ABCMdb

PMID: 22960984

Rowe SM, Borowitz DS, Burns JL, Clancy JP, Donaldson SH, Retsch-Bogart G, Sagel SD, Ramsey BW
Progress in cystic fibrosis and the CF Therapeutics Development Network.
Thorax. 2012 Oct;67(10):882-90. doi: 10.1136/thoraxjnl-2012-202550., [PubMed]

Sentences

No. Mutations Sentence Comment

24 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp CFTR modulator therapies have been directed towards specific disease-causing mutations and the molecular pathways that underlie their cause.12 16 A crucial phase II trial that tested the CFTR potentiator ivacaftor (Kalydeco, VX-770, Vertex Pharmaceuticals, Boston, MA, USA) in 40 patients with CF with at least one copy of the G551D mutation, a relatively common class 3 gating mutant, in a two-part randomised placebo-controlled design was the first to definitively establish that CFTR functional rescue detected by simultaneous improvement in nasal potential difference (NPD) and sweat chloride could result in meaningful changes in lung function.17 This was rapidly followed by two phase III trials in patients with G551D CF to establish the clinical effect of ivacaftor during a sustained period. Login to comment 26 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp Similar results were reported in a study of patients with G551D aged 6-12,18 enabling prompt approval of the drug for patients with G551D CF aged 6 and above by the FDA and European regulatory authorities. Login to comment 28 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp The rapid approval and availability of ivacaftor has also enabled the G551D observational study (GOAL), which will assess the clinical effects of ivacaftor in patients with G551D CF post-approval, including the response of several mechanistic biomarkers such as sweat rate, mucociliary clearance imaging, gastrointestinal pH, and sputum measures of inflammation and microbiology; these studies are intended to advance our understanding of the effects of efficacious CFTR modulation on disease-relevant biomarkers and pathways. Login to comment 29 ABCC7 p.Gly551Asp Since ivacaftor also exhibits robust activity in other rare but clinically relevant CFTR gating mutations, the drug is also being studied in patients with CFTR gating mutations other than G551D. Login to comment 30 ABCC7 p.Arg117His Ivacaftor will also be tested in the archetype conductance mutation R117H, which could establish whether potentiation of CFTR gating is sufficient to partially ameliorate non-gating mutations, setting the stage for other studies involving rare mutations localised to the cell surface. Login to comment 48 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Arg117His Since then, newer agents with improved pharmacokinetic and pharmacodynamic properties have been developed, and early phase trials have been conducted to test Table 2 CFTR-based therapies completed or in progress within the Therapeutics Development Network CFTR mutation Proportion of patients with causative mutation (%) Therapeutic approach Status G551D/other 4 Ivacaftor FDA approved, age ≥6 Age 3-5 planned Non-G551D gating/other 1 Ivacaftor Phase II/III R117H/other 5 Ivacaftor Phase III F508del/ F508del 49 Lumacaftor+ ivacaftor Phase II; phase III planned VX-661+ ivacaftor Phase II PTC/other 10 Ataluren Phase III (primary endpoint negative) CF, cystic fibrosis; CFTR, CF transmembrane conductance regulator; PTC, premature termination codon. Login to comment 110 ABCC7 p.Gly551Asp From these efforts, sweat chloride has emerged as a robust, standardised and validated method to monitor the bioactivity of CFTR potentiators and correctors.6 17 19 20 110 NPD has also performed reasonably well as a CFTR biomarker,111-113 successfully detecting ivacaftor activity in patients with G551D CF. Login to comment 116 ABCC7 p.Gly551Asp Finally, TDCs have participated in non-invasive techniques to monitor mild lung disease and responses to intervention, including CT imaging55 116-119 and Lung Clearance Index measurements in ivacaftor-treated patients with G551D CF. Login to comment