Symdeko Found Safe, Effective For Up to 4 Years in Phase 3 Trial

Trial tracked long-term use of approved therapy in CF patients

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Up to four years of treatment with Symdeko (tezacaftor/izacaftor) is safe and effective in people with cystic fibrosis (CF) with one or two copies of F508del, a common CF-causing mutation.

That’s according to new long-term data from an open-label Phase 3 trial that tested the approved CF therapy in more than 1,000 patients.

Clinical gains observed in earlier trials, including improvements in lung function and nutrition, were generally maintained through two back-to-back extension phases, totaling about four years of treatment.

“These results further support the long-term safety and efficacy of [Symdeko] in this patient population,” the researchers concluded.

The trial findings were discussed in a study published in the Journal of Cystic Fibrosis, titled “Long-term tezacaftor/ivacaftor safety and efficacy in people with cystic fibrosis and an F508del-CFTR mutation: 96-week, open-label extension of the EXTEND trial.”

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CF is caused by mutations in the CFTR gene, resulting in a faulty CFTR protein or no protein at all, which drives the disease’s symptoms.

The most common CF-causing mutation is called F508del, but other types of mutations that result in some residual CFTR function occur in some patients.

Vertex Pharmaceuticals‘ Symdeko, marketed as Symkevi in Europe and the U.K., is an approved oral treatment for CF patients. It contains ivacaftor and tezacaftor, two CFTR modulators that work to restore CFTR function.

Clinical trials have demonstrated that the treatment is safe and effective for up to six months in patients who have two copies of F508del, as well as people with one copy of F508del in addition to another type of CFTR mutation. Patients with two copies of this mutation are called homozygous, whereas those with one copy are called heterozygous.

The EXTEND Phase 3 trial (NCT02565914) sponsored by Vertex, enrolled a total of 1,044 patients, ages 12 and older, who participated in any of six previous, or parent, trials of Symdeko. Its goal was to evaluate the longer-term safety and efficacy of the treatment among patients homozygous or heterozygous for F508del.

Participants were enrolled at multiple sites across North America, Australia, Israel, and Europe.

All are receiving a tablet of Symdeko (100 mg tevacaftor/150 mg ivacaftor) each morning, and a tablet containing 150 mg of ivacaftor-only in the evenings.

Findings from Part A of the trial, which lasted 96 weeks, or about two years, demonstrated that the treatment was generally safe and well-tolerated through the extension phase, totaling up to 120 weeks of treatment.

It also was effective, with improvements in lung function and nutritional status observed in the parent studies generally maintained throughout the extension phase.

In Part B of EXTEND — the topic of the newly published study — patients continued to receive Symdeko for an additional 96 weeks, totaling up to 216 weeks of Symdeko treatment, or longer than four years.

This part enrolled 464 people, 377 of whom had participated in Part A. The remaining 87 patients had participated in either of two other parent studies of Symdeko.

Overall, 215 people completed Part B and 248 people discontinued treatment. The main reason for stopping treatment, for 79.8% of these patients, was the commercial availability of the medication. Other reasons were rollover into another study (10.1%), and adverse events (1.6%).

Safety findings were similar to Part A, and consistent with previous trials of Symdeko. Most participants (92.2%) reported at least one side effect, which were usually mild to moderate in severity and considered unlikely to be related to Symdeko treatment.

The most common side effect was acute exacerbations of CF lung symptoms — called pulmonary exacerbations — related to an infection (51.6%). Other common side effects were cough (24.2%), common cold (19%), coughing up blood (14.7%), and headache (10.2%).

Serious adverse events were reported for 136 people (29.4%) and most commonly involved infective pulmonary exacerbations and coughing up blood.

The clinical benefits observed with [Symdeko] treatment … were maintained over an additional 96 weeks of treatment in Part B, with a safety profile consistent with previous data.

The efficacy analysis involved 347 people who were homozygous for F508del and 106 who were heterozygous, in combination with another CF-associated mutation.

Lung function remained generally stable throughout Part B for both homozygous and heterozygous patients. While a numerical decline in lung function was observed for homozygous patients across parts A and B, that change “was smaller than what may be expected,” in patients not receiving Symdeko treatment, the researchers noted.

Yearly rates of pulmonary exacerbations were consistent with Part A, reaching 0.51 in the heterozygous group and 0.77 in the homozygous group — values lower than those observed in the placebo group of the EVOLVE trial (NCT02347657).

Overall, lung function tended to be higher and pulmonary exacerbations fewer in the heterozygous patients than the homozygous patients.

Gradual increases in body mass index (a measure body fat) observed in part A were maintained in both groups, suggesting a beneficial effect of the treatment on growth and nutrition.

“The clinical benefits observed with [Symdeko] treatment … were maintained over an additional 96 weeks of treatment in Part B, with a safety profile consistent with previous data,” the team concluded.

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