Kalydeco Benefits Patients With Gating Mutations: Real-World Study

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Treatment with Kalydeco (ivacaftor) led to improved lung function and weight gain as well as fewer respiratory infections and hospitalizations among cystic fibrosis (CF) patients with certain CFTR gating mutations, according to a real-world study.

“These results support the long-term effectiveness and use of ivacaftor [Kalydeco] for the treatment of [people with] CF with indicated CFTR mutations,” the researchers wrote.

The study, “VOCAL: An observational study of ivacaftor for people with cystic fibrosis and selected non-G551D-CFTR gating mutations,” was published in the Journal of Cystic Fibrosis

CF is caused by mutations in the CFTR gene, which is involved in making a channel of the same name that regulates the flow of chloride and sodium in and out of cells.

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Different types of CFTR mutations influence the channel differently. Gating mutations cause the gate that allows ions to move through the channel to be stuck closed, impairing the ions’ movement. The most common of this type of mutation is called G551D.

Kalydeco is a CFTR potentiator designed by Vertex Pharmaceuticals to help keep the gate open for longer at the cell’s surface in patients with gating mutations, but it has also proven effective in patients with other mutation types.

The treatment is approved in the U.S. and Europe for patients at least 4 months old with any of the indicated mutations.

A research team conducted the observational Phase 4 VOCAL study (NCT02445053) to evaluate the real-world effects of Kalydeco in patients with at least one of eight gating mutations other than G551D living in Italy, the Netherlands, and the U.K.

Overall, the analysis included 73 patients ages 6 and older who were enrolled at 15 trial sites. Patients’ mean age at Kalydeco initiation was 26.9, and 65.8% were female.

Reported side effects were generally consistent with common CF manifestations and known adverse events associated with Kalydeco. Specifically, 180 adverse events were reported, 154 of which were considered nonserious and 26 were considered serious.

Kalydeco generally led to positive effects on CF symptoms among the patients.

Lung function, measured with the percent predicted forced expiratory volume in 1 second (ppFEV1), showed significant improvements with Kalydeco treatment. Specifically, the mean ppFEV1 score rose by a mean of 10.8 points during the first six months of treatment, reflecting improvements in lung function. These gains were maintained through four years of treatment.

“This is clinically meaningful because lung damage in [people with] CF without CFTR modulator treatment is usually progressive to the point of respiratory failure, transplant, or even death,” the researchers wrote.

Pulmonary exacerbations — acute incidents of worsening lung symptoms — occurred significantly less often with Kalydeco. Estimated annualized rates, the number of days in which exacerbations occurred, and the number that required hospitalizations all decreased by more than 50% during the year after starting Kalydeco compared with the year before. The need for antibiotics due to pulmonary exacerbations was similarly reduced.

Bacterial cultures were performed to determine Kalydeco’s ability to prevent lung infections common in CF patients. Results showed that fewer patients had at least one positive culture for any of the tested pathogens after starting treatment than in the year before.

In particular, infections with Pseudomonas aeruginosa, Aspergillus fumigatus, or Stenotrophomonas maltophilia declined with Kalydeco treatment.

Patients also saw healthy gains in body mass index and absolute weight during the first six months of treatment, which showed some fluctuations, but were generally maintained through four years.

The overall use of healthcare resources was lower after starting Kalydeco, including the annualized rate and number of days of hospitalizations for any cause. The annualized rate of sick clinic and emergency room visits was numerically lower during the year after starting Kalydeco than in the year before, a trend that was maintained throughout follow-up.

“These reductions will likely have a positive impact on both [people with] CF and healthcare systems; disease burden, treatment burden, time spent managing CF, and healthcare costs may decrease,” the team wrote.

The findings overall “demonstrate the positive long-term effectiveness of ivacaftor on clinical outcomes and [use of healthcare resources] in [people with] CF with non–G551D-CFTR gating mutations in real-world settings,” the team wrote.

The study was funded by Vertex, and some study authors are affiliated with the company.