Three-Drug Combo Improves Lung Function in Patients with Cystic Fibrosis


The FDA approved elexacaftor/tezacaftor/ivacaftor (Trikafta) earlier this month based on the results of a phase 3 clinical trial.

A 3-drug combination has improved lung function and reduced symptoms in patients with cystic fibrosis (CF) who had a single copy of the most common genetic mutation for the disease, according to a phase 3 clinical trial.1

The FDA approved the therapy elexacaftor/tezacaftor/ivacaftor (Trikafta, Vertex Pharmaceuticals) earlier this month based on the results of an international study published in the New England Journal of Medicine (NEJM).1 At the same time, a companion study published in The Lancet examined patients with 1 or 2 copies of the mutation.2

Although there are over 1000 different disease-causing mutations in CF, nearly 90% of patients with CF have at least 1 copy of the most common mutation, the Phe508del CF transmembrane conductance regulator allele. An estimated 80,000 people worldwide are affected by mutations in the CFTR protein. Patients inherit a gene from each parent that encodes the CFTR protein.2

The 3-drug combination was highly effective in people with CF who inherited the Phe508del CFTR mutation, improving health outcomes and symptoms in the NEJM study in participants with 1 mutated copy of the gene.1

The clinical trial was conducted at 115 sites in 13 countries from June 2018 to April 2019. Approximately 403 patients ages 12 and older were randomized to receive either elexacaftor/tezacaftor/ivacaftor combined therapy or a placebo.1

Lung function was measured at 4 and 24 weeks. Compared with patients receiving a placebo, lung function in the treatment group was significantly improved at 4 weeks and sustained through week 24. In addition, lung flare-ups, or increases in adverse events, were 63% lower in the treatment group compared with a placebo.1

Study participants also answered questionnaires regarding their quality of life and respiratory symptoms, with those in the treatment group reporting higher scores in improvement.1

The treatment group had a lower concentration of salt in their sweat than the placebo group, which demonstrates how this therapy targets the underlying cause of the disease, the authors noted.2

Adverse events leading to discontinuation occurred in 1% of patients getting the drug combination. Although the therapy was generally safe and well-tolerated, long-term studies are needed to further understand potential adverse events.1

Overall, the study concluded that elexacaftor/tezacaftor/ivacaftor was effective in patients with CF with Phe508del-minimal function genotypes, in whom previous CFTR modulatory regimens were ineffective.1

A previously-published study of patients with CF who were prescribed CFTR modulator medications found that, although there was a positive adherence to the medications, there was also a substantial financial burden on both patients and third-party payers responsible for the medication cost.3

For the study, the researchers used prescription refill and patient assessment data from a national specialty pharmacy database. They analyzed data of patients using CFTR modulator therapies, such as ivacaftor, lumacaftor/ivacaftor and tezacaftor/ivacaftor, between September 2017 and August 2018, and calculated adherence using a proportion of days covered (PDC) measurement.3

Of the 3482 patients using CFTR modulator therapies, 50.8% of patients were on lumacaftor/ivacaftor, followed by 24.8% on tezacaftor/ivacaftor, and 24.4% on ivacaftor, according to the study. The PDC values for the CFTR modulator therapies were above 80%, signifying patients were adherent to the newer therapies.3

During that period, a total of 4444 patients contributed to 57,960 refills of CFTR modulator therapies. Most refills (62%) were for patients with only primary insurance, whereas approximately 37% of refills were for patients with both primary and secondary insurances.3

Therefore, although CFTR therapies can help patients with CF, there is also more research needed to monitor the characteristics of CF and the impact of co-pays across different insurances and patient outcomes the study authors concluded.3

For now, CFTR therapies can be an option for those who have the Phe508del CFTR mutation.

“The CF community is working hard to find highly effective therapies for people who are not eligible for this treatment because they don't have the appropriate gene mutation," Raksha Jain, MD, a Dedman Family Scholar in Clinical Care and director of the UT Southwestern Medical Center Adult Cystic Fibrosis Center, said in a statement.1


  • Middleton PG, Mall MA, Drevinek P, et al. Elexacaftor-tezacaftor-izacaftor for cystic fibrosis with a single Phe508del allele. New England Journal of Medicine. 2019. Doi: 10.1056/NEJMoa1908639
  • Three-drug combo improves lung function in most common genetic form of cystic fibrosis [press release]. UT Southwestern Medical Center. Published October 31, 2019. Accessed November 11, 2019.
  • High Adherence but High Cost for Patients with Cystic Fibrosis Prescribed with Modulator. Published November 8, 2019. Accessed November 11, 2019.

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