFTR modulators has entered clinical practice. These drugs interact with the CFTR protein to restore its function, with different modulators (or combinations of modulators) suitable for patients with different CFTR mutations. Previous research has established that the modulator ivacaftor is effective in decreasing blood glucose and sometimes resolving CFRD in patients with certain CFTR mutations (class III mutations). However, early modulator therapies for individuals with the common ΔF508 mutation (e.g., a combination of the modulators lumacaftor and ivacaftor) have largely proven ineffective in improving glucose regulation. More recently, a combination therapy of three modulators, namely elexacaftor, tezacaftor, and ivacaftor (ETI), has entered clinical practice for patients with the ΔF508 mutation. However, it is not clear whether this therapy is effective in treating dysglycemia. We searched for studies of any design that examined the effects of ETI on measures of blood glucose. All available studies were observational studies comparing patients before and after initiating ETI therapy. Measures of daily-life blood glucose (those obtained with continuous glucose monitoring systems or by measuring glycated hemoglobin (HbA1c)) and post-prandial glucose spikes from oral glucose tolerance tests showed significant improvements in at least some studies. The majority of studies showed significant improvements from pre- to post-ETI in one or more blood glucose measures. While the interpretation of this evidence is complicated by the lack of randomized controlled trials, it appears that ETI therapy is associated with improved glucose regulation for at least some patients with the ΔF508 mutation.

It Takes Two to Tango! Protein-Protein Interactions behind cAMP-Mediated CFTR Regulation.

Over the last fifteen years, with the approval of the first molecular treatments, a breakthrough era has begun for patients with cystic fibrosis (CF), the rare genetic disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). These molecules, known as CFTR modulators, have led to unprecedented improvements in the lung function and quality of life of most CF patients. However, the efficacy of these drugs is still suboptimal, and the clinical response is highly variable even among individuals bearing the same mutation. Furthermore, not all patients carrying rare CFTR mutations are eligible for CFTR modulator therapies, indicating the need for alternative and/or add-on therapeutic approaches. Because the second messenger 3',5'-cyclic adenosine monophosphate (cAMP) represents the primary trigger for CFTR activation and a major regulator of different steps of the life cycle of the channel, there is growing interest in devising ways to fine-tune the cAMP signaling pathway for therapeutic purposes. This review article summarizes current knowledge regarding the role of cAMP signalosomes, i.e., multiprotein complexes bringing together key enzymes of the cAMP pathway, in the regulation of CFTR function, and discusses how modulating this signaling cascade could be leveraged for therapeutic intervention in CF.

827-P: Effects of Elexacaftor/Tezacaftor/Ivacaftor Triple Combination Therapy on Glycaemic Control and Body Composition in Patients with Cystic Fibrosis–Related Diabetes

Introduction: Cystic fibrosis related diabetes (CFRD) is the most common extra pulmonary complication of cystic fibrosis (CF). Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are a group of new drugs for the treatment of CF and elexacaftor+tezacaftor+ivacaftor (ETI) triple combination therapy has been approved as first choice therapy in the treatment of patients with at least 1 copy of F508del mutation. Data on the effects of CFTR modulators on glucose metabolism in patients with or without CFRD are limited to small studies with conflicting results. Aim of the study: to evaluate the effectiveness of ETI on glucose metabolism, glucose variability and body composition in patients with CFRD. Methods: We conducted a prospective observational study on 24 CF patients with CFRD requiring insulin therapy. We performed an evaluation of glycometabolic control, glucose variability (assessed with 14 days-flash glucose monitoring) and body composition (with bio-impedance analysis) before and six months after the beginning of ETI. Data are expressed as median and interquartile ranges. Results: We demonstrated an improvement in both HbA1c [from 7.0% (6.5, 7.4) to 6.6 (6.0, 7.1), p<0,05] and coefficient of variation [CV - from 35.0 (29.0, 44.5) to 28.2 (25.2, 33.1), p< 0.01], despite unchanged insulin requirements. Over the treatment period, percent of fat mass (FM) significantly increased [from 12.1% (7.2, 16.2) to 15.4% (11.8, 18.6), p<0.05]. Conclusions: ETI improves glycometabolic regulation in patients with CFRD on insulin therapy. A longer follow-up is needed to better characterize the body composition changes induced by ETI and their metabolic consequences. Disclosure V.Grancini: None. A.Gramegna: None. L.Zazzeron: None. G.Alicandro: None. L.L.Porcaro: None. F.V.Piedepalumbo: None. C.Lanfranchi: None. V.Daccò: None. E.Orsi: None.

Proliferative activity of antigen-specific CD154+ T cells against bacterial and fungal respiratory pathogens in cystic fibrosis decreases after initiation of highly effective CFTR modulator therapy.

Background: Together with impaired mucociliary clearance, lung disease in cystic fibrosis (CF) is driven by dysregulation of innate and adaptive immunity caused by dysfunctional CFTR (Cystic Fibrosis Transmembrane Conductance Regulator), leading to airway infection and hyperinflamma-tion. The highly effective CFTR modulator therapy (HEMT) elexacaftor/tezacaftor/ivacaftor (ETI) generates substantial improvements in clinical outcomes of people with CF (pwCF) by restoration of CFTR activity. Aberrant immune responses of lymphocytes due to CFTR dysfunction has been described in the past, but not the effects of CFTR restoration by HEMT on these cells. We aimed to examine the effect of ETI on the proliferative activity of antigen-specific CD154 (+) T cells against bacterial and fungal species relevant in CF and on total IgG and IgE as markers of B cell adaptive immunity. Methods: We performed ex vivo analyses of Ki-67 expression in antigen-specific CD154 (+) T cells against Pseudomonas aeruginosa, Staphylococcus aureus, Aspergillus fumigatus, Scedosporium apiospermum and Candida albicans from 21 pwCF by cytometric assay based on antigen-reactive T cell enrichment (ARTE), and analysis of total serum IgE and IgG before and after initiation of ETI. Results: Mean Ki-67 expression in antigen-specific CD154 (+) T cells against P. aeruginosa, A. fumigatus, S. apiospermum and C. albicans, but not S. aureus, mean total serum IgG and mean total serum IgE decreased significantly after initiation of ETI. No correlation was found to change in sputum microbiology of the examined pathogens. Mean BMI and FEV1 increased significantly. Conclusion: HEMT is associated with decreased antigen-specific CD154 (+) T cell proliferation activity in our cohort, independent of findings in sputum microbiology of the examined pathogens. Together with the observed clinical improvement and the decrease in total IgE and IgG, this indicates effects due to CFTR restoration on CD154 (+) T cells by ETI and a reduction of B cell activation with subsequent lower immunoglobulin synthesis under HEMT therapy. These results endorse earlier evidence of CFTR dysfunction in T and B cells leading directly to aberrant immune responses with hyperinflammation.

Real-world outcomes and direct care cost before and after elexacaftor/tezacaftor/ivacaftor initiation in commercially insured members with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is a chronic, progressive genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene resulting in a dysfunctional CFTR protein. Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) is a triple combination oral drug therapy with an annual cost greater than $300,000 and available to nearly 90% of the CF population based on age and genotype. Limited real-world direct medical cost offset data are available for ELX/TEZ/IVA among commercially insured individuals. OBJECTIVE: To describe and compare total cost of care and health care resource utilization (HRU) 180 days before and 180 days after first ELX/TEZ/IVA drug claim among CFTR modulator treatment-naive, commercially insured members. METHODS: This study was a retrospective analysis of integrated pharmacy and medical claims data from 17.9 million commercially insured members. A 180-day prestudy and 180-day poststudy design was used to compare outcomes prior to and following ELX/TEZ/IVA initiation. Study inclusion was limited to members with first ELX/TEZ/IVA claim (index date) between October 21, 2019, and December 31, 2021, continuously enrolled 180 days before and 180 days after index date, and no CFTR-modulator drug claim 180 days prior to index date. Total paid amounts from medical and pharmacy claims after network discounts (defined as total cost of care), HRU, and pulmonary exacerbation events were summarized using descriptive statistics and compared using Wilcoxon signed rank test. RESULTS: 494 members newly initiating ELX/TEZ/IVA met inclusion criteria. Prestudy to poststudy mean member total cost of care increased from $58,180 to $198,815 (difference: $140,635; P < 0.001). Mean member medical benefit costs decreased from $28,764 to $12,484 (difference: -$16,280; P < 0.001), whereas mean member pharmacy benefit costs increased from $29,416 to $186,331 (difference: $156,915; P < 0.001). Mean member inpatient hospitalizations (62% absolute reduction; P < 0.001), emergency department visits (43% absolute reduction; P < 0.01), and pulmonary exacerbation events (44% absolute reduction; P < 0.001) were significantly lower in the postperiod compared with the preperiod. CONCLUSIONS: Among members with CF newly initiating CFTR modulator with ELX/TEZ/IVA, mean member total cost of care increased 3-fold despite significant and meaningful reductions in pulmonary exacerbation events, HRU, and medical benefit spend. Pharmacy benefit spend outpaced medical benefit spend at a rate of $9.64 to $1 in the 180 days following ELX/TEZ/IVA initiation. Real-world data should be used to objectively measure the clinical and economic benefits of costly medications, such as CFTR modulators, to align price with value. DISCLOSURES: Drs Marshall, Espinosa, Starner, and Gleason are employees of Prime Therapeutics. The study was funded by Prime Therapeutics.

WS19.03 Triple therapy for Cystic Fibrosis (elexacaftor/tezacaftor/ivacaftor): desensitization after an adverse reaction with severe skin rash

Background: Cystic fibrosis (CF) is an autosomal recessive disorder of the CF transmembrane conductance regulator (CFTR) gene. CFTR modulators are novel approved therapies and triple therapy with elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) is the current gold-standard for patients with at least one F508del mutation. CFTR modulators are usually well tolerated but some adverse effects may occur, including skin rash, that usually does not require drug discontinuation. Rash is more common in women, particularly those on hormonal contraception.

Q1291H-CFTR molecular dynamics simulations and ex vivo theratyping in nasal epithelial models and clinical response to elexacaftor/tezacaftor/ivacaftor in a Q1291H/F508del patient.

Background: Cystic fibrosis (CF) is caused by a wide spectrum of mutations in the CF transmembrane conductance regulator (CFTR) gene, with some leading to non-classical clinical presentations. We present an integrated in vivo, in silico and in vitro investigation of an individual with CF carrying the rare Q1291H-CFTR allele and the common F508del allele. At age 56years, the participant had obstructive lung disease and bronchiectasis, qualifying for Elexacaftor/Tezacaftor/Ivacaftor (ETI) CFTR modulator treatment due to their F508del allele. Q1291H CFTR incurs a splicing defect, producing both a normally spliced but mutant mRNA isoform and a misspliced isoform with a premature termination codon, causing nonsense mediated decay. The effectiveness of ETI in restoring Q1291H-CFTR is largely unknown. Methods: We collected clinical endpoint measurements, including forced expiratory volume in 1s percent predicted (FEV1pp) and body mass index (BMI), and examined medical history. In silico simulations of the Q1291H-CFTR were compared to Q1291R, G551D, and wild-type (WT)-CFTR. We quantified relative Q1291H CFTR mRNA isoform abundance in patient-derived nasal epithelial cells. Differentiated pseudostratified airway epithelial cell models at air liquid interface were created and ETI treatment impact on CFTR was assessed by electrophysiology assays and Western blot. Results: The participant ceased ETI treatment after 3months due to adverse events and no improvement in FEV1pp or BMI. In silico simulations of Q1291H-CFTR identified impairment of ATP binding similar to known gating mutants Q1291R and G551D-CFTR. Q1291H and F508del mRNA transcripts composed 32.91% and 67.09% of total mRNA respectively, indicating 50.94% of Q1291H mRNA was misspliced and degraded. Mature Q1291H-CFTR protein expression was reduced (3.18% ± 0.60% of WT/WT) and remained unchanged with ETI. Baseline CFTR activity was minimal (3.45 ± 0.25μA/cm2) and not enhanced with ETI (5.73 ± 0.48μA/cm2), aligning with the individual's clinical evaluation as a non-responder to ETI. Conclusion: The combination of in silico simulations and in vitro theratyping in patient-derived cell models can effectively assess CFTR modulator efficacy for individuals with non-classical CF manifestations or rare CFTR mutations, guiding personalized treatment strategies and optimizing clinical outcomes.

WS18.01 Impact of elexacaftor/tezacaftor/ivacaftor therapy on sputum metabolomics in adult cystic fibrosis

Background: Adults with cystic fibrosis (CF) suffer from chronic inflammation, infection, and airway obstruction, and often have enhanced sputum production. Although CF transmembrane conductance regulator modulator therapies such as elexacaftor-tezacaftor-ivacaftor (ETI) confer lung function gains in patients with CF, their impact on inflammation and infection is not fully understood. CF sputum contains metabolites and proteins that reflect inflammation. We hypothesized the impact of ETI therapy on CF airway inflammation would be mirrored by changes in the sputum metabolome.

WS01.04 Longtime follow-up on exercise capacity and quality of life in people with cystic fibrosis receiving elexacaftor/tezacaftor/iIvacaftor – a Copenhagen cohort

Background: People with Cystic Fibrosis (CF) have decreased exercise capacity and quality of life (HRQoL) compared to the background population. Since 2020 third generation CF transmembrane conductance regulator modulator, elexacaftor, tezacaftor, ivacaftor (ETI) was approved for people with CF from the age of 12 in Denmark. The results of the treatment over short time, show among other increased lungfunction, HRQoL and BMI. The longterm effect regarding the new treatment is to date not fully evaluated especially not regarding exercise capacity.

WS08.02 Change in hepatobiliary ultrasound measures, incl. shear wave elastography, after introduction of elexacaftor/tezacaftor/ivacaftor: results from 12-month follow-up in the Danish cystic fibrosis cohort

Objectives: A new era in cystic fibrosis (CF) since the introduction of CF transmembrane conductance regulator modulators with elexacaftor/tezacaftor/ivacaftor (ETI) is marked by significantly improved lung function and nutritional status. However, the impact of ETI on the liver remains poorly characterized, as advanced liver disease was an exclusion criterion in clinical trials. Clinical experience from the Danish CF cohort has shown ETI to be generally well-tolerated in term of liver biomarkers. The objective of this study is to assess hepatobiliary ultrasonographic changes before and twelve months after the initiation of ETI.

P161 Desensitization to highly effective modulator therapy – international approach and call for collaboration

Cutaneous adverse reactions have been documented in patients initiated on available cystic fibrosis transmembrane conductance regulator modulators (CFTRm), ivacaftor, lumacaftor/ivacaftor, and tezacaftor/ivacaftor, with a reported incidence of less than 5%. It is increased, up to 10.9%, in patients initiated on elexacaftor/tezacaftor/ivacaftor (E/T/I). Reports have been published regarding various approaches to management of highly effective modulator therapy (HEMT) rash, including graded challenges and a standardized desensitization.

P020 Therapy with elexacaftor/tezacaftor/ivacaftor in a patient with compound heterozygous CFTR mutation and the complex CFTR-allele Phe508del; Leu467Phe

Background: Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy with elexacaftor/tezacaftor/ivacaftor (ETI) was shown to be highly efficacious in patients who have at least one copy of the F508del variant. Cis variants in F508del mutations might influence the response to CFTR modulator therapy. We report the response to ETI in a patient with CF who is heterozygous for the complex Phe508del;Leu467Phe allele.

P321 Impact of short-term CFTR modulators treatment on changes in nutritional and glucose status in cystic fibrosis paediatric patients with different glucose tolerance

Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies are drugs that could change the course of the disease in cystic fibrosis (CF) patients and also nutrition status and glucose metabolism. Our study aimed to assess the impact of CFTR modulators treatment on nutritional and glucose status in CF pediatric patients with different glucose tolerance.

P342 Serum sodium, chloride and potassium levels after start CFTR modulators treatment in CF pediatric patients

Cystic fibrosis can lead to electrolyte imbalance. Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies target the underlying cause of cystic fibrosis (CF) and also could change the ions’ status. However, there is a lack of evidence on whether the electrolyte level in the blood differs after CFTR modulator treatment.

EPS1.08 Immunogenic adverse events to CFTR modulators – an international survey

Objective: Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy has been rolled out across Europe for the treatment of Cystic Fibrosis (CF). These new therapies have a predominately positive effect on people with CF (pwCF), improving lung function, weight and reducing pulmonary exacerbations. However, immunogenic reactions to CFTR modulators can occur and may lead to drug discontinuation. We aimed to assess the frequency and severity of these reactions.

P306 Changes in glucose tolerance in people with cystic fibrosis after initiation of first-generation CFTR modulator treatment

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have been shown to have a beneficial effect on pulmonary function and nutritional status, but their effect on glucose tolerance is not yet fully understood. In the current study, we evaluated the change in glucose tolerance and insulin secretion after first-generation CFTR modulator treatment in adults with cystic fibrosis (CF).