Kalydeco (ivacaftor) / Vertex - LARVOL DELTA

Addressing the Release and Permeation Challenges of High-Tg Drugs in Amorphous Solid Dispersions. (PubMed, Mol Pharm) - "Ivacaftor and ARV-825 were selected as model drugs and were formulated as ASDs with hydroxypropyl methylcellulose acetate succinate (HPMCAS). Addition of glyceryl tributyrate, while increasing the release rate, decreased the permeation rate due to formation of larger droplets. In conclusion, the addition of a plasticizer to an ASD containing a high Tg drug led to an improvement in release rate but increased the size of drug-rich nanodroplets produced via the release process with unknown potential implications for in vivo performance."

Journal

WHEN TRIALS FALL SHORT: LEVERAGING REAL-WORLD EVIDENCE TO ADVANCE PRECISION THERAPIES (ISPOR 2026) - "Analysis of landmark cases (e.g., pembrolizumab, carglumic acid, and ivacaftor) demonstrates that RWE can successfully support initial approvals and indication expansions where RCTs are impractical or unethical. RWE is no longer supplementary but foundational to precision medicine. Transitioning to a hybrid evidentiary standard of proof, wherein RCTs provide internal validity, and RWE provides external generalizability, accelerates patient access to targeted therapies. For Health Economics and Outcomes Research (HEOR) stakeholders, these findings emphasize the need for robust data governance and standardized analytical frameworks to realize the full potential of genetically guided healthcare."

Clinical • HEOR • Real-world • Real-world evidence • Genetic Disorders

WHEN TRIALS FALL SHORT: LEVERAGING REAL-WORLD EVIDENCE TO ADVANCE PRECISION THERAPIES (ISPOR 2026) - "Analysis of landmark cases (e.g., pembrolizumab, carglumic acid, and ivacaftor) demonstrates that RWE can successfully support initial approvals and indication expansions where RCTs are impractical or unethical. RWE is no longer supplementary but foundational to precision medicine. Transitioning to a hybrid evidentiary standard of proof, wherein RCTs provide internal validity, and RWE provides external generalizability, accelerates patient access to targeted therapies. For Health Economics and Outcomes Research (HEOR) stakeholders, these findings emphasize the need for robust data governance and standardized analytical frameworks to realize the full potential of genetically guided healthcare."

Clinical • HEOR • Real-world • Real-world evidence • Genetic Disorders

TIPS: Immunomodulatory Treatment of Interstitial Lung Disease Associated With Surfactant Related Gene Variants (clinicaltrials.gov) - P2 | N=30 | Not yet recruiting | Sponsor: Assistance Publique - Hôpitaux de Paris

New P2 trial • Interstitial Lung Disease • Pulmonary Disease • Respiratory Diseases • ABCA3 • SFTPA1 • SFTPA2

Elexacaftor/Tezacaftor/Ivacaftor for Cystic Fibrosis and Rare CFTR Variants: In Vitro Translation to a Phase 3, Double-Blind, Randomized, Placebo-controlled Trial and Real-World Study. (PubMed, Am J Respir Crit Care Med) - "In vitro, clinical, and real-world data support elexacaftor/tezacaftor/ivacaftor treatment in people carrying a range of CFTR variants and no F508del. The response of 84% of rare CFTR variants that produce protein to protein-stabilizing therapy suggests variants in many regions of the protein causes disease via protein destabilization."

Journal • P3 data • Preclinical • Real-world evidence • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Therapeutic hopes for CFTR-related recurrent pancreatitis: a case-series. (PubMed, J Cyst Fibros) - "We collected clinical, biological, imaging and CFTR functional data in 4 patients with recurrent pancreatitis and CFTR-RD, treated with CFTR modulators and assessed the efficacy of the treatment. With a follow-up of minimum 9 months, we found that ETI and ivacaftor reduced or even resolved the number of acute pancreatitis episodes."

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

Ceragenins in Combination with Ivacaftor Prevent the Formation of Biofilm by Bacteria That Cause Rhinosinusitis. (PubMed, Pharmaceutics) - " We determined the minimal inhibitory and bactericidal concentrations (MIC and MBC) and the fractional inhibitory concentration index (FICI) for ceragenins (CSA-13, CSA-44, CSA-131), ivacaftor (IVA), selected conventional antibiotics, and their combinations against both reference and clinical strains...AFM showed that CSA-44, IVA, vancomycin, and their combinations altered the nanomechanical properties of Pseudomonas aeruginosa and Staphylococcus aureus cells... These findings indicate that ceragenins, particularly in combination with ivacaftor, represent a promising therapeutic strategy for challenging chronic infections caused by the studied bacteria. This supports further research aimed at developing new treatment methods for CRS."

Journal • Cystic Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Otorhinolaryngology • Pulmonary Disease • Respiratory Diseases • Sinusitis

Effects of cAMP and CFTR modulation on apical fluid pH in human airway Calu-3 cells. (PubMed, Physiol Rep) - "Our results show that pharmacological interventions with cAMP elevating agents and CFTR modulator VX-770 led to significant increases in pH, with combinations leading to greater increases compared to single drug interventions. Our study suggests that cAMP and CFTR modulation has potential as a therapeutic strategy for elevating ASL pH and may be beneficial for respiratory diseases with ASL abnormalities."

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

Systemic and airway T cell dynamics with influenza-specific immune recovery by cystic fibrosis elexacaftor/tezacaftor/ivacaftor therapy. (PubMed, Respir Res) - No abstract available

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

Divergent neurobehavioral effects of CFTR modulators elexacaftor and ivacaftor in mice. (PubMed, Acta Psychol (Amst)) - "Among these, the elexacaftor-tezacaftor-ivacaftor combination (Trikafta) and vanzacaftor-tezacaftor-deutivacaftor (Alyftrek), represent major therapeutic milestones. Additionally, we confirmed the presence of Cftr mRNA in the amygdala and hippocampus, brain regions implicated in anxiety and depression. These findings provide preclinical support for the reported mental health side effects experienced by some people with CF and offer new insights into CFTR function within the central nervous system, potentially guiding the development of future CF therapies with improved neuropsychiatric profiles."

Journal • Preclinical • CNS Disorders • Cystic Fibrosis • Depression • Genetic Disorders • Immunology • Mood Disorders • Psychiatry • Pulmonary Disease • Respiratory Diseases • CFTR

Repurposing of ivacaftor shows potential to treat ROR1 expressing high-grade serous ovarian cancer. (PubMed, Ther Adv Med Oncol) - "Flow cytometry was used to assess apoptosis, DNA damage and cell proliferation following treatment with either 15 µM ivacaftor or 30 µM carboplatin at 24, 48 and 72 h. ROR1 signalling associated oncogenic pathways including the BMI-1 and the PI3K/AKT pathways were modulated following ivacaftor treatment. In summary, ivacaftor demonstrated significant anti-tumour potential in preclinical HGSOC models, supporting its further investigation as a repurposed therapy for ovarian cancer."

Journal • Cystic Fibrosis • Genetic Disorders • High Grade Serous Ovarian Cancer • Immunology • Oncology • Ovarian Cancer • Pulmonary Disease • Respiratory Diseases • Solid Tumor • ANXA5 • BMI1 • ROR1

Insilico analysis of the pathogenic deletion mutations (CFTR-F508del) associated with cystic fibrosis disease. (PubMed, Comput Biol Chem) - "The integration of genetic, structural, and docking analyses supports the role of Ivacaftor as an effective modulator of F508del-CFTR function. The identified interaction hotspots offer a structural basis for optimizing CFTR-targeted therapeutics and support further exploration of personalized drug design in CF treatment."

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

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