Highly Effective Modulator Therapy in Cystic Fibrosis: Addressing Unusual Variants in the Middle East

Background: Elexacaftor/tezacaftor/ivacaftor (ETI) is the newest cystic fibrosis transmembrane conductance regulator (CFTR) modulator drug approved for the treatment of patients with cystic fibrosis (pwCF) aged ≥6 years with at least one copy of the F508del mutation (F) in the CFTR gene or another mutation that is responsive to treatment with ETI. This study determined the effectiveness and safety of ETI in a cohort of severely affected pwCF with an F/F genotype. Methods: Retrospective observational study in F/F pwCF treated for 48 weeks, enrolled in an ETI managed access program available to subjects with advanced lung disease (ppFEV1 < 40). Twenty-six patients from three centres were included. The main outcomes included lung function, sweat chloride concentration (SCC), nutrition, frequency of pulmonary exacerbations (PEx), CFQ-R, and safety. Results: ppFEV1 improved by 12.06 (95%CI 8.54, 15.57) from baseline after 4 weeks of treatment with ETI, 15.32 (11.3, 19.34) after 24 weeks, and 14.48 (10.64, 18.32) after 48 weeks. The increase in FEV1 was accompanied by a decrease in SCC, improvement of BMI, and noticeable reduction in PEx. An overall good safety profile was observed. Conclusions: In F/F pwCF with advanced lung disease with an F/F genotype, ETI was safe and associated with clinical improvement.

Cystic fibrosis is a life-limiting genetic condition that affects over 9000 people in England. Cystic fibrosis is usually diagnosed through newborn screening and causes symptoms throughout the body, including the lungs and digestive system. Around 90% of individuals with cystic fibrosis have at least one copy of the F508del mutation on the cystic fibrosis transmembrane conductance regulator gene. To appraise the clinical effectiveness and cost-effectiveness of elexacaftor-tezacaftor-ivacaftor, tezacaftor-ivacaftor and lumacaftor-ivacaftor within their expected marketing authorisations for treating people with cystic fibrosis and at least one F508del mutation, compared with each other and with established clinical management before these treatments. A de novo systematic literature review (search date February 2023) was conducted searching electronic databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials), bibliographies of relevant systematic literature reviews, clinical trial registers, recent conferences and evidence provided by Vertex Pharmaceuticals (Boston, MA, USA). Data on the following outcomes were summarised: acute change in per cent predicted forced expiratory volume in 1 second (change in weight-for-age z-score; and change in pulmonary exacerbation frequency requiring intravenous antibiotics. Network meta-analyses were conducted where head-to-head data were not available. Data from clinical trials and real-world evidence were examined to assess long-term effectiveness. A patient-level simulation model was developed to assess the cost-effectiveness of the three modulator treatments. The model employed a lifetime horizon and was developed from the perspective of the NationalHealthService. Data from 19 primary studies and 7 open-label extension studies were prioritised in the systematic literature review. Elexacaftor/tezacaftor/ivacaftor was associated with a statistically significant increase in predicted forced expiratory volume in 1 second and weight-for-age z-score and a reduction in pulmonary exacerbations compared with established clinical management, lumacaftor/ivacaftor and tezacaftor/ivacaftor, and also led to a reduction in the rate of predicted forced expiratory volume in 1 second decline relative to established clinical management, although the magnitude of this decrease was uncertain. Lumacaftor/ivacaftor and tezacaftor/ivacaftor were also associated with a statistically significant increase in predicted forced expiratory volume in 1 second and reduction in pulmonary exacerbations relative to established clinical management, but with a smaller effect size than elexacaftor/tezacaftor/ivacaftor. There was some evidence that tezacaftor/ivacaftor reduced the rate of predicted forced expiratory volume in 1 second decline relative to established clinical management, but little evidence that lumacaftor/ivacaftor reduced the rate of predicted forced expiratory volume in 1 second decline relative to established clinical management. The incremental cost-effectiveness ratios from the economic analysis were confidential. However, for all genotypes studied the incremental cost-effectiveness ratios were above what would be considered cost-effective based on the National Institute for Health and Care Excellence threshold of £20,000-30,000 per quality-adjusted life-year gained. Despite the improved clinical benefits observed, none of the cystic fibrosis transmembrane conductance regulator gene modulators assessed would be considered cost-effective based on the National Institute for Health and Care Excellence threshold of £20,000-30,000 per quality-adjusted life-year gained. This is largely driven by the high acquisition costs of cystic fibrosis transmembrane conductance regulator gene modulator treatments. This study is registered as PROSPERO CRD42023399583. This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR135829) and is published in full in Health Technology Assessment; Vol. 29, No. 19. See the NIHR Funding and Awards website for further award information.

Background. Cystic fibrosis (CF) is a multisystem disease caused by variants in the CF transmembrane conductance regulator (CFTR) gene affecting ion transport. CFTR modulator therapy has become a significant treatment option for many CF patients. However, access to modulator therapy remains a challenge for cases with rare variants. Case Presentation. Our 9-year-old female patient, diagnosed with CF by elevated sweat chloride and history of steatorrhea from birth, carried the rare W1282X variant with no clear eligibility for modulator therapy. The family self-financed one month of elexacaftor / tezacaftor / ivacaftor (ETI) treatment. After one-month, clinical evaluation showed improvements in body mass index (BMI; 14.98 to 15.05 kg/m2), an increase in forced expiratory volume in 1 second (FEV1%) by 12% (72% to 84%), decreased sweat chloride levels (from 83 mEq/L to 9 mEq/L), and enhanced exercise capacity. No pulmonary exacerbations occurred during therapy. Based on these findings, modulator therapy approval was obtained for continued treatment. Our patient is currently 10 years old and has been on modulator therapy for approximately 12 months. Conclusions. Facilitating access to modulator therapies for patients with rare mutations is crucial, considering the potential long-term complications of CF. While organoid studies may not always predict clinical response, real-world cases demonstrate clinically meaningful benefit despite lack of organoid responsiveness. Short-term assessment of modulator response may not adequately reflect improvement in pulmonary function or exacerbation frequency, but decreases in sweat chloride, improvements in nutritional and functional parameters such as weight, BMI, and exercise capacity may be indicative of improvement in pulmonary function and exacerbation rates.

Some residues in the cystic fibrosis transmembrane conductance regulator (CFTR) channel are the site of more than one CFTR variant that cause cystic fibrosis. Here, we investigated the function of S1159F and S1159P, two variants associated with different clinical phenotypes, which affect the same pore-lining residue in transmembrane segment 12 that are both strongly potentiated by ivacaftor when expressed in CFBE41o- bronchial epithelial cells. To study the single-channel behaviour of CFTR, we applied the patch-clamp technique to Chinese hamster ovary cells heterologously expressing CFTR variants incubated at 27°C to enhance channel residence at the plasma membrane. S1159F- and S1159P-CFTR formed Cl- channels activated by cAMP-dependent phosphorylation and gated by ATP that exhibited thermostability at 37°C. Both variants modestly reduced the single-channel conductance of CFTR. By severely attenuating channel gating, S1159F- and S1159P-CFTR reduced the open probability (Po ) of wild-type CFTR by ≥75% at ATP (1mM); S1159F-CFTR caused the greater decrease in Po consistent with its more severe clinical phenotype. Ivacaftor (10-100nM) doubled the Po of both CFTR variants without restoring Po values to wild-type levels, but concomitantly, ivacaftor decreased current flow through open channels. For S1159F-CFTR, the reduction of current flow was marked at high (supersaturated) ivacaftor concentrations (0.5-1μM) and voltage-independent, identifying an additional detrimental action of elevated ivacaftor concentrations. In conclusion, S1159F and S1159P are gating variants, which also affect CFTR processing and conduction, but not stability, necessitating the use of combinations of CFTR modulators to optimally restore their channel activity. KEY POINTS: Dysfunction of the ion channel cystic fibrosis transmembrane conductance regulator (CFTR) causes the genetic disease cystic fibrosis (CF). This study investigated two rare pathogenic CFTR variants, S1159F and S1159P, which affect the same amino acid in CFTR, to understand the molecular basis of disease and response to the CFTR-targeted therapy ivacaftor. Both rare variants diminished CFTR function by modestly reducing current flow through the channel and severely inhibiting ATP-dependent channel gating with S1159F exerting the stronger adverse effect, which correlates with its association with more severe disease. Ivacaftor potentiated channel gating by both rare variants without restoring their activity to wild-type levels, but concurrently reduced current flow through open channels, particularly those of S1159F-CFTR. Our data demonstrate that S1159F and S1159P cause CFTR dysfunction by multiple mechanisms that require combinations of CFTR-targeted therapies to fully restore channel function.

The advent of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy, especially the triple therapy combining the drugs elexacaftor, tezacaftor, ivacaftor (ETI), has significantly changed the course of the disease in people with cystic fibrosis (pwCF). ETI, which is approved for the majority (80-90%) of pwCF, partially restores CFTR channel function, resulting in improved mucociliary clearance and, consequently, improved lung function, respiratory symptoms and pulmonary exacerbations. The bacterial burden of classical CF pathogens such as Pseudomonas aeruginosa and Staphylococcus aureus is reduced without reaching eradication in the majority of infected patients. Limited data is available on less common or emerging bacterial pathogens. ETI has a positive effect on the lung microbiome but does not fully restore it to a healthy state. Due to the significant reduction in sputum production under ETI, respiratory samples such as deep-throat swabs are commonly taken, despite their inadequate representation of lower respiratory tract pathogens. Currently, there are still unanswered questions related to this new therapy, such as the clinical impact of infection with cystic fibrosis (CF) pathogens, the value of molecular diagnostic tests, the durability of the effects on respiratory infection and the role of fungal and viral infections. This article reviews the changes in bacterial lung infections and the microbiome in CF to provide evidence for the use of antibiotics in the era of ETI.

Real-life impact of genotype and severity of lung disease on efficacy of elexacaftor-tezacaftor-ivacaftor in people with cystic fibrosis.

Introduction Cystic fibrosis (CF) is a heterogeneous multisystemic disease. Despite considerable improvement in survival, CF remains a life-shortening disease with respiratory failure as the main cause of death. In 2020, elexacaftor/tezacaftor/ivacaftor (ETI) became available as a new highly effective CFTR-modulator therapy targeting the basic protein defect for people with a specific gene variant, and it was shown to improve lung function respiratory symptoms, and other clinical outcomes, including pulmonary exacerbations (PEx) [1]. However, despite the reduced frequency of PEx, these events remain an important driver of morbidity and mortality in people with CF (pwCF) [2]: in 2023, 16% of adults with CF in Europe experienced at least one PEx during the year [3]. The full extent of CFTR modulators effect on chronic airway infections and the recurrent PEx, especially in the long-term, remains uncertain with some studies reporting inconsistent results [4]. Objectives This study aimed to evaluate the real-world effectiveness of ETI therapy on PEx frequency in pwCF followed up between 2018 and 2023, using data from the European Cystic Fibrosis Society Patient Registry (ECFSPR). Specifically, a longitudinal comparison was conducted to evaluate the effectiveness of the new CFTR-modulator therapy on the number of PEx and the prevalence of chronic infections over time. Methods Data were obtained from the ECFSPR, a population-based Registry that collects clinical and demographic data on an annual basis according to agreed definitions of a common set of variables from Centres and national Registries in Europe and neighbouring countries from 2008 to 2023 [9]. To determine the effectiveness of ETI on PEx and chronic infections, a retrospective and longitudinal comparison from 2018 to 2023 was implemented. The analysis included the following variables: total number of days of intravenous antibiotics (IV Abx), including those performed both in hospital and at home (as a proxy for PEx), number of days of IV Abx performed exclusively in hospital, total number of days in hospital for any cause and the presence of chronic infections, including Pseudomonas aeruginosa, Burkholderia Cepacia Complex and Staphylococcus aureus. The first three variables were analysed both as continuous and as categorical (≥1 day vs. 0 days). The chronic infections were instead categorized as the presence of at least one infection versus no infection. To assess whether there were significant differences between the paired periods before and after treatment, the Wilcoxon signed-rank test and McNemar's test for paired data were used, as the same pwCF were evaluated at two time points. All analyses were performed using R software. Results The study included pwCF aged 12-60 years; pwCF who underwent solid organ transplants were excluded. Participants had either an F508del homozygous genotype or were F508del heterozygous with a minimal function variant The analyses were restricted to those who started ETI modulator therapy in 2020 (N= 6,628). Only people with available data on the number of days on IV Abx therapy administered at home and in hospital were considered, resulting in a final study population of 4,602 pwCF. Comparison of two years before and two years after starting ETI showed that the percentage of pwCF with at least one day on IV Abx decreased significantly from 64% to 23% (p&lt;0.001), the percentage of pwCF with at least one day on IV Abx in hospital decreased from 50% to 16% (p&lt;0.001) and, in parallel, that the percentage of pwCF hospitalized dropped from 56% to 24% (p&lt;0.001). Also considering the corresponding variables as continuous, all the differences remain statistically significant. Notably, these improvements measured by total days on IV antibiotics and related variables persisted through three years post-ETI initiation. The prevalence of at least one chronic infection significantly decreased from 67.8% to 36.8% after 2 years of ETI therapy (p&lt;0.001). Number of chronic infections further decreased to 34.5% after 3 years of treatment. Conclusions This analysis of the ECFSPR data demonstrates a marked reduction in PEx after the introduction of the new highly effective CFTR-modulator therapy. The introduction of ETI significantly reduced the clinical burden in pwCF, with decreases of days on IV Abx, hospitalizations and chronic infections. These benefits were observed consistently after 3 years of therapy. Further steps will include the implementation of statistical models to study changes in days on IV Abx as well as in other clinical outcomes before and after ETI.

Cystic fibrosis (CF) is caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. The combination of the CFTR modulators elexacaftor, tezacaftor, and ivacaftor (ETI) enables the effective rescue of CFTR function in people with the most prevalent F508del mutation. However, the functional restoration of rare CFTR variants remains unclear. Here, we use patient-derived intestinal organoids (PDIOs) to identify rare CFTR variants and potentially individuals with CF that might benefit from ETI. First, steady-state lumen area (SLA) measurements were taken to assess CFTR function and compare it to the level observed in healthy controls. Secondly, the forskolin-induced swelling (FIS) assay was performed to measure CFTR rescue within a lower function range, and to further compare it to ETI-mediated CFTR rescue in CFTR genotypes that have received market approval. ETI responses in 30 PDIOs harboring the F508del mutation served as reference for ETI responses of 22 PDIOs with genotypes that are not currently eligible for CFTR modulator treatment, following European Medicine Agency (EMA) and/or U.S. Food and Drug Administration (FDA) regulations. Our data expand previous datasets showing a correlation between in vitro CFTR rescue in organoids and corresponding in vivo ppFEV1 improvement upon a CFTR modulator treatment in published clinical trials, and suggests that the majority of individuals with rare CFTR variants could benefit from ETI. CFTR restoration was further confirmed on protein levels using Western blot. Our data support that CFTR function measurements in PDIOs with rare CFTR genotypes can help to select potential responders to ETI, and suggest that regulatory authorities need to consider providing access to treatment based on the principle of equality for people with CF who do not have access to treatment.

Background: Cystic Fibrosis is an inherited disorder caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene, encoding a chloride and bicarbonate channel widely expressed in epithelia. Loss of CFTR function leads to dehydration of the epithelium surface with thicker mucus secretions from tissues. The lungs, pancreas, liver, intestines, and sweat glands are the most common affected organs. However, pulmonary disease remains the main cause of morbidity and mortality. Fortunately, elexacaftor/tezacaftor/ivacaftor (ETI) therapy is showing unprecedented clinical benefits in patients with Cystic Fibrosis (CF) carrying at least one F508del mutation in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. However, almost 35% of the CF population living in the Mediterranean area still lacks effective CFTR modulator therapies because of the elevated incidence of patients with (pw)CF harboring CFTR rare mutations (RMs), different from F508del. Methods: Twenty-three pwCF harboring RM including the N1303K underwent off-label ETI treatment for 6-12 months. Respiratory function in terms of FEV1 and FVC was measured after 3, 6, and 12 months of treatment. In addition, we analyzed sweat chloride concentration, body mass index (BMI), and quality of life before and after treatment. Possible adverse effects were recorded. Results: All patients included in this off-label program displayed a substantial improvement in respiratory function. In particular, patients carrying the N1303K mutation showed an improvement in FEV1 and FVC similar to that observed in subjects harboring the F508del mutation, although sweat chloride concentration was not significantly decreased. No severe adverse effect was reported. Conclusions: This study strengthens the clinical efficacy of ETI in pwCF harboring the N1303K and other CFTR rare variants. Since these CFTR RMs have not been approved for ETI therapy in Europe, this study may promote the inclusion of these variants in the list of CFTR mutations responsive to ETI.

Generation of Novel AAV Variants by Directed Evolution for Improved CFTR Delivery to Human Ciliated Airway Epithelium

Over the past decade, the development of highly effective cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators has dramatically ameliorated the manifestations of CF for most patients. Perhaps most importantly, CFTR modulators impact the development and progression of advanced lung disease (ALD) and are changing the CF population accessing lung transplant. A recent phase 3 trial of elexacaftor/tezacaftor/ivacaftor (ETI) demonstrated efficacy for individuals with at least one copy of the most common CF mutation, F508del. Studies of CFTR modulator therapy in patients with ALD have demonstrated similar improvements in lung function, nutrition, and pulmonary exacerbation frequency as seen in individuals with higher lung function. Due to improvements with ETI, rates of lung transplant for CF have declined and individuals are achieving stability in lung function. Nevertheless, the Cystic Fibrosis Foundation guidelines for lung transplant referral should be used to guide referral decisions for all individuals with CF, including those on CFTR modulator therapy, to allow remediation of modifiable barriers to transplant. ETI may be used in the posttransplant setting but for selected individuals and with close monitoring. Increasing access to highly effective CFTR modulators has changed the trajectory of lung disease in CF for many, but not all, individuals and there remain individuals who cannot access therapy or whose mutations do not respond to modulators. Lung transplant remains an important treatment option for individuals with advanced CF lung disease. Increasing attention will be required to optimize decisions of when to list for transplant.

The triple combination of elexacaftor/tezacaftor/ivacaftor (ETI) has dramatically improved the outcome of people with Cystic Fibrosis (pwCF) with at least one F508del mutation. However, carriers of rare cystic fibrosis transmembrane conductance regulator (CFTR) variants are not candidates for this innovative treatment. In this observational study, we report the results of the compassionate use of ETI in 10 pwCF carriers of rare mutations after 2 months of treatment. Rectal organoids and short-term cultures of nasal epithelium obtained from rectal suction biopsies and nasal brushing were obtained from four subjects. After 2 months of ETI, all patients (4 males, mean age 30.1 ± 13.3 years) showed a significant increase of FEV1% predicted values [+8.0 (3.5-12.7) %, p < 0.010], body mass index [+0.85 (0-1.22) kg/m2, p < 0.020] and cystic fibrosis questionnaire-revised [+19.5 (6.3-29.2) points, p < 0.009]. A significant decrease of sweat chloride concentration [-11.2 (-1.7 to -34.0) mmol/L, p < 0.020] and exacerbations [-1.5 (-2 to -1), p < 0.008] was also recorded. Overall, 7 out of 10 participants were considered full responders. All patients reported cough disappearance (n = 3) or reduction (n = 7). Long-term oxygen was discontinued in two out of three patients and one also stopped noninvasive ventilation and was removed from the lung transplantation waiting list. Despite the limited number of cases, our results support the use of CFTR modulators in patients with rare CFTR variants that are not currently approved for ETI in Europe.

N1303K (p.Asn1303Lys) variant: Expanding frontiers in the treatment of cystic fibrosis.

Linoleic acid supplement in cystic fibrosis: friend or foe?

Safety and efficacy of elexacaftor/tezacaftor/ivacaftor in people with Cystic Fibrosis following liver transplantation: A systematic review