Kalydeco (ivacaftor) / Vertex - LARVOL DELTA

Beyond CFTR: Ivacaftor's role in restoring cellular redox balance and preventing ferroptosis. (PubMed, Redox Biol) - "Moreover, we demonstrate that ivacaftor acts as a regulator of cellular innate antioxidant defense pathways, restoring physiological levels of Nrf2 and GPx4, and upregulating the expression of FSP1. These findings reveal a previously unexplored aspect of ivacaftor's pharmacological profile, suggesting potential therapeutic applications extending beyond the realm of CF, particularly in disease contexts characterized by elevated oxidative stress and ferroptotic cell death."

Journal • Cystic Fibrosis • Genetic Disorders • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • AIFM2 • CFTR • GPX4

Cystic Fibrosis and CFTR Modulators: The Impact on Bone Density, Muscle Mass and Strength in Children and Young Adolescents. (PubMed, Children (Basel)) - "On the other hand, the impact of CFTR modulators on muscle mass and strength seems to vary among studies. Besides the current literature, further studies are needed to validate the existing claims."

Journal • Review • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

A Phase 2 Study Evaluating Safety and Tolerability of RCT2100 (CFTR mRNA) in Healthy Participants and in Participants With CF (clinicaltrials.gov) - P2 | N=192 | Recruiting | Sponsor: ReCode Therapeutics | Phase classification: P1 ➔ P2 | Trial completion date: Mar 2026 ➔ Dec 2026 | Trial primary completion date: Dec 2025 ➔ Aug 2026

Phase classification • Trial completion date • Trial primary completion date • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

ABCB4 disease-causing variants S242R, S346I, T437I and T1077M significantly impair its function and display differential sensitivity to potentiators. (PubMed, Sci Rep) - "The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) potentiators ivacaftor and Small Binder of CFTR 219 (SBC219) significantly rescued the function defect of the mutants with differential sensitivity. Our results demonstrate the importance of the four mutated residues for ABCB4 function, which may explain the pathogenic phenotype. They provide an experimental evidence that targeted pharmacotherapy for genetic diseases caused by ABCB4 deficiency is likely to be mutation-specific."

Journal • Cholestasis • Cystic Fibrosis • Gene Therapies • Genetic Disorders • Hepatology • Immunology • Pulmonary Disease • Respiratory Diseases • ABCB4 • CFTR

PDE4 inhibitor apremilast rebalances inflammatory responses to Pseudomonas aeruginosa infection in CF rats (NACFC 2025) - "We previously found Apremilast (Apr), an FDA-approved phosphodiesterase-4 (PDE4) inhibitor for psoriasis, enhances CFTR activation and mucus transport in CF models in addition to Ivacaftor (Iva). PDE4 inhibition represents a promising therapeutic approach for CF, offering dual benefits of anti-inflammatory action and enhanced CFTR function. The synergistic action of PDE4 inhibitors with CFTR modulators to activate CFTR clearly indicates the compatibility of these drugs with HEMT in managing CF by directly addressing inflammatory damage and accelerate decline. The findings of our in vivo study also provide insights into molecular pathways that can be targeted to discover novel anti-inflammatory drugs."

Preclinical • Cystic Fibrosis • Dermatology • Genetic Disorders • Infectious Disease • Inflammation • Psoriasis • Respiratory Diseases • IFNG • IL17A • IL1B • IL6 • TNFA

Mechanism of Action of X316761, A Highly Efficacious Potentiator, Studied Using Structural Biology & Electrophysiology (NACFC 2025) - "In conclusion, we demonstrated that X316761 is a CFTR potentiator more effective than VX-770 and GLPG1837. Cryo-EM and electrophysiology data revealed the amino acids engaged in X316761 binding, a crucial finding that paves the way for knowledge-based drug design."

CFTR

Increased small airway clearance after starting highly effective modulator therapy: Decoding "the purge" in CF (NACFC 2025) - "We hypothesized that small airway clearance would improve following ivacaftor treatment in this model and that the response might be influenced by the airway microenvironment... Short-term invacaftor re-initiation rapidly restored small airway clearance, offering insight into the mechanisms underlying the clinical "purge" response. These data could help shape treatment outcomes and may guide future strategies for optimizing HEMT initiation, ultimately improving therapeutic outcomes in CF."

Cystic Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Inflammation • Pulmonary Disease • Respiratory Diseases • CFTR

Restoration of anion transport to W1282X-CFTR expressing human bronchial epithelial cells by synthetic anion transporters (NACFC 2025) - "As controls, cells were chronically treated with the nonsense-mediated mRNA decay (NMD) inhibitor SMG1i (1 μM), elexacaftor (2 μM), tezacaftor (3 μM) and ivacaftor (1 μM) (S/E/T/I) for 24 h at 37 °C. diF-OPBU anionophores restored anion transport to human bronchial epithelial cells expressing W1282X-CFTR and their action was synergistic with NMD inhibition and CFTR modulation. Future studies will evaluate whether MSNs achieve efficient, controlled delivery of anionophores to airway epithelial cells."

CFTR

Rational design of ivacaftor-derived antimicrobial peptidomimetics: Membrane-targeting strategy enhances broad-spectrum antimicrobial efficacy against MDR pathogens. (PubMed, Eur J Med Chem) - "More crucially, in vivo toxicity studies and murine corneal infection models with Staphylococcus aureus confirmed the low toxicity and potent antibacterial efficacy of 27. In summary, as a novel molecular entity, compound 27 is a valuable broad-spectrum, low-toxicity candidate antibacterial agent capable of combating multidrug-resistant (MDR) bacteria."

Journal • Infectious Disease

Long term causal effects of ivacaftor on airway microbiology and lung function outcomes in people with CF: An emulation of target trials with the U.S. CF Foundation Patient Registry data (NACFC 2025) - "The per-protocol analysis censored individuals who deviated from their initial treatment, and a third approach further censored those who started other modulators (lumacaftor/ivacaftor or tezacaftor/ivacaftor). Our findings demonstrate a robust long-term clinical benefit over a 7-year period of ivacaftor across both clinical and microbiological outcomes, particularly among younger patients and those with gating mutations. These results provide real-world support for sustained ivacaftor use in eligible CF populations."

Clinical • Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

First Nationwide Screening of Cystic Fibrosis Among Chinese Bronchiectasis Patients: Distinct Clinical and Genetic Profiles with Therapeutic Implications. (WBC 2025) - "This study represents the first large-scale CF screening in bronchiectasis patients in China, uncovering novel CFTR mutations and revealing distinctive clinical features of CF in this population. The identification and classification of CFTR mutations in this cohort significantly deepen the understanding of CF in China. Furthermore, Tezacaftor-Elexacaftor-Ivacaftor therapy shows promise in restoring CFTR function in Class II mutation carriers."

Clinical • Bronchiectasis • Cystic Fibrosis • Genetic Disorders • Immunology • Nontuberculous Mycobacterial Disease • Pulmonary Disease • Respiratory Diseases • CFTR

The response of rare CFTR mutations to specific modulator combinations. (PubMed, ERJ Open Res) - "The combination of the cystic fibrosis transmembrane conductance regulator (CFTR) modulators elexacaftor (VX-445)-tezacaftor (VX-661)-ivacaftor (VX-770) (ETI) enables the effective rescue of CFTR function in people with the F508del mutation and 177 other US Food and Drug Administration-approved alleles. Our results support that CFTR function measurements in patient-derived intestinal organoids carrying rare CFTR alleles can detect potential responders to modulator treatment and serve as the basis for drug approval by health providers. Furthermore, this approach allows for patient-specific optimisation of modulator combinations, minimising unnecessary exposure to ineffective treatments."

Journal • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • CFTR

Novel readthrough compounds for the treatment of CF patients with nonsense mutations (NACFC 2025) - "16HBEge cells, primary human nasal epithelial (HNE) cells, and intestinal organoids, carrying G542X or Y122X mutations, were treated with URN-1 and URN-2 molecules and compared to the reference compound ELX-02 at 100 or 200 μM for 48 h before experiments, alone or in combination with a NMD inhibitor (SMG1, 0.5 μM, 24 h) and ETI (VX-661 3 μM/VX-445 3 μM/VX-770 100 nM). A structure-based drug design approach yielded compounds that efficiently readthrough CFTR UGA and UAA PTCs. URN molecules are more efficient than ELX-02 to rescue G542X- and Y122X-CFTR activity in heterologous and primary in vitro models."

Clinical

Pulmonary ionocyte specific CFTR reactivation restores chloride absorption and secretion in CF (NACFC 2025) - "ferrets resulted in a novel CF model (CFTRint1-eGFP(lsl)/G551D) with disease onset manageable via administration of CFTR modulator VX-770...Moreover, ionocyte CFTR-cKI cultures subjected to OH-tamoxifen treatment demonstrated a restoration of chloride secretion under symmetrical chloride and low apical chloride conditions. Reactivation of CFTR in ionocytes restores both chloride secretion and absorption in CF. Ongoing studies are evaluating airway surface liquid properties in ionocyte CFTR-cKI ferrets."

CFTR • MUC5B • SOX9

Progress towards a better outcome measure to dose pancreatic enzyme replacement therapy (NACFC 2025) - "One article each compared 2 different brands of PERT, PERT + ivacaftor and PERT + proton-pump inhibitors, without differences in CFA identified. There is conflicting evidence to support CFA as a tool to distinguish among doses, however it remains the criterion standard. The O3-SACT is the only statistically significant outcome that distinguishes among therapeutic lipase doses. Thus, we aim to compare the O3-SACT to CFA in the Phase 2 dose-ranging trial of ANG003."

Cystic Fibrosis • Gastrointestinal Disorder • Genetic Disorders • Immunology • Respiratory Diseases • Short Bowel Syndrome • Targeted Protein Degradation

A personalized approach to CFTR modulator therapy on CFTR-driven pancreatic dysfunction (NACFC 2025) - "This study highlights the versatility of our personalized model as a diagnostic, therapeutic, and prognostic tool for CF-related exocrine pancreatic diseases. Overall, our findings reveal a novel aspect of CFTR-related pathology in EPD, highlighting the potential therapeutic role of the CFTR modulator Ivacaftor beyond its traditional use in cystic fibrosis."

Cystic Fibrosis • Gastrointestinal Disorder • Genetic Disorders • Immunology • Pancreatic Cancer • Pancreatitis • Respiratory Diseases • CFTR

Intervention mapping for the development of a new model of care for people with cystic fibrosis in the era of highly effective modulator therapy. (PubMed, Arch Pediatr) - "It will combine quantitative and qualitative research approaches and rely on an 'action research' method. Anticipating and supporting the reorganization of CF care in France requires a robust research program to find the best model that meets the expectations of all key stakeholders."

Journal • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Identification of early changes in multiple biomarkers following CFTR modulator initiation in patients with cystic fibrosis. (PubMed, Ther Adv Respir Dis) - "This study identified clinical, biologic, and functional parameters showing treatment effect early after initiation of CFTR modulator therapy. These parameters may serve as potential predictors of long-term responses to CFTR modulator treatment."

Biomarker • Journal • Observational data • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • CFTR • CRP

Implications for cystic fibrosis therapy: Potentiator icenticaftor is superior to ivacaftor in improving function and maintaining stability of F508del CFTR. (PubMed, Sci Prog) - "CFTR-expressing BHK-21 cells and non-cystic fibrosis (CF) and CF primary human bronchial epithelial cultures were treated for 48 hours with elexacaftor/tezacaftor (ELX/TEZ) plus IVA or icenticaftor and then western blot analyses were performed to assess CFTR protein maturation. Primary N1303K CFTR cultures did not exhibit enhanced rescue with icenticaftor when compared to IVA, indicating that different CFTR mutations respond differently to potentiators.ConclusionIcenticaftor is superior to IVA as a potentiator for ELX/TEZ-rescued F508del CFTR, as 48-hour treatment with icenticaftor enhanced F508del function but did not destabilize F508del. Understanding the mechanisms underlying CFTR potentiator activities may offer further benefits for people with CF who have F508del or other CFTR mutations."

Journal • Chronic Obstructive Pulmonary Disease • Cystic Fibrosis • Genetic Disorders • Immunology • Non‐Cystic Fibrosis Bronchiectasis • Pulmonary Disease • Respiratory Diseases • CFTR

Evaluation of Elexacaftor/Tezacaftor/Ivacaftor (ELX/TEZ/IVA) in Cystic Fibrosis (CF) Participants 12 to Less Than 24 Months of Age (clinicaltrials.gov) - P3 | N=70 | Completed | Sponsor: Vertex Pharmaceuticals Incorporated | Active, not recruiting ➔ Completed

Trial completion • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

A systematic review and meta-analysis of the treatment modalities available for children afflicted from cystic fibrosis. (PubMed, BMC Pediatr) - "The study underscores the effectiveness of certain treatments, such as triple therapy and physiotherapy exercises, for CF while highlighting the considerable variability in treatment outcomes. Notably, nutritional interventions need to be carefully reassessed. The findings emphasize integrating physiotherapy and targeted pharmacological interventions into standard CF management tailored to individual needs."

Journal • Retrospective data • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Uncovering CF carrier phenotype: Insights from a heterozygous CFTRF508del rabbit model (NACFC 2025) - "The radiographic analysis indicated sinus hypoplasia (reduced sinus size) in CF carrier rabbits, which aligns with sinonasal observations in human CFTR heterozygotes. Additionally, the novel CF carrier rabbits demonstrated electrophysiologic characteristics that resemble the human carriers. The enhanced ivacaftor response in primary nasal epithelial cultures suggests therapeutic potential and supports further exploration of CFTR modulators in CRS associated with CF carrier status."

Preclinical • Otorhinolaryngology • Respiratory Diseases • Sinusitis • CFTR

Differential cell count in bronchoalveolar lavage fluid of cystic fibrosis ferrets: insights into lung inflammation and immune response (NACFC 2025) - "These findings highlight both local (BALF) and systemic (plasma) immune alterations in CF ferrets, notably increased neutrophilic inflammation and elevated TGF-β1 levels. Our data also suggests that VX-770 treatment did not reduce the abundance of viable neutrophils obtained in the CF BALF. This underscores the need for further investigation into how HEMT modifies the inflammatory and infectious landscape in CF airways."

Cystic Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Inflammation • Pneumonia • Pulmonary Disease • Respiratory Diseases • CXCL8 • IFNG • IL6 • TGFB1

Clinically approved β 2 agonist formoterol enhances CFTR modulator rescue of N1303K-CFTR via a dual mode of action (NACFC 2025) - "In vitro, N1303K rescue by the CFTR modulator combination elexa-/teza-/ivacaftor (ETI) is limited... We identified long-acting β2-agonist formoterol, currently used as a maintenance therapy for asthma/COPD and are currently investigating its precise mechanism. We envision this study will contribute to optimizing CFTR modulator therapies, i.e. through combinations with clinically approved repurposed small molecules like formoterol, to increase the level of CFTR rescue and linked to that clinical parameters such as FEV1. Due to its mutation-agnostic mechanism, this combination therapy can be expected to be clinically meaningful for many CFTR variants that are poorly rescued to date."

Clinical • Asthma • Chronic Obstructive Pulmonary Disease • Immunology • Respiratory Diseases • CFTR

CFTR-mediated anion and fluid transport by primary ferret alveolar epithelial cells (NACFC 2025) - "However, the pretreatment of CFTR potentiator VX-770 restored the CFTR function and led the forskolin-induced swelling in G551D ferret AT2 organoids...In the presence of amiloride and DIDS to inhibit ENaC and non-CFTR anion channels, IBMX/forskolin stimulation elicited a significant CFTR-mediated secretory chloride current in wild-type ferret alveolar epithelia (ΔIsc ± 33.57 ± 9.65 μA/cm2), whereas G551D ferret AT2 cultures exhibited a negligible response (ΔISC ± 0.13 ± 0.69 μA/cm2)... We demonstrate the ability to propagate ferret AT2 cells and maintain them as undifferentiated epithelia in organoid cultures, differentiate into AT1 cells in an ALI state. Our results suggest that CFTR-dependent transepithelial chloride movement by AT2 cells facilitates salt-mediated fluid secretion. The mechanisms by which these processes interact in native mixed epithelial populations containing both AT2 and AT1 cells remain to be determined."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases