Safety and efficacy of the cystic fibrosis transmembrane conductance regulator potentiator icenticaftor (QBW251)

Kazani, Shamsah; Rowlands, David J.; Bottoli, Ivan; Milojevic, Julie; Alcantara, Jose; Jones, Ieuan; Kulmatycki, Kenneth; Machineni, Surendra; Mostovy, Lidia; Nicholls, Ian A.; Nick, Jerry A.; Rowe, Steven M.; Simmonds, Nicholas J.; Vegesna, Raju V. K.; Verheijen, Jeroen C.; Danahay, Henry; Gosling, Martin; Ayalavajjala, Phaninatha Sarma; Salman, Mohammed; Strieter, Robert M.

doi:10.1016/j.jcf.2020.11.002

Cited by 13 publications

(10 citation statements)

References 18 publications

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“…94 Novartis has developed icenticaftor (QBW251), a novel potentiator that showed to improve lung function (6.5 ppFEV 1 ) and reduce sweat Clconcentration in individuals with CF carrying a class III or IV CFTR mutation in at least one allele. 95 In parallel, QBW251 was evaluated in individuals with chronic obstructive pulmonary disease in a phase II trial and demonstrated to improve systemic inflammation and sputum bacterial colonization, 96 indicating that CFTR potentiators may benefit individuals with other lung diseases. Proteostasis Therapeutics also developed a potentiator termed as Dirocaftor (PTI-808) that was shown to have a similar efficacy to VX-770, and its effect was also assessed in an aforementioned clinical trial (NCT03500263) in individuals with the F508del mutation in at least one allele.…”

Section: Class II Mutations: Correctorsmentioning

confidence: 99%

Pharmacological Modulation of Ion Channels for the Treatment of Cystic Fibrosis

Pinto¹,

Silva²,

Figueira³

et al. 2021

JEP

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Cystic fibrosis (CF) is a life-shortening monogenic disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein, an anion channel that transports chloride and bicarbonate across epithelia. Despite clinical progress in delaying disease progression with symptomatic therapies, these individuals still develop various chronic complications in lungs and other organs, which significantly restricts their life expectancy and quality of life. The development of high-throughput assays to screen drug-like compound libraries have enabled the discovery of highly effective CFTR modulator therapies. These novel therapies target the primary defect underlying CF and are now approved for clinical use for individuals with specific CF genotypes. However, the clinically approved modulators only partially reverse CFTR dysfunction and there is still a considerable number of individuals with CF carrying rare CFTR mutations who remain without any effective CFTR modulator therapy. Accordingly, additional efforts have been pursued to identify novel and more potent CFTR modulators that may benefit a larger CF population. The use of ex vivo individual-derived specimens has also become a powerful tool to evaluate novel drugs and predict their effectiveness in a personalized medicine approach. In addition to CFTR modulators, pro-drugs aiming at modulating alternative ion channels/transporters are under development to compensate for the lack of CFTR function. These therapies may restore normal mucociliary clearance through a mutation-agnostic approach (ie, independent of CFTR mutation) and include inhibitors of the epithelial sodium channel (ENaC), modulators of the calcium-activated channel transmembrane 16A (TMEM16, or anoctamin 1) or of the solute carrier family 26A member 9 (SLC26A9), and anionophores. The present review focuses on recent progress and challenges for the development of ion channel/transporter-modulating drugs for the treatment of CF.

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Section: Class II Mutations: Correctorsmentioning

confidence: 99%

Pharmacological Modulation of Ion Channels for the Treatment of Cystic Fibrosis

Pinto¹,

Silva²,

Figueira³

et al. 2021

JEP

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“…Icenticaftor is a new CTFR potentiator whose safety and efficacy were demonstrated by Kazani et al in their first-in-human RCT of this molecule (NCT02190604) that included both healthy subjects and CF patients with ≥1 pre-specified CFTR Class III or IV mutation, or homozygous for F508del mutation [ 28 ]. Over 14 days of intervention period, Icenticaftor was well tolerated among enrolled individuals with no unexpected events or discontinuations in the CF groups; the most frequent AEs in CF patients were nausea (12.2%), headache (10.2%), and fatigue (6.1%).…”

Section: Ctfr Potentiatorsmentioning

confidence: 99%

“…Regarding efficacy, Kazani et al registered significant improvements in ppFEV1 (+6.46%), LCI2.5 (−1.13 points), and sweat chloride (−8.36 mmol/L) in patients with class III and IV mutations treated with Icenticaftor, while no significant efficacy was observed in patients homozygous for a single F508del. Authors concluded that, similarly to Ivacaftor, monotherapy with Icenticaftor is not clinically sufficient in this subgroup of patients but, based on their results, this molecule might be useful when used in a combination therapeutic with CFTR correctors [ 28 ].…”

Section: Ctfr Potentiatorsmentioning

confidence: 99%

State of the Art on Approved Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulators and Triple-Combination Therapy

et al. 2021

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Cystic fibrosis (CF) is the most common life-limiting inherited disease in Caucasian populations, affecting approximately 80,000 people worldwide. CF is a complex multi-organ monogenic autosomal recessive disorder caused by a mutation in cystic fibrosis transmembrane conductance regulator (CFTR) gene. Since the discovery of the CFTR gene in 1989, more than 2000 mutations have been identified so far and about 240 can cause CF. Until recently, the treatment for CF was aimed to prevent and manage the manifestations of CFTR dysfunction, primarily recurrent pulmonary infections and pancreatic exocrine failure. Over the past few decades, the therapeutic approach to CF has been revolutionized by the development of a new class of small molecules called CFTR modulators that target specific defects caused by mutations in the CFTR gene. CFTR modulators have been shown to change profoundly the clinical course of the CF, leading to meaningful improvements in the lives of a large proportion of people of CF heterozygous for F508del, especially if started in young children. Further studies are needed to extend the use of triple CFTR modulation therapy also for young children in order to prevent the irreversible effects of the disease and for patients with very rare mutations with a personalized approach to treatment.

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“…CFTR potentiators may even have use outside the realm of CF. The novel potentiator QBW251 (icenticaftor) demonstrated modest improvements in lung function for CF adults with class III or class IV mutations [ 18 ], but has also been trialled in COPD to target cigarette smoke-induced CFTR dysfunction. In phase 2 trials, COPD patients treated with icenticaftor demonstrated some improvements in FEV 1 and sputum bacterial colonisation [ 19 ], highlighting acquired CFTR dysfunction as a novel therapeutic target in COPD.…”

Section: Cftr Modulatorsmentioning

confidence: 99%

Progress in precision medicine in cystic fibrosis: a focus on CFTR modulator therapy

Tewkesbury

Robey²,

Barry³

2021

Breathe

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The genetic multisystem condition cystic fibrosis (CF) has seen a paradigm shift in therapeutic approaches within the past decade. Since the first clinical descriptions in the 1930s, treatment advances had focused on the downstream consequences of a dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) chloride ion channel. The discovery of the gene that codes for CFTR and an understanding of the way in which different genetic mutations lead to disruption of normal CFTR function have led to the creation and subsequent licensing of drugs that target this process. This marks an important move towards precision medicine in CF and results from clinical trials and real-world clinical practice have been impressive. In this review we outline how CFTR modulator drugs restore function to the CFTR protein and the progress that is being made in this field. We also describe the real-world impact of CFTR modulators on both pulmonary and multisystem complications of CF and what this will mean for the future of CF care.

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Safety and efficacy of the cystic fibrosis transmembrane conductance regulator potentiator icenticaftor (QBW251)

Cited by 13 publications

References 18 publications

Pharmacological Modulation of Ion Channels for the Treatment of Cystic Fibrosis

Pharmacological Modulation of Ion Channels for the Treatment of Cystic Fibrosis

State of the Art on Approved Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulators and Triple-Combination Therapy

Progress in precision medicine in cystic fibrosis: a focus on CFTR modulator therapy

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