Elexacaftor/Tezacaftor/Ivacaftor
Elexacaftor/TEZ/IVA (ETI) is the most exciting highly effective modulator available in the US since late 2019. In the past year, there were two phase 3 trials reported: one in 258 participants over age 12 with one F508del mutation and a gating or residual function mutation already on IVA or TEZ/IVA and transitioned to ETI over 8 weeks24 and a second trial over 24 weeks in 6-11 year old participants with two copies F508del or a F508del and a minimal function mutation25. Neither study had changes in safety signal, and both demonstrated improvements in FEV1pp, SC, CFQ-R. Additionally, growth parameters were improved in the 6–11-year-old evaluation. It is important to note those PwCF who were already on IVA or TEZ/IVA, demonstrated a between group difference of 3.5% in FEV1pp, thus showing additional improvement with ETI above IVA or TEZ/IVA. Moreover, indication for ETI was shown in a patient with N1303K/E193X mutations who had improvement in the lab, followed by improvements in FEV1pp, BMI, CT scan of the chest, and sinus imaging26. Thus, ETI has been shown to be effective in those transitioning from other modulators, the 6–11-year-old age group and an individual with the N1303K/E193X mutation.
The long term effects of ETI in PwCF over 12 years of age, was reported in three studies, a post approval multicenter study at four German centers27, the PROMISE study, the US’s post approval, real -world observational study28, and an interim analysis of the open label extension study for participants from the clinical trials29. Timing differed between the studies, from 8-16 weeks post ETI initiation27, through 6 months of ETI use28, or once all participants completed 24 weeks in the clinical trials29. None of the studies showed additional safety concerns. Participants had improvements in FEV1pp, BMI, and SC (if not previously on ETI as part of clinical trial). It is also important to note that patients already on a modulator who transitioned to ETI had additional improvements in clinical outcomes (FEV1pp increased 6.1-9.2%, SC decreased -23.9 to 43.4 mmol/L)28. Both the PROMISE and the German evaluations demonstrated a correlation between SC changes and FEV1pp27,28; whereby the PROMISE reported for every 10-point decrease in SC there was a 0.89% increase in FEV1pp28. As with prior findings with LUM/IVA, the PROMISE study found a larger decline in SC in females28. Improvements in nasal potential difference (NPD) and intestinal current measurement (ICM), with improvements up to 40-50% of normal CFTR levels, in the German studies27. Changes in NPD did not correlate with FEV1 or BMI; however, ICM was noted to have a weak correlation. From PROMISE, self-reported use of pulmonary maintenance medications usage decreased by 6% for dornase alpha, 9.8 % for hypertonic saline, 9.1% for azithromycin, and 34% for inhaled antibiotics.
Expanding usage of ETI to population not studied in the original clinical trials, use for PwCF and ADL, based primarily on a FEV1pp <40% or referral/evaluation for lung transplantation demonstrated improvements in FEV1pp30-34, BMI31-34, CFQ-R32,34, and decreases in antibiotic use/exacerbations32,34. Where reported, oxygen use was decreased/eliminated32,34, with one study demonstrating a decrease in noninvasive ventilation use31. Most importantly, transplantation status primarily changed in a positive direction, with decreases in transplant related discussions, referrals, and wait list numbers30-33. Overall, lung transplants decreased by 56.4% in France, attributed to ETI, as the COVID related decrease in non -CF indications only dropped 26.4%31. When data from prior to 2002 was comparted to late 2020/early 2021, France saw a tenfold reduction in transplantation rate35. Similarly, according to an analysis of the International Society of Health Lung Transplantation, between 1990-2017, there was a decrease in CF as an indication for lung transplantation36. Therefore, the use of highly effective modulators have changed the landscape of lung transplantation.