Cystic Fibrosis Transmembrane Regulator Modulators Research Articles

Exploring perceptions of and decision-making about CFTR modulators.

Cystic fibrosis (CF)treatment has increasingly focused on highly effective modulators. Despite measurable benefits of modulators, there is little guidance for CF care team members on providing education and support to patients regarding initiation of these therapies. We aimed to explore patient, caregiver, and clinician perceptions of modulators and influences on decisions about starting cystic fibrosis transmembrane regulator (CFTR) modulators. We conducted semistructured interviews with CF clinicians, adults with CF, and caregivers of children with CF. We reviewed audio recordings and coded responses to identify central themes. We interviewed 8 CF clinicians, 9 adults with CF, and 11 caregivers of children with CF. Themes centered on emotional responses to modulator availability, influences on decision-making, concerns about side effects, impact of modulators on planning for the future, the benefits of the multidisciplinary CF care team in supporting treatment decisions, and the unique needs of people with CF who are not eligible for modulators. Clinicians described changes in conversations about modulators since the approval of elexacaftor/tezacaftor/ivacaftor, specifically greater willingness to prescribe with less nuanced conversations with patients and/or caregivers regarding their use. Based on perspectives and experiences of CF clinicians, adults with CF, and caregivers of children with CF, we suggest clinicians approach conversations about CFTR modulators thoughtfully and thoroughly, utilizing the multidisciplinary model of CF care in exploring patient and caregiver emotions while filling in knowledge gaps, asking about treatment goals beyond potential clinical benefit, and having compassionate conversations with those who are ineligible for modulators.

Cystic Fibrosis Transmembrane Regulator Modulator Therapy Perspective: Findings in Clinical Outcomes in a Series of Pediatric Patients

Cystic Fibrosis (CF) is the most frequent autosomal recessive disorder in Caucasians and has reduced life expectancy. It is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene which results in impairment of production, expression, and trafficking of the CFTR protein. CF has a multifaceted clinical representation with respiratory involvement as a main cause of morbidity and mortality. The multidisciplinary approach, care in specialized centers, early diagnosis through neonatal screening, and development of symptomatic treatments improved survival in the last decades. CFTR modulators were developed based on the discovery of the CF gene in 1989 and the improvement of genetic testing and have changed the perspective of a debilitating disease. These therapies, acting more upstream in the pathogenic cascade, overcome the underlying dysfunctions caused by CFTR mutations, having the ability to enhance or restore the resulting functional effects. CFTR modulator therapies are highly effective treatments for cystic fibrosis patients as shown in many clinical trials and real-life analyses so far. Improvement of quality of life, lung function, and pulmonary exacerbation rates are indisputable targets when evaluating the efficacy and efficiency of medical interventions in such a disease as CF, and they have been substantially changed in the era of modulators. We analyzed a small group of patients who were initiated on Kaftrio as per the indicated protocol. All significant clinical and functional aspects were improved, demonstrating the disease-changing potential of this therapy. We did not observe threatening side effects, no patients were stopped from the medication. CFTR modulators are the beginning of a new era in CF, a perspective for the improvement and effectiveness of precision medicine in CF patients.

Effects of Social Determinants of Health on Clinical Outcomes in Pediatric Cystic Fibrosis Patients

Background and Objective: 
 Advances in the treatment of cystic fibrosis (CF) with cystic fibrosis transmembrane regulator modulators have improved morbidity and mortality, however, clinical outcomes vary among genetically similar patients due to contributions of social determinants of health (SDOH). Pancreatic insufficiency, CF-related diabetes (CFRD), Pseudomonas infections, and lower BMI increase risk of severe lung disease, measured by forced expiratory volume in 1 second (FEV1). This project aims to identify socially vulnerable patients and evaluate the impact of SDOH on clinical outcomes. 
 Methods: 
 From January to July 2023, SDOH screeners were distributed to families of children with CF at Riley Hospital for Children, documenting transportation, housing, food insecurity, insurance, and medication costs. Clinical outcomes for each patient including FEV1% predicted, BMI/WFL percentile, CFRD, hospitalizations, respiratory infections with Pseudomonas aeruginosa, and pancreatic insufficiency within the past 12 months were recorded. Patients were categorized by SDOH vulnerability, and associations with poor clinical outcomes were analyzed using the Chi-squared test of independence. 
 Results: 
 A total of 193 screeners were analyzed: males represented 52.6% of the cohort, 2.60% identified as non-white race, and 3.65% reported Hispanic ethnicity. Overall, 51.8% screened positive for at least one SDOH (SDOH+) and 48.1% screened negative (SDOH-). The average FEV1% predicted decline among SDOH+ patients was 5.79% and 3.51% among SDOH- patients. SDOH+ patients were more likely to have at least a 5% decline in FEV1% predicted (p=0.037) and to be hospitalized due to exacerbations of CF lung disease at least once in the past 12 months (p=0.030). Although low BMI percentile, Pseudomonas infection, and CFRD were not significantly associated with SDOH, socially vulnerable patients demonstrated higher rates of these clinical outcomes. 
 Conclusion and Clinical Implications: 
 SDOH impact CF clinical outcomes. Screeners are effective in identifying socially vulnerable patients and serve as the first step in addressing unmet social needs.

Use of CFTR modulators in special populations, part 2: Severe lung disease.

Safety and efficacy data surrounding cystic fibrosistransmembrane regulator(CFTR) modulator administration for people with CF (pwCF) and severe lung disease elect has remained unclear as a result of exclusion from key trials.A scoping review of English language articles from the period of 1 January2012, to 31 July2023 was conducted utilizing PubMed and EmBase databases with the following terms: "severe lung disease" OR "advanced lung disease" AND "ivacaftor OR lumacaftor OR tezacaftor OR elexacaftor"; "cystic fibrosis transmembrane conductance regulator" AND "off label drug use." Search results were reviewed by title and abstract for relevance.Twenty articles specific to CFTR modulator use in the setting of severe lung disease were included for review, with few specific to pediatric-aged pwCF. PwCF and severe lung disease experienced significant improvement in pulmonary function, body weight, number of IV antibiotic days, and quality of life. A few studies reported a transient decline in pulmonary function among pwCF shortly after LUM/IVA initiation. However, preemptive reductions in the dose of LUM/IVA may mitigate this reaction. ELE/TEZ/IVA utilization in pwCF and severe lung disease appears to be devoid of the transient decline in pulmonary function observed with LUM/IVA while providing the same clinical benefit.Current available data regarding use of CFTR modulators in pwCF and severe lung disease is reassuring; however, there remains a lack data regarding outcomes among the pediatric population including long-term outcomes. Therefore, treatment decisions should be individualized and coproduced.

Delivering a New Future for People With Cystic Fibrosis.

Treatment, prognosis, and quality of life for people with cystic fibrosis (CF) have improved steadily since the initial description of the disease, but most dramatically in the past decade. In 2021, the median predicted survival increased to 53 years, compared with 17 years in 1970. The recent improvement in outcomes is attributable to the advent of cystic fibrosis transmembrane regulator (CFTR) modulators, small molecules that enhance the function of defective CFTR protein. The first CFTR modulator, ivacaftor, received Food and Drug Administration approval in 2011 to treat a single CFTR variant, comprising only 4% of those affected by CF. With the demonstration of efficacy, drug approval has been expanded to other variants. Multiple CFTR modulators used in combination with ivacaftor augment efficacy and increase the number of CFTR variants amenable to therapy. Approval of elexecaftor/tezecaftor/ivacaftor in 2019 increased the number of individuals who could benefit from highly effective modulator therapy (HEMT) to ∼90% of the CF population in the United States. HEMT has been dramatically effective, with overall improvements in lung function, quality of life, nutritional status, and, in women, increased fertility. HEMT may delay the onset of other CF-related comorbidities. Although off-target effects, including hepatotoxicity, drug-drug interactions, and putative mental health issues can complicate use, modulator therapy has been generally well tolerated. Ten percent of people with CF have variants that are not amenable to modulator treatment. HEMT, despite its great cost and limited global access, has brought legitimate hope and changed the lives of a significant majority of individuals and families affected by CF in North America.

Health inequities in the modulator era.

To discuss the existing health inequities in people with cystic fibrosis (CF) and how the recent development of cystic fibrosis transmembrane regulator (CFTR) modulators may impact these inequities. People with CF (pwCF) from low socioeconomic status (SES) have more pulmonary exacerbations, worse nutritional status, lower pulmonary function, and an increased mortality rate with less access to lung transplantation. pwCF who identify as racial and ethnic minorities have earlier mortality, lower lung function, are less likely to be detected on newborn screening resulting in a delayed diagnosis, are underrepresented in clinic trials, and less likely to be eligible for a CFTR modulator. Female sex is associated with more pulmonary exacerbations and earlier mortality. Sexual gender minorities are a vulnerable population with worse health outcomes, and more research is needed in CF. CFTR modulators are inaccessible to low to middle-income countries due to significant cost burden. People with CF from low SES, racial and ethnic minorities, female sex, and sexual gender minorities face health inequities. CFTR modulator use will further widen existing health inequities given the unequal access to modulators based on nonqualifying genetics and exorbitant cost restricting use both on an individual and global level.

Identification of single nucleotide variants in SLC26A9 gene in patients with cystic fibrosis (p.Phe508del homozygous) and its association to Orkambi® (Lumacaftor and Ivacaftor) response in vitro

BackgroundSince patients with cystic fibrosis with different Cystic Fibrosis Transmembrane Regulator (CFTR) genotypes present a wide response variability for modulator drugs such as Orkambi®, it is important to screen variants in candidate genes with an impact on precision and personalized medicine, such as Solute Carrier Family 26, member 9 (SLC26A9) gene. MethodsSanger sequencing for the exons and intron–exon boundary junctions of the SLC26A9 gene was employed in nine individuals with p.Phe508del homozygous genotype for the CFTR gene who were not under CFTR modulators therapy. The sequencing variants were evaluated by in silico prediction tools. The CFTR function was measured by cAMP–stimulated current (ΔIsc-eq-FSK) in polarized CFTR of human nasal epithelial cells cultured in micro–Ussing chambers with Orkambi®. ResultsWe found 24 intronic variants, three in the coding region (missense variants – rs74146719 and rs16856462 and synonymous – rs33943971), and three in the three prime untranslated region (3′ UTR) region in the SLC26A9 gene. Twenty variants were considered benign according to American College of Medical Genetics and Genomics guidelines, and ten were classified as uncertain significance. Although some variants had deleterious predictions or possible alterations in splicing, the majority of predictions were benign or neutral. When we analyzed the ΔIsc-eq-FSK response to Orkambi®, there were no significant differences within the genotypes and alleles for all 30 variants in the SLC26A9 gene. ConclusionsAmong the nine individuals with p.Phe508del homozygous genotype for the CFTR gene, no pathogenic SLC26A9 variants were found, and we did not detect associations from the 30 SLC26A9 variants and the response to the Orkambi® in vitro.

Pregnancy in Cystic Fibrosis-Past, Present, and Future.

The introduction of mutation-specific therapy led to a revolution in cystic fibrosis (CF) care. These advances in CF therapies have changed the disease profile from a severe incurable disease with limited survival to a treatable disease with improved quality of life and survival into adulthood. CF patients are now able to plan their future, including marriage and parenthood. Side by side with the optimism, new issues and concerns are arising, including fertility and preparation for pregnancy, maternal and fetal care during pregnancy, and post-partum care. While cystic fibrosis transmembrane regulator (CFTR) modulators show promising results for improving CF lung disease, data on their safety in pregnancy are still limited. We performed a literature review on pregnancy in CF from the past, with the first described pregnancy in 1960, through the current fascinating changes in the era of CFTR modulators, to ongoing studies and future directions. Current advances in knowledge give hope for improved outcomes of pregnancy, towards the best possible prognosis for the mother and for the baby.

Increased aminotransferases do not necessarily mean hepatotoxicity of CFTR modulator therapy.

The presence of macroenzymes may mimic treatment related hepatotoxicity. We present a female subject who developed high alanine aminotransferase (ALT)/aspartate aminotransferase (AST) activity during cystic fibrosis transmembrane regulator (CFTR) modulator therapy. The differential work-up did not show any underlying liver disease. CFTR modulators were stopped with subsequent normalization and immediate rise of ALT/AST after modulators were restarted, which was interpreted as the presentation of CFTR modulator hepatotoxicity. Before permanent CFTR modulators' discontinuation the patient's blood was tested for the presence of macroALT/macroAST and the result was positive. The patient is continuing a CFTR modulator treatment that is being supervised using standard laboratory tests and a test detecting the presence of macroenzymes. At three subsequent measurements the tests showed the presence of macroenzymes. Our patient shows that increased ALT/AST during CFTR modulator therapy may be related to the induction of macroenzymes and not necessarily to hepatotoxicity. Patients with high ALT/AST activity should be considered for testing for the presence of macroenzymes.

Modifier Factors of Cystic Fibrosis Phenotypes: A Focus on Modifier Genes.

Although cystic fibrosis (CF) is recognized as a monogenic disease, due to variants within the CFTR (Cystic Fibrosis Transmembrane Regulator) gene, an extreme clinical heterogeneity is described among people with CF (pwCF). Apart from the exocrine pancreatic status, most studies agree that there is little association between CFTR variants and disease phenotypes. Environmental factors have been shown to contribute to this heterogeneity, accounting for almost 50% of the variability of the lung function of pwCF. Nevertheless, pwCF with similar CFTR variants and sharing the same environment (such as in siblings) may have highly variable clinical manifestations not explained by CFTR variants, and only partly explained by environmental factors. It is recognized that genetic variants located outside the CFTR locus, named "modifier genes", influence the clinical expression of the disease. This short review discusses the latest studies that have described modifier factors associated with the various CF phenotypes as well as the response to the recent CFTR modulator therapies.

Small-molecule eRF3a degraders rescue CFTR nonsense mutations by promoting premature termination codon readthrough.

The vast majority of people with cystic fibrosis (CF) are now eligible for CF transmembrane regulator (CFTR) modulator therapy. The remaining individuals with CF harbor premature termination codons (PTCs) or rare CFTR variants with limited treatment options. Although the clinical modulator response can be reliably predicted using primary airway epithelial cells, primary cells carrying rare CFTR variants are scarce. To overcome this obstacle, cell lines can be created by overexpression of mouse Bmi-1 and human TERT (hTERT). Using this approach, we developed 2 non-CF and 6 CF airway epithelial cell lines, 3 of which were homozygous for the W1282X PTC variant. The Bmi-1/hTERT cell lines recapitulated primary cell morphology and ion transport function. The 2 F508del-CFTR cell lines responded robustly to CFTR modulators, which was mirrored in the parent primary cells and in the cell donors’ clinical response. Cereblon E3 ligase modulators targeting eukaryotic release factor 3a (eRF3a) rescued W1282X-CFTR function to approximately 20% of WT levels and, when paired with G418, rescued G542X-CFTR function to approximately 50% of WT levels. Intriguingly, eRF3a degraders also diminished epithelial sodium channel (ENaC) function. These studies demonstrate that Bmi-1/hTERT cell lines faithfully mirrored primary cell responses to CFTR modulators and illustrate a therapeutic approach to rescue CFTR nonsense mutations.

Aplasia Cutis Congenita in the Setting of Maternal Cystic Fibrosis

Aplasia cutis congenita is a rare scalp defect. An affected neonate was delivered after in utero exposure beginning in the midtrimester to elexacaftor/tezacaftor/ivacaftor for maternal cystic fibrosis management. Although aplasia cutis congenita has many potential etiologies, maternal cystic fibrosis transmembrane regulator modulator therapy has not been implicated.

Impact of highly effective CFTR modulator therapy on digital clubbing in patients with cystic fibrosis

BackgroundThe association of certain disease processes with digital clubbing is well documented. Digital clubbing is often reversible after successful treatment of the underlying pathology, for example, after lung transplantation in patients with cystic fibrosis (CF). We examined the effect of highly effective Cystic Fibrosis Transmembrane Regulator (CFTR) modulators, defined for the purposes of this study as ivacaftor or the combination of ivacaftor, tezacaftor, and elexacaftor (ETI), on digital clubbing. Materials and MethodsClubbing index was measured on plaster of Paris casts of right index fingers obtained from 15 patients with cystic fibrosis, before and after initiation of CFTR modulator therapy. Similar measurements were made on casts for 9 cystic fibrosis patients who underwent lung transplantation. Measurements were made on the most recent casts available before treatment and the first cast available at least 3 months after initiation of treatment. The Wilcoxon signed-rank text was used to detect any significant difference in the pre- and post-treatment casts for each individual. ResultsA significant decrease in the clubbing index was found after both lung transplantation and treatment with highly effective CFTR modulator therapy. ConclusionsThese results add to the body of evidence demonstrating the efficacy of highly effective CFTR modulator therapy, the first agents that act directly at the dysfunctional chloride channel responsible for CF. By demonstrating that CFTR modulator therapy is capable of reversing digital clubbing, this study suggests a beneficial effect on lung pathology aside from air flow and gas transfer.

PCR166 Adherence to Cystic Fibrosis Transmembrane Regulator Modulator Therapies, Hospitalizations, and Medical Costs in Patients with Cystic Fibrosis Using Marketscan Commercial Claims and Encounters Database

As new cystic fibrosis transmembrane conductance regulator modulators (CFTRm) continue to come to market and improve health in patients with cystic fibrosis (CF), CFTRm therapy adherence is increasingly more important to address. The goal of this research study was to examine the association between CFTRm therapy adherence and the outcomes of hospitalization and medical costs in CF patients using MarketScan commercial claims from 2019.

P157 A modified rapid review of gastrointestinal symptoms in people with cystic fibrosis on cystic fibrosis transmembrane regulator modulator therapies

P157 A modified rapid review of gastrointestinal symptoms in people with cystic fibrosis on cystic fibrosis transmembrane regulator modulator therapies

0608 Characterization of Sleep in Emerging Adults with Cystic Fibrosis on CFTR Modulator Therapy

Abstract Introduction Sleep disturbances are common among youth and adults with cystic fibrosis (CF). However, few CF programs regularly screen for sleep disorders beyond sleep disordered breathing. Emerging adults (18 to 25 years) with CF are a unique population, experiencing changes in sleep and life transitions (e.g., education, work, relationships), while also managing a complex chronic illness. CF transmembrane regulator (CFTR) modulator therapies have significantly improved medical and quality of life outcomes, yet the impact on sleep remains to be determined. Methods Emerging adults with CF (EA-CF; n=22, 59.1% female) and without CF (EA-Control; n=17, 76.5% female) completed an online survey that queried (1) symptoms of restless legs syndrome, parasomnias, and daytime sleepiness, and (2) frequency of exogenous sleep aid use (i.e., prescription medications, melatonin, over-the-counter [OTC] sleep aids, and marijuana/CBD). EA-CF were also asked about perceived changes in falling asleep, night waking frequency and duration, and daytime sleepiness since starting CFTR modulator therapy. Results Sleep disorder symptoms were more frequently reported by EA-CF compared to EA-Control, including restless legs syndrome (31.8% vs. 23.5%, small effect size), parasomnias (40.9% vs. 29.4%, small effect size), and excessive daytime sleepiness/fatigue (50.0% vs. 23.5%, medium effect size). OTC sleep aid use did not differ by group (EA-CF 31.8% vs. EA-Control 35.3%), but the frequency was significantly greater in EA-CF (>once/month: EA-CF 27.3% vs. EA-Control 0%, <once/month: EA-CF 4.5% vs. EA-Control 35.3%, large effect size). More EA-CF reported CBD/marijuana use compared to EA-Control (36.4% vs. 17.6%, small effect size), with 31.8% of EA-CF reporting use of CBD/marijuana at least several nights a week (vs. 5.9% of EA-Control, small effect size). Since starting CFTR modulatory therapy, 27.3% of EA-CF reported falling asleep faster, 31.8% reported fewer night wakings, 36.4% reported shorter night wakings, and 36.4% reported reduced daytime sleepiness. Conclusion This study is one of the first to examine sleep in emerging adults with CF on CFTR modulator therapy, with results highlighting the importance of screening for sleep disorders other than sleep disordered breathing, use of exogenous sleep aids to facilitate sleep, and the benefits of CFTR modulator therapy on sleep. Data collection is ongoing. Support (If Any) Natalie V. Zucker Award

An Update on CFTR Modulators as New Therapies for Cystic Fibrosis.

Over the past decade there have been significant developments in the field of Cystic Fibrosis Transmembrane Regulator modulator drugs. Following treatment in patients with cystic fibrosis with common gating mutations using the potentiator drug ivacaftor, successive development of corrector drugs used in combination has led to highly effective modulator therapy being available to more than 85% of the cystic fibrosis population over 12 years of age in the form of elexacaftor/tezacaftor/ivacaftor. In this article, we review the evidence from clinical trials and mounting real-world observational and registry data that demonstrates the impact highly effective modulators have on both pulmonary and extra-pulmonary manifestations of cystic fibrosis. As clinical trials progress to younger patient groups, we discuss the challenges to demonstrating drug efficacy in early life, and also consider practicalities of drug development in an ever-shrinking modulator-naïve population. Drug-drug interactions are an important consideration in people with cystic fibrosis, where polypharmacy is commonplace, but also as the modulated population look to remain healthier for longer, we identify trials that aim to address treatment burden too. Inequity of care, through drug cost or ineligibility for modulators by genotype, is widening without apparent strategies to address this; however, we present evidence of hopeful early-stage drug development for non-modulatable genes and summarise the current state of gene-therapy development.

Changes in Glucose Breath Test in Cystic Fibrosis Patients Treated With 1 Month of Lumacaftor/Ivacaftor.

Alteration of the airway microbiota is a hallmark of cystic fibrosis (CF) pulmonary disease. Dysfunction of cystic fibrosis transmembrane regulator (CFTR) in the intestine also promotes changes in local microbiota such as small intestinal bacterial overgrowth (SIBO), which is common in CF. We evaluated whether therapy with the CFTR modulator combination lumacaftor/ivacaftor (luma/iva) has a beneficial impact on SIBO as measured by breath testing (BT). A multicenter longitudinal study of CFTR-dependent disease profiling (NCT02477319) included a prospective evaluation for SIBO by BT. Tidal breath samples were collected after fasting and 15, 30, 45, 60, 90, and 120 minutes after ingestion of glucose, before and 1 month after subjects initiated luma + iva. Forty-two subjects enrolled in the sub-study (mean age = 23.3 years; 51% female; 9.5% Latinx); 38 completed a hydrogen BT at both time points, of which 73.7% had a positive BT before luma/iva (baseline) and 65.8% had a positive test after luma/iva ( P = 0.44); shifts from negative to positive were also seen. Use of azithromycin (63.1%) and inhaled antibiotics (60.5%) were not associated with positive BT. Acid-blocking medications were taken by 73% of those with a negative BT at baseline and by 35% with a positive baseline BT ( P = 0.04). We found a high rate of positive hydrogen breath tests in individuals with CF, confirming that SIBO is common. One month of luma/iva did not significantly change the proportion of those with positive breath hydrogen measurements.

Unmasking hereditary hemochromatosis with CFTR modulator therapy

Cystic Fibrosis (CF) is a genetic condition affecting the ability to excrete chloride, resulting in multi-system organ damage. Liver disease is one co-morbidity that affects 20-40% of people with CF. This case describes a 16-year-old male with CF (F508Del and Q493X mutations) who was started one lexacaftor/tezacaftor/ifacaftortriple CF Transmembrane Regulator (CFTR) modulator therapy. Prior to starting treatment, it was noted that he had transaminitis (AST 69, ALT 120, Total bilirubin 0.4). His liver enzymes continued to increase with therapy and at week 8 of treatment he complained of abdominal pain, body aches, and fatigue warranting further evaluation. At that time, AST and ALT were elevated at 5- and 13-times the Upper Limits of Normal (ULN) and creatinine kinase was elevated at 12-times ULN. A dose reduction led to a decrease in AST and ALT to 2 and 4-times ULN, but total and direct bilirubin increased to 2.2 mg/dl and 0.5 mg/dl, warranting a liver ultrasound and biopsy. Pathology showed fatty liver and hepatocyte iron deposition, but no indications of cirrhosis. Iron studies and genetic testing confirmed a diagnosis of HH (Homozygous HIS63ASP gene mutation). After stopping triple CFTR modulator therapy, AST and ALT continued to rise, prompting further evaluation by hepatology and hematology. Upon discontinuation of drug therapy, his lung function dropped significantly back to baseline values and respiratory symptoms returned. Discussion: Hereditary hemochromatosis gene mutations have been shown to have a gene modulating impact on CFTR gene mutations that can affect CF disease phenotype, which negatively affects pulmonary function and gastrointestinal disease. In this case, the introduction of a new medication instigated further work-up leading to the discovery of a potential alternative cause of hepatic dysfunction while attempting to optimize medications to sustain improvements in pulmonary function. Although elevated hepatic transaminases can be expected from CF and CFTR modulator therapy, further investigation may be indicated in patients with persistent elevations despite medication adjustments. This workup may lead to important considerations in balancing liver function with lung function. Keywords: cystic fibrosis; elexacaftor; tezacaftor; ivacaftor; liver transaminases; hereditary hemochromatosis.

Anticipating New Treatments for Cystic Fibrosis: A Global Survey of Researchers.

Cystic fibrosis is a life-threatening disease that affects at least 100,000 people worldwide. It is caused by a defect in the cystic fibrosis transmembrane regulator (CFTR) gene and presently, 360 CFTR-causing mutations have been identified. Since the discovery of the CFTR gene, the expectation of developing treatments that can substantially increase the quality of life or even cure cystic fibrosis patients is growing. Yet, it is still uncertain today which developing treatments will be successful against cystic fibrosis. This study addresses this gap by assessing the opinions of over 524 cystic fibrosis researchers who participated in a global web-based survey. For most respondents, CFTR modulator therapies are the most likely to succeed in treating cystic fibrosis in the next 15 years, especially through the use of CFTR modulator combinations. Most respondents also believe that fixing or replacing the CFTR gene will lead to a cure for cystic fibrosis within 15 years, with CRISPR-Cas9 being the most likely genetic tool for this purpose.