Middleton, P.G. et al. Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele. The New England Journal of Medicine. 10.1056/NEJMoa1908639 (2019).
This article discusses the phase three trial of an Elexacaftor-Tezacaftor-Ivacaftor (ETI) treatment of cystic fibrosis with a single Phe805del Allele. Cystic fibrosis is a mutation of the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. 90% of patients have at least one copy of the mutation, this trial focuses on those who are heterozygous for the allele. The CFTR protein quantity is severely impacted with this genetic mutation, lowering stability and weakening transport channels in cells. Treatments that act as modulators for CFTR work to improve processing and trafficking of the protein to restore some semblance of normal function. This process is trying to address the underlying causes of the mutation. There are some findings that there exist treatments for those who are homozygous for the alleles.
The team conducted a 24-week randomized, double-blind, placebo-controlled trial on 403 patients over the age of twelve who had the disease and were heterozygous for the allele. The trial was split 1:1, where 200 mg of elexacaftor was given once daily, with 100 mg of tezacaftor once daily and 150 mg of ivacaftor given every 12 hours. The trial was designed by Vertex Pharmaceuticals and all clinical trial protocols and consent processes were approved by an independent ethics committee. 200 persons received the medication while 203 received the placebo.
The first endpoint occurred at four weeks where the percentage of predicted Forced Expiratory Volume (FEV) was compared to baseline. A secondary endpoint was taken from baseline to 24 weeks as well. At 24 weeks, the number of pulmonary exacerbations, sweat chloride concentration changes, and Cystic Fibrosis Questionnaire- Revised (CFQ-R) respiratory domain score, quality of life regarding respiratory symptoms, body mass index compared to baseline, body weight changes, percentage of predicted FEV, and side effect profile data was compiled for statistical analysis.
As a result, the primary endpoint found that at four weeks, persons who had received the ETI treatment had an average 13.6 percent change in FEV by week four that sustained to 13.9 at week 24. The placebo group had a negligible change in their FEV. More secondary endpoint data resulted in 72 less pulmonary exacerbations through week 24, a 63% drop, a decrease of 41.8 mmol/liter in sweat chloride concentration, a 20.2 score increase on the CFQ-R, and a 1.04 change in body mass index when compared to the placebo group.
There were no deaths in this trial, with more than 90% of patients in both the placebo and medicated group reporting at least one adverse event. Most events were reported as mild or moderate in severity and were generally resolved during the trial. Two patients discontinued the trial due to a rash and portal hypertension; both were in the medicated group. The increased instance of rashes, 22 of 200 medicated persons were linked due to elevated aminotransferase levels in the blood. No placebo group patients discontinued the trial. This resulted in a 99% completion rate of the trial.
The article reports that based on the improved lung function, CFQ-R domain scores, BMI, and the decreased rate of pulmonary exacerbations and sweat chloride concentration, that the therapy improved multiple outcome measures. The results also note a generally safe and acceptable side-effect profile. These findings are consistent with the findings of the phase two trial for ETI treatment. Currently Ivacaftor ad Tezacaftor-Ivacaftor treatments are approved therapies. While the team notes that there are increased aminotransferase levels that continue to lead to a rash, noted in phase two, the affect is generally minor compared to the benefits. The ETI treatments is an effective and generally safe method for addressing the underlying issues of persons with cystic fibrosis and are heterozygous for the Phe508del allele.