icenticaftor (QBW251) / Novartis - LARVOL DELTA

Novel Maintenance Therapies for Chronic Obstructive Pulmonary Disorder. (PubMed, Ann Pharmacother) - "Evidence supports LABA/LAMA with nuanced use of ICS. Several novel therapies are approved or are being studied for patients suboptimally controlled. Pharmacists can assist in medication optimization and access; however, patient-specific factors like exacerbation history, blood eosinophils, and COPD endotype must be considered. Implementing early identification screening tools such as CAPTURE should factor into patient assessment."

Journal • Review • Chronic Obstructive Pulmonary Disease • Immunology • Infectious Disease • Pneumococcal Infections • Pulmonary Disease • Respiratory Diseases • Respiratory Syncytial Virus Infections

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

Beyond ivacaftor: potentiator icenticaftor enhances function and maintains stability of corrected F508del CFTR (NACFC 2025) - "Rescue of F508del and other mutant CFTR proteins is feasible with the triple therapy, Trikafta/Kaftrio, composed of two corrector compounds, elexacaftor (ELX) and tezacaftor (TEZ), plus potentiator ivacaftor (IVA). Icenticaftor is superior to IVA as a potentiator for ELX/TEZ-rescued F508del CFTR as chronic treatment with icenticaftor enhanced F508del function but did not destabilize F508del. Understanding the mechanisms underlying CFTR potentiator activities may offer further benefits for pwCF harboring F508del or other CFTR mutations, thereby improving therapeutics aimed at increasing CFTR maturation and function."

Chronic Obstructive Pulmonary Disease • Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • CFTR

Effects of cystic fibrosis transmembrane conductance regulator potentiators on clinical outcomes of chronic obstructive pulmonary disease: a systematic review and meta-analysis. (PubMed, Expert Rev Respir Med) - "George's Respiratory Questionnaire (SGRQ) score or acute exacerbation times, with low-to-moderate quality evidence.Review registration PROSPERO Identifier: CRD42024538708. Our meta-analysis demonstrated CFTR-potentiators' potential efficacy in increasing FEV1, decreasing sweat chloride and fibrinogen levels, despite limited impacts on FEV1% predicted, FVC, CAT score, SGRQ score and acute exacerbations, underscoring the necessity for future research to evaluate its effects on mucus hypersecretion, acute exacerbations, hospitalizations and mortality in COPD management.Review registration PROSPERO Identifier: CRD42024538708."

Clinical data • Journal • Retrospective data • Review • Chronic Obstructive Pulmonary Disease • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • CFTR

Absorption, Distribution, Metabolism, and Excretion of Icenticaftor (QBW251) in Healthy Male Volunteers at Steady State and In Vitro Phenotyping of Major Metabolites. (PubMed, Drug Metab Dispos) - "The most abundant metabolites, M8 and M9, were formed by N-glucuronidation and O-glucuronidation of icenticaftor, respectively. Phenotyping demonstrated that [14C]icenticaftor was metabolized predominantly by UGT1A9 with a remarkably low Km value."

Journal • Preclinical • Chronic Obstructive Pulmonary Disease • Immunology • Metabolic Disorders • Pulmonary Disease • Respiratory Diseases • UGT1A9

Drug-drug interactions of icenticaftor (QBW251) with a 5-probe cytochrome P450 cocktail and oral contraceptives. (PubMed, Clin Transl Sci) - "with monophasic OC containing 30-μg EE and 150-μg LVG once daily reduced the plasma exposure of both components by approximately 50% and led to increased levels of follicle-stimulating hormone and luteinizing hormone. These results provide valuable guidance for the use of icenticaftor in patients taking concomitant medications that are substrates of CYP enzymes or patients using OCs."

Clinical • Journal • CYP2C19 • CYP3A4

Concentration-QTcF Modeling of Icenticaftor from a Randomized, Placebo- and Positive-Controlled Thorough QT Study in Healthy Participants. (PubMed, Clin Pharmacol Drug Dev) - "Based on the concentration-QTc analysis, an effect on ΔΔQTcF exceeding 10 milliseconds can be excluded within the full observed ranges of plasma concentrations on icenticaftor, up to approximately 9540 ng/mL. Icenticaftor at the studied doses demonstrated a mild shortening in QTcF, which is unlikely to be of clinical relevance in a therapeutic setting."

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

Potential systemic effects of acquired CFTR dysfunction in COPD. (PubMed, Respir Med) - "This dysfunction is, on average, about half of that found in CF. Herein we review the literature focusing on acquired CFTR dysfunction and the potential role in the pathogenesis of comorbidities associated with COPD and chronic bronchitis."

Journal • Review • Chronic Obstructive Pulmonary Disease • Cystic Fibrosis • Developmental Disorders • Fibrosis • Gastrointestinal Disorder • Genetic Disorders • Immunology • Infectious Disease • Inflammation • Pulmonary Disease • Respiratory Diseases • CFTR

Icenticaftor, A Novel Treatment for COPD: Needs Further Verification of Its Effectiveness. (PubMed, Am J Respir Crit Care Med) - No abstract available

Journal • Chronic Obstructive Pulmonary Disease • Immunology • Pulmonary Disease • Respiratory Diseases

Clinical Study to Assess the Mode of Action of QBW251 in Patients With Chronic Obstructive Pulmonary Disease (COPD) (clinicaltrials.gov) - P2 | N=54 | Terminated | Sponsor: Novartis Pharmaceuticals | Completed ➔ Terminated; Sponsor decision

Trial termination • Chronic Obstructive Pulmonary Disease • Immunology • Pulmonary Disease • Respiratory Diseases

Reply to: Icenticaftor, A Novel Treatment for COPD: Needs Further Verification of Its Effectiveness. (PubMed, Am J Respir Crit Care Med) - No abstract available

Journal • Chronic Obstructive Pulmonary Disease • Immunology • Pulmonary Disease • Respiratory Diseases

Study of Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of QBW251 in Subjects With Bronchiectasis (clinicaltrials.gov) - P2 | N=42 | Terminated | Sponsor: Novartis Pharmaceuticals | Active, not recruiting ➔ Terminated; Strategic business decision

Trial termination • Bronchiectasis • Pulmonary Disease • Respiratory Diseases

Icenticaftor, Novel Therapy for COPD: This Glass Is Half Full. (PubMed, Am J Respir Crit Care Med) - No abstract available

Journal • Chronic Obstructive Pulmonary Disease • Immunology • Pulmonary Disease • Respiratory Diseases

Icenticaftor, a CFTR Potentiator, in COPD: A Multicenter, Parallel-Group, Double-Blind Clinical Trial. (PubMed, Am J Respir Crit Care Med) - P2 | "The primary endpoint was negative as icenticaftor did not improve trough FEV over 12 weeks. Although the findings must be interpreted with caution, icenticaftor improved trough FEV, cough, sputum, rescue medication use and lowered fibrinogen levels at 24 weeks. Clinical trial registration available at www."

Journal • Chronic Obstructive Pulmonary Disease • Cough • Immunology • Pulmonary Disease • Respiratory Diseases

Study of Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of QBW251 in Subjects With Bronchiectasis (clinicaltrials.gov) - P2 | N=42 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Recruiting ➔ Active, not recruiting | N=72 ➔ 42

Enrollment change • Enrollment closed • Bronchiectasis • Pulmonary Disease • Respiratory Diseases

Study of Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of QBW251 in Subjects With Bronchiectasis (clinicaltrials.gov) - P2 | N=72 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Jan 2025 ➔ Jun 2023 | Trial primary completion date: Jan 2025 ➔ Jun 2023

Trial completion date • Trial primary completion date • Bronchiectasis • Pulmonary Disease • Respiratory Diseases

Pharmacokinetic Study of Icenticaftor in Participants With Hepatic Impairment (clinicaltrials.gov) - P1 | N=40 | Completed | Sponsor: Novartis Pharmaceuticals | Recruiting ➔ Completed

Trial completion • Hepatology • Liver Failure

Potentiator Icenticaftor Is Superior to Ivacaftor in Rescuing F508del CFTR and Does Not Destabilize Corrected Mature Protein (NACFC 2022) - "Based on our results, we conclude that ICN is a superior CFTRmodulator than IVA because it enhances function but does not destabilizerescued F508del, thus improving function. These data are critical forconsidering development of advanced therapies. Understanding thedifferent mechanisms of CFTR potentiator activities may provide furtherbenefits for people with CF with F508del and other mutations."

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

Inflammation augments elexacaftor/tezacaftor/ivacaftor-induced cystic fibrosis transmembrane conductance regulator rescue in primary airway epithelia carrying F508del and rare cystic fibrosis transmembrane conductance regulator mutations (NACFC 2022) - "Supported by Cystic Fibrosis Foundation (Cores fromBOUCHE19R0) and National Institutes of Health (p30DK065988). The CF airway inflammatory milieu improves the efficacy ofF508del rescue by ELX/TEZ/IVA or a triple combination containing thepotentiator QBW251. Rescue of rare CFTR mutations that do not respondsignificantly to HEMT can be attained in inflamed airway epithelia. Thus,evaluation of HEMT efficacy must be performed under conditionsmimicking the native inflammatory status of CF airways."

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

Study of Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of QBW251 in Subjects With Bronchiectasis (clinicaltrials.gov) - P2 | N=72 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Nov 2023 ➔ Jan 2025 | Trial primary completion date: Nov 2023 ➔ Jan 2025

Trial completion date • Trial primary completion date • Bronchiectasis • Non‐Cystic Fibrosis Bronchiectasis • Pulmonary Disease • Respiratory Diseases

Clinical Study to Assess the Mode of Action of QBW251 in Patients With Chronic Obstructive Pulmonary Disease (COPD) (clinicaltrials.gov) - P2 | N=55 | Completed | Sponsor: Novartis Pharmaceuticals | Active, not recruiting ➔ Completed

Trial completion • Chronic Obstructive Pulmonary Disease • Immunology • Pulmonary Disease • Respiratory Diseases

Dose response of icenticaftor in patients with COPD and chronic bronchitis on triple inhaled therapy (ERS 2022) - P2 | "Conclusion Icenticaftor improved symptoms over 24 weeks with associated improvements in FEV1, E-RS total score, and RM in COPD patients with CB on triple therapy. Figure"

Clinical • Chronic Obstructive Pulmonary Disease • Cough • Immunology • Pulmonary Disease • Respiratory Diseases

Clinical Study to Assess the Mode of Action of QBW251 in Patients With Chronic Obstructive Pulmonary Disease (COPD) (clinicaltrials.gov) - P2 | N=55 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Recruiting ➔ Active, not recruiting | N=100 ➔ 55 | Trial completion date: Jan 2023 ➔ Sep 2022 | Trial primary completion date: Jan 2023 ➔ Sep 2022

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Chronic Obstructive Pulmonary Disease • Immunology • Pulmonary Disease • Respiratory Diseases

Icenticaftor: Primary publication of data from P2 trial (NCT04072887) for COPD in H2 2022 (Novartis) - Q2 2022 Results

P2 data • Chronic Obstructive Pulmonary Disease

The Effect of the CFTR Potentiator Icenticaftor (QBW251) on Regional High-Resolution Computed Tomography Features in COPD Patients with Chronic Bronchitis (ATS 2022) - "In a 4-week study of COPD-CB patients, treatment with icenticaftor was associated with changes in spirometric and regional lung radiographic intensity measures; consistent with improvement in small airways disease. These findings suggest that a regional reduction in gas retention accompanies improvements in functional spirometric measures in response to CFTR potentiation and that regional analysis of HRCT with respect to global spirometric reads adds more understanding of local compound action, physiology and drug delivery. An extended treatment duration study in a broader COPD patient spectrum is ongoing with the aim to further elucidate biological treatment effects and evaluate the potential benefit of icenticaftor."

Clinical • Chronic Obstructive Pulmonary Disease • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • CFTR