From the Journals

Next-gen triple correctors look safe and effective for cystic fibrosis

View on the News

Major breakthrough with triple therapy

These recent investigations show that triple combination therapy improves lung function more than double combination therapy in patients with cystic fibrosis and Phe508del mutations, according to Fernando Holguin, MD, of the division of pulmonary sciences and critical care at the University of Colorado, Aurora.

“These reports represent a major breakthrough in cystic fibrosis therapeutics, with the potential for improving health and possibly survival in all patients who carry the most common cystic fibrosis transmembrane conductance regulator [CFTR] mutation,” Dr. Holguin said in an editorial.

Neither study reported dose-limiting side effects or toxicity, and only three patients in the VX-445 study stopped treatment due to adverse events, he remarked in his editorial.

However, it remains to be seen whether the lung function improvements will be maintained for longer treatment periods, he said. Patients in the phase 2 studies received a total of 4 weeks of the trial regimen, according to the reports. Also unknown is whether the new therapies will reduce exacerbation rates, or impact outcomes such as weight gain.

“These questions should soon be answered in the ongoing phase 3 trials of these regimens,” he added.

These comments are excerpted from an editorial by Dr. Holguin that accompanied the study (N Eng J Med. Oct 18; doi: 10.1056/NEJMe1811996). Dr. Holguin reported that he had no disclosures related to his editorial.



Adding a next-generation corrector to dual corrector-potentiator therapy is safe and effective in cystic fibrosis patients with one or two Phe508del alleles, results of two randomized phase 2, proof-of-concept clinical trials suggest.

CTRPhotos /thinkstock

The two trials, which evaluated the use of VX-445 or VX-659, respectively, in combination with tezacaftor-ivacaftor (Symdeko), were reported in the New England Journal of Medicine.

Both triple combinations improved lung function for patients heterozygous for the Phe508del cystic fibrosis transmembrane conductance regulator (CFTR) mutation and a minimal function mutation (Phe508del-MF) who had not previously received CFTR modulators, according to the investigators, who reported results simultaneously at the North American Cystic Fibrosis Conference in Denver.

These therapies also were effective in patients homozygous for Phe508del CFTR mutation (Phe508del-Phe508del) who had previously been treated with tezacaftor-ivacaftor, the results show.

No dose-limiting side effects or toxic effects were observed in the phase 2 studies, which included 4-week treatment periods.

“These trials provide proof of the concept that targeting the Phe508del CFTR protein with a triple-combination corrector–potentiator regimen can restore CFTR function and has the potential to represent a clinical advance for patients with cystic fibrosis who harbor either one or two Phe508del alleles, approximately 9 of every 10 patients with the disease,” Steven M. Rowe, MD, of the University of Alabama at Birmingham and his coauthors said in the report on VX-659 phase 2 study.

In that report, 63 patients with the Phe508del-MF genotype were randomized to one of three VX-659 doses in combination with tezacaftor and ivacaftor versus triple placebo for 4 weeks, while 29 Phe508del-Phe508del patients underwent a 4-week tezacaftor-ivacaftor run-in phase before starting 4 weeks of the triple combination.

The primary efficacy endpoint of the study was the absolute increase in percentage of predicted forced expiratory volume in 1 second (FEV1).

In the Phe508del-MF patients, adding VX-659 improved that endpoint by up to 13.3 points versus baseline (P less than .001), whereas the absolute change was just 0.4 in the placebo group, the report shows. In the Phe508del-phe508del group, there was a 9.7-point increase over baseline.

Similarly, the companion study on VX-445, reported by Jennifer L. Taylor‑Cousar, MD, of National Jewish Health, Denver, and her colleagues, showed an increase in percentage of predicted FEV1 of up to 13.8 points for Phe508del-MF patients (P less than .001), and an increase of 11.0 points in the Phe508del-Phe508del group (P less than .001).

Those results suggest that targeting the Phe508del CFTR mutation with a combination of two correctors and a potentiator can produce effective CFTR function in patients who have these forms of cystic fibrosis, according to Dr. Taylor-Cousar and her colleagues.

“Lung function was improved by a magnitude similar to that achieved with the CFTR modulator ivacaftor in patients with gating mutations, in whom treatment has been disease modifying,” the researchers wrote in their report.

Sweat chloride concentrations were reduced and respiratory domain scores were improved in patients receiving triple therapy, investigators reported.

Triple therapy improved Phe508del CFTR protein processing and trafficking, and chloride transport more so than any two agents in combination, according in vitro results, also described in the studies.

Phase 3 trials of these compounds are now underway, they said.

Both studies were supported by Vertex Pharmaceuticals, which received funding from the Cystic Fibrosis Foundation for the development of both VX-445 and VX-659. Dr. Rowe and Dr. Taylor-Cousar reported grants, personal fees, and nonfinancial support from Vertex while conducting the study. Study authors also reported disclosures related to AstraZeneca, Novartis, Bayer, Proteostasis, Gilead, Galapagos/AbbVie, and Celtaxsys, among other entities. Full disclosures for all authors were provided in the journal.

SOURCES: Keating D et al. N Engl J Med. 2018 Oct 18. doi: 10.1056/NEJMoa1807120; Davies JC et al. N Engl J Med. 2018 Oct 18. doi: 10.1056/NEJMoa1807119.

Next Article: