'Major Breakthrough' in Cystic Fibrosis Treatment, Data Suggest 

Janis C. Kelly

October 18, 2018

Adding either of two new drugs — VX-659 or VX-445 — to the standard tezacaftor-ivacaftor combination improves both lung function and sweat chloride concentrations in most patients with cystic fibrosis (CF), according to two phase 2 trials published online today in the New England Journal of Medicine.

"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 CFTR [cystic fibrosis transmembrane conductance regulator] mutation," Fernando Holguin, MD, MPH, writes in an accompanying editorial. Holguin, who was not involved in the studies, is an associate professor of medicine at the University of Colorado School of Medicine and Center for Lungs and Breathing, University of Colorado Hospital, Aurora.

Current treatments for CF aim to restore CFTR function using drugs that are either CFTR correctors (which bind CFTR at the cell surface and augment intracellular processing and trafficking) or CFTR potentiators (which increase the activity of CFTR on the cell surface). However, existing treatments are not approved for all patients and do not normalize lung function in those who are eligible for treatment.

For example, patients with CF who carry two copies of the Phe508del CFTR mutation are typically treated with the CFTR corrector tezacaftor plus the CFTR potentiator ivacaftor. This treatment produces more mature CFTR protein at the cell surface and increases chloride transport, but does not restore normal function.

The newly reported phase 2 trials asked whether adding an additional CFTR corrector (either VX-659 or VX-445, which have slightly different mechanisms of action) could further increase CFTR activity and improve lung function measured as percentage of predicted FEV1 (forced expiratory volume in 1 second).

The investigators studied responses to these triple-therapy regimens in two CF patient groups. The first were those who carry two copies of the Phe508del CFTR mutation, for which tezacaftor-ivacaftor is standard therapy. The second were CF patients who carry one Phe508del mutation plus some other mutation that resulted in minimally functional CFTR (Phe508del-MF), for whom there is no standard treatment.

Reporting for the VX-659 study group, J. C. Davies, MD, from Imperial College London and Royal Brompton and Harefield NHS Foundation Trust, United Kingdom, and colleagues explain that current treatment improves chloride transport by restoring some CFTR channel function in about 60% of patients with CF. They write, "There are currently no approved CFTR modulators to treat the estimated 30% of patients who are heterozygous for the Phe508del CFTR mutation and a minimal function CFTR mutation...which leaves a substantial portion of the patient population without a treatment addressing the basic defect."

The two new drugs were tested in parallel studies with the goal of speeding development. For both trials, the primary endpoints were safety, side effect profile, and absolute change in percentage predicted FEV1 between baseline and day 29. Secondary endpoints were the absolute change in sweat chloride concentrations between baseline and day 29 and absolute change in the respiratory domain of the Cystic Fibrosis Questionnaire-Revised (CFQ-R, minimal clinically important difference: 4 points) from baseline to day 29.

Both studies were randomized, controlled, double-blind trials. Because tezacaftor-ivacaftor is an approved treatment for Phe508del-Phe508del patients, the test drug for those patients was added to background tezacaftor-ivacaftor, and the control group was placebo plus tezacaftor-ivacaftor.

In the VX-659 study, Phe508del-Phe508del patients were randomized to the control group (n = 11) or to triple-therapy that included 400 mg/day VX-659 triple therapy (n = 10). In the In the VX-445 trial, Phe508del-Phe508del patients were randomized to placebo plus tezacaftor-ivacaftor (n = 7) or to triple therapy including 200 mg/day VX-445 (n = 21).

In the absence of approved standard therapy for Phe508del-MF, the control group was triple placebo. In the VX-659 study, patients were randomized to control (n = 10) or triple therapy including 400 mg/day (n = 11), 240 mg/day (n = 10), or 80 mg/day (n = 11) of the test drug. In the VX-445 trial patients were randomized to control (n = 12) or to 50 mg (n = 10), 100 mg (n = 22), or 200 mg (n = 21) of VX-445 plus tezacaftor-ivacaftor.

Davies and colleagues write that the VX-659 triple therapy "resulted in significant mean increases in the percentage of predicted FEV1 through day 29," including increases of up to an additional 9.7 points in the Phe508del-Phe508del group and up to 13.3 points in the Phe505del-MF group. Sweat chloride and CFQ-R scores improved significantly in both groups of patients. All changes were statistically significant.

Similarly in the VX-445 trial, Dominic Keating, MD, from Alfred Hospital in Melbourne, Australia, and colleagues report that VX-445-tezacaftor-ivacaftor increased percentage of predicted FEV1 by 11.0 points in the Phe508del-Phe508del group and by 13.8 points in the Phe508del-MF group. In addition, sweat chloride concentrations decreased and the CFQ-R scores improved in both groups. All changes were statistically significant.

Keating and colleagues write, "These results support the hypothesis that targeting the Phe508del CFTR mutation with a combination of two correctors and a potentiator can lead to effective CFTR function in patients with these forms of CF. Both the VX-445 and VX-659 triple combinations improved lung function...in patients with Phe58del-MF genotypes who had not previously been treated with CFTR modulators and in patients with the Phe508del-Phe508del genotype, who had previously received treatment with tezacaftor-ivacaftor."

The researchers report that in these phase 2 trials with 4-week treatment periods, no dose-limiting side effects or toxic effects were seen.

However, in his editorial, Holguin cautions that major unknowns include whether these combinations will reduce exacerbation rates or improve weight gain in CF patients and whether the treatment effects are durable over longer periods of time.

Phase 3 clinical trials (including studies in patients age 6-11 years) are underway with both VX-659 and VX-445 and in patients with both the Phe508del-Phe508del and Phe508del-MF genotypes.

Tezacaftor-ivacaftor is marketed by Vertex as Symdeko and costs $292,000 per year. The additional cost of adding VX-659 or VX-445 is not yet known.

Both studies were supported by Vertex, which received funding from the Cystic Fibrosis Foundation for development of VX-659 and VX-445. Disclosures for the other authors are listed in the article.  Holguin has reported no relevant financial relationships.  

N Engl J Med. Published online October 18, 2018. VX-659 study, VX-445 trial, Editorial  

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