WS01.6 Preliminary safety and efficacy of triple combination CFTR modulator regimens in cystic fibrosis

Davies, Jane; Colombo, Claudio; Tullis, Elizabeth; McKee, Charlotte M.; DeSouza, Cynthia; Waltz, David A.; Savage, J. R. K.; Fisher, M.; Shilling, Rebecca A.; Moskowitz, Samuel M.; Robertson, S.; Tian, Simon; Taylor‐Cousar, Jennifer L.; Rowe, Steven M.

doi:10.1016/s1569-1993(18)30124-3

Cited by 7 publications

(6 citation statements)

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“…Using C1 correctors as the foundation for triple agent combination therapies, coupled with the recent proof-ofconcept studies demonstrated by Vertex (Davies et al, 2018b;Taylor-Cousar et al, 2018), there is the potential to treat all patients who harbor at least one copy of the F508del mutation (∼90% of patients). However, there are still patients with known heterozygous missense variants that are not responsive to this triple combination therapy.…”

Section: Discussionmentioning

confidence: 99%

“…1). Proof of concept for such triple combination small molecule therapy to yield an efficacious readout was recently demonstrated by Vertex Pharmaceuticals in their phase 1 and 2 clinical trial results (Davies et al, 2018b;Taylor-Cousar et al, 2018) and in subsequent results from their phase 3 clinical trials with one triple combination with cyclopropyl) ethoxy)-1H-pyrazol-1-yl)-2-((4S)-2,2,4-trimethyl-1-pyrrolidinyl)-, potassium salt) (Davies et al, 2018a) and the other with VX-…”

Section: Introductionmentioning

confidence: 99%

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Biological Characterization of F508delCFTR Protein Processing by the CFTR Corrector ABBV-2222/GLPG2222

Singh

Fan

Balut

et al. 2019

J Pharmacol Exp Ther

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Cystic fibrosis (CF) is the most common monogenic autosomal recessive disease in Caucasians caused by pathogenic mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene (CFTR). Significant small molecule therapeutic advances over the past two decades have been made to target the defective CFTR protein and enhance its function. To address the most prevalent defect of the defective CFTR protein (i.e., F508del mutation) in CF, two biomolecular activities are required, namely, correctors to increase the amount of properly folded F508delCFTR levels at the cell surface and potentiators to allow the effective opening, i.e., function of the F508delCFTR channel. Combined, these activities enhance chloride ion transport yielding improved hydration of the lung surface and subsequent restoration of mucociliary clearance. To enhance clinical benefits to CF patients, a complementary triple combination therapy consisting of two corrector molecules, type 1 (C1) and type 2, with additive mechanisms along with a potentiator are being investigated in the clinic for maximum restoration of mutated CFTR function. We report the identification and in vitro biologic characterization of ABBV-2222/GLPG2222 ( 4potent, and orally bioavailable C1 corrector developed by AbbVie-Galapagos and currently in clinical trials-which exhibits substantial improvements over the existing C1 correctors. This includes improvements in potency and drug-drug interaction (DDI) compared with 3- (6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (VX-809, Lumacaftor) and improvements in potency and efficacy compared with 1- Tezacaftor). ABBV-2222/GLPG2222 exhibits potent in vitro functional activity in primary patient cells harboring F508del/F508del CFTR with an EC 50 value ,10 nM.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Biological Characterization of F508delCFTR Protein Processing by the CFTR Corrector ABBV-2222/GLPG2222

Singh

Fan

Balut

et al. 2019

J Pharmacol Exp Ther

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“…Other CFTR correctors are in development for use in combination therapy for CF. For example, the next-generation correctors VX-659 (NCT03224351 and NCT03029455), VX-445 (NCT03227471), VX-440 (NCT02951182), and VX-152 (NCT02951195) have demonstrated improvements in CF outcomes when given with tezacaftor and ivacaftor in phase 1 or 2 studies in subjects homozygous for F508del or heterozygous for F508del and a minimal function CFTR mutation [25][26][27][28]. These and other investigational combinations, such as the triple combination PTI-428/PTI-801/PTI-808 (NCT03500263), may expand the treatment armamentarium available to CF patients in the future.…”

Section: Discussionmentioning

confidence: 99%

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

Bell

Barry

Boeck

et al. 2019

Journal of Cystic Fibrosis

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a b s t r a c tBackground: Several treatment approaches in cystic fibrosis (CF) aim to correct CF transmembrane conductance regulator (CFTR) function; the efficacy of each approach is dependent on the mutation(s) present. A need remains for more effective treatments to correct functional deficits caused by the F508del mutation. Methods: Two placebo-controlled, phase 2a studies evaluated GLPG2222, given orally once daily for 29 days, in subjects homozygous for F508del (FLAMINGO) or heterozygous for F508del and a gating mutation, receiving ivacaftor (ALBATROSS). The primary objective of both studies was to assess safety and tolerability. Secondary objectives included assessment of pharmacokinetics, and of the effect of GLPG2222 on sweat chloride concentrations, pulmonary function and respiratory symptoms. Results: Fifty-nine and 37 subjects were enrolled into FLAMINGO and ALBATROSS, respectively. Treatment-related treatment-emergent adverse events (TEAEs) were reported by 29.2% (14/48) of subjects in FLAMINGO and 40.0% (12/30) in ALBATROSS; most were mild to moderate in severity and comprised primarily respiratory, gastrointestinal, and infection events. There were no deaths or discontinuations due to TEAEs. Dose-dependent decreases in sweat chloride concentrations were seen in GLPG2222-treated subjects (maximum decrease in FLAMINGO: -17.6 mmol/L [GLPG2222 200 mg], p b 0.0001; ALBATROSS: -7.4 mmol/L [GLPG2222 300 mg], p b 0.05). No significant effects on pulmonary function or respiratory symptoms were reported. Plasma GLPG2222

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“…Over the past few years, new treatment strategies have been evolving; different types of CFTR channel modulators have been shown to be effective in improving channel activity in CF patients [4,5,6,7,8,9,10]. Most recently, a triple combinational therapy with VX-440, tezacaftor, and ivacaftor has shown significant clinical benefits in an ongoing phase II trial [11]. While substantial progress has been made in the development of CF therapies, current treatment strategies including the multiple channel modulator/corrector usage impose a heavy drug burden on patients.…”

Section: Introductionmentioning

confidence: 99%

TALEN-Mediated Gene Targeting for Cystic Fibrosis-Gene Therapy

Xia

Zhang

Cao

et al. 2019

Genes

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Cystic fibrosis (CF) is an inherited monogenic disorder, amenable to gene-based therapies. Because CF lung disease is currently the major cause of mortality and morbidity, and the lung airway is readily accessible to gene delivery, the major CF gene therapy effort at present is directed to the lung. Although airway epithelial cells are renewed slowly, permanent gene correction through gene editing or targeting in airway stem cells is needed to perpetuate the therapeutic effect. Transcription activator-like effector nuclease (TALEN) has been utilized widely for a variety of gene editing applications. The stringent requirement for nuclease binding target sites allows for gene editing with precision. In this study, we engineered helper-dependent adenoviral (HD-Ad) vectors to deliver a pair of TALENs together with donor DNA targeting the human AAVS1 locus. With homology arms of 4 kb in length, we demonstrated precise insertion of either a LacZ reporter gene or a human cystic fibrosis transmembrane conductance regulator (CFTR) minigene (cDNA) into the target site. Using the LacZ reporter, we determined the efficiency of gene integration to be about 5%. In the CFTR vector transduced cells, we were able to detect CFTR mRNA expression using qPCR and function correction using fluorometric image plate reader (FLIPR) and iodide efflux assays. Taken together, these findings suggest a new direction for future in vitro and in vivo studies in CF gene editing.

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WS01.6 Preliminary safety and efficacy of triple combination CFTR modulator regimens in cystic fibrosis

Cited by 7 publications

References 0 publications

Biological Characterization of F508delCFTR Protein Processing by the CFTR Corrector ABBV-2222/GLPG2222

Biological Characterization of F508delCFTR Protein Processing by the CFTR Corrector ABBV-2222/GLPG2222

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

TALEN-Mediated Gene Targeting for Cystic Fibrosis-Gene Therapy

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