CFTR activity is enhanced by the novel corrector GLPG2222, given with and without ivacaftor in two randomized trials

Bell, S. C.; Barry, Peter J.; Boeck, K. De; Dřevı́nek, Pavel; Elborn, J. Stuart; Plant, Barry J.; Minic, P.; Braeckel, Eva Van; Verhulst, Stijn; Muller, Karine; Kanters, D.; Bellaire, Susan; Kock, Herman de; Geller, David E.; Conrath, Katja; Steen, Olivier Van de; Ent, Cornelis K. van der

doi:10.1016/j.jcf.2019.04.014

Cited by 43 publications

(28 citation statements)

References 20 publications

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“…Significant decreases in sweat chloride concentrations were described for p.Phe508del homozygous patients with both the corrector ABBV-2222 (formerly GLPG2222) alone and the potentiator GLPG2737 on top of LUM/IVA (−15.8 and −11.7 mmol/L, respectively) [ 29 , 31 ]; and for p.Gly551Asp patients with the potentiator GLPG1837 after IVA wash-out (−28.8 mmol/L) [ 30 ].…”

Section: Resultsmentioning

confidence: 99%

From Ivacaftor to Triple Combination: A Systematic Review of Efficacy and Safety of CFTR Modulators in People with Cystic Fibrosis

Gramegna

Contarini

Aliberti

et al. 2020

IJMS

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Over the last years CFTR (cystic fibrosis transmembrane conductance regulator) modulators have shown the ability to improve relevant clinical outcomes in patients with cystic fibrosis (CF). This review aims at a systematic research of the current evidence on efficacy and tolerability of CFTR modulators for different genetic subsets of patients with CF. Two investigators independently performed the search on PubMed and included phase 2 and 3 clinical trials published in the study period 1 January 2005–31 January 2020. A final pool of 23 papers was included in the systematic review for a total of 4219 patients. For each paper data of interest were extracted and reported in table. In terms of lung function, patients who had the most beneficial effects from CFTR modulation were those patients with one gating mutation receiving IVA (ivacaftor) and patients with p.Phe508del mutation, both homozygous and heterozygous, receiving ELX/TEZ/IVA (elexacaftor/tezacaftor/ivacaftor) had the most relevant beneficial effects in term of lung function, pulmonary exacerbation decrease, and symptom improvement. CFTR modulators showed an overall favorable safety profile. Next steps should aim to systematize our comprehension of scientific data of efficacy and safety coming from real life observational studies.

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Section: Resultsmentioning

confidence: 99%

From Ivacaftor to Triple Combination: A Systematic Review of Efficacy and Safety of CFTR Modulators in People with Cystic Fibrosis

Gramegna

Contarini

Aliberti

et al. 2020

IJMS

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“…ABBV-3221 also rescued CFTR function in F508del-expressing cells with a greater effect in combination with ABBV-2222 and ABBV-974 (Scanio et al, 2019). In phase IIa clinical trials, ABBV-2222 reduced sweat chloride concentrations but did not improve ppFEV 1 in F508del-homozygous patients or F508delheterozygous patients with a gating mutation and receiving ivacaftor (Bell et al, 2019). Based on previous studies evaluating drugs with a similar mechanism of action in F508del-homozygous patients (Clancy et al, 2012;Boyle et al, 2014;Wainwright et al, 2015), a substantial improvement in lung function would be unusual for a single corrector.…”

Section: Correctors: Rescuing the Protein Folding Processing And Trmentioning

confidence: 96%

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

2020

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Cystic fibrosis (CF) is a lethal inherited disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which result in impairment of CFTR mRNA and protein expression, function, stability or a combination of these. Although CF leads to multifaceted clinical manifestations, the respiratory disorder represents the major cause of morbidity and mortality of these patients. The life expectancy of CF patients has substantially lengthened due to early diagnosis and improvements in symptomatic therapeutic regimens. Quality of life remains nevertheless limited, as these individuals are subjected to considerable clinical, psychosocial and economic burdens. Since the discovery of the CFTR gene in 1989, tremendous efforts have been made to develop therapies acting more upstream on the pathogenesis cascade, thereby overcoming the underlying dysfunctions caused by CFTR mutations. In this line, the advances in cell-based high-throughput screenings have been facilitating the fast-tracking of CFTR modulators. These modulator drugs have the ability to enhance or even restore the functional expression of specific CF-causing mutations, and they have been classified into five main groups depending on their effects on CFTR mutations: potentiators, correctors, stabilizers, read-through agents, and amplifiers. To date, four CFTR modulators have reached the market, and these pharmaceutical therapies are transforming patients' lives with short-and long-term improvements in clinical outcomes. Such breakthroughs have paved the way for the development of novel CFTR modulators, which are currently under experimental and clinical investigations. Furthermore, recent insights into the CFTR structure will be useful for the rational design of next-generation modulator drugs. This review aims to provide a summary of recent developments in CFTR-directed therapeutics. Barriers and future directions are also discussed in order to optimize treatment adherence, identify feasible and sustainable solutions for equitable access to these therapies, and continue to expand the pipeline of novel modulators that may result in effective precision medicine for all individuals with CF.

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“…The compound was generally well tolerated and some changes in sweat chloride values were seen in the treated groups. 46 Phase 1 data also support further development of correctors GLPG2737 and GLPG2451. 47 In vitro data for corrector/potentiator combination FDL169/ FDL176 encourage further development for clinical use.…”

Section: Triple Combination Therapymentioning

confidence: 76%

Treating the Underlying Cystic Fibrosis Transmembrane Conductance Regulator Defect in Patients with Cystic Fibrosis

Cuyx

Boeck

2019

Semin Respir Crit Care Med

Self Cite

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Detailed knowledge of how mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene disturb the trafficking or function of the CFTR protein and the use of high-throughput drug screens have allowed novel therapeutic strategies for cystic fibrosis (CF). The main goal of treatment is slowly but surely shifting from symptomatic management to targeting the underlying CFTR defect to halt disease progression and even to prevent occurrence of CF complications. CFTR potentiators for patients with class III mutations, mutation R117H (and in United States also for patients with specific residual function mutations) and the combination of a CFTR modulator plus a potentiator for patients homozygous for F508del, are the two classes of modulators that are in use in the clinic. Approval of these therapeutics has progressively expanded to include both younger patients and a wider range of CFTR mutations. For a significant proportion of patients with CF, current treatment is however still insufficient or unavailable.This review provides an overview of the clinical trial results and the real-life efficacy data of approved CFTR modulators. In addition, we discuss the entire pipeline of CFTR modulators: novel potentiators and correctors, amplifiers, stabilizers, and read-through agents. Furthermore, we discuss other strategies to improve CFTR function like nonsense-mediated decay inhibitors, modified transfer ribonucleic acids, antisense oligonucleotides, and genetic therapies.CFTR modulators are already changing the face of CF and the pipeline of new therapies continues to be exciting.

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CFTR activity is enhanced by the novel corrector GLPG2222, given with and without ivacaftor in two randomized trials

Cited by 43 publications

References 20 publications

From Ivacaftor to Triple Combination: A Systematic Review of Efficacy and Safety of CFTR Modulators in People with Cystic Fibrosis

From Ivacaftor to Triple Combination: A Systematic Review of Efficacy and Safety of CFTR Modulators in People with Cystic Fibrosis

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

Treating the Underlying Cystic Fibrosis Transmembrane Conductance Regulator Defect in Patients with Cystic Fibrosis

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