Assessment of safety and efficacy of long-term treatment with combination lumacaftor and ivacaftor therapy in patients with cystic fibrosis homozygous for the F508del-CFTR mutation (PROGRESS): a phase 3, extension study

Nasospheroids permit measurements of CFTR-dependent fluid transport

“…Modulator monotherapy treatment (lumacaftor, 25 hours, 5 μM) resulted only in minimal restoration of the volume reduction following CFTR activation, while combination therapy including a potentiator caused a greater response. This incremental finding is consistent with clinical trials that showed no significant improvement in clinical symptoms following lumacaftor administration alone (27) but resulted in significant improvements in percent predicted forced expiratory volume in 1 second (ppFEV 1 ), BMI, and pulmonary exacerbation rate when lumacaftor and ivacaftor (Orkambi) were administered in combination (61)(62)(63). Although the number of subjects included in this study is low, our results suggest that this assay may offer a directly observable real-time measure of CFTR activity and may be exploited as a rapid (2-to 5-day) functional assay to test patient-specific CFTR responses to modulators.…”

“…The average slopes of the fitted lines were estimated to be -8.85 ( [-24.39, 6.70], P = 0.6765). Because clinical efficacy was not demonstrated with lumacaftor alone (27), we also evaluated the effect of 24-hour treatment with both lumacaftor and ivacaftor (5 μM), representative of the currently approved clinical regimen for F508del homozygotes using Orkambi (58)(59)(60)(61)(62). Combination treatment reveals a synergistic effect with both an increase in average fractional reduction and the resulting estimated mean slope becoming more negative than lumacaftor (-15.77 [-27.15, -4.39]), representing a significant reduction in size (P < 0.0001 compared with untreated CF, Figure 3C and Table 1) and greater restoration of CFTR activity.…”

The safety of lumacaftor and ivacaftor for the treatment of cystic fibrosis

“…The CFQ-R respiratory domain score increase from baseline continued through week 96. Importantly, the annual rate of pulmonary exacerbation through 120 weeks remained lower in the lumacaftor-ivacaftor group 18 .…”

“…While the pivotal phase III studies in patients at least 12 years of age, conducted over 24 weeks with an open label follow-on through week 96 weeks did not measure sweat chloride 17 , 18 , an open label phase III trial in patients 6–11 years of age revealed a significant decrease in sweat chloride level, with return to baseline 2 weeks following discontinuation of therapy 19 . Similar sweat chloride reductions were seen in a placebo controlled trial in this age group 20 .…”

Orkambi in patients with severe disease — Bumps in the road to CFTR modulation

“…In the phase 2 trials, there was also a dose related decrement in FEV 1 in the lumacaftor monotherapy arm [4]. Interestingly, these effects appear to be worse after initiation of the medication, and may abate with time [6]. Withdrawal of therapy appears to lead to resolution of these symptoms [1].…”