General Information

Symdeko is a combination of tezacaftor and ivacaftor. Tezacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) corrector. Ivacaftor is a CFTR potentiator.

Symdeko is specifically indicated for the treatment of patients with cystic fibrosis (CF) aged 12 years and older who are homozygous for the F508del mutation or who have at least one mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that is responsive to tezacaftor/ivacaftor based on in vitro data and/or clinical evidence. The FDA subsequently approved Symdeko tablets (June 2019) for treatment of pediatric patients ages 6 years and older with cystic fibrosis who have certain genetic mutations. The Symdeko drug label was expanded in December of 2020 to include patients who are 6 years and older with one of 127 additional mutations.

Symdeko is supplied as a tablet for oral administration. The recommended dose is one tablet (tezacaftor 100 mg/ivacaftor 150 mg) taken in the morning and one tablet (ivacaftor 150 mg) taken in the evening, approximately 12 hours apart. The tablets should be swallowed whole. Symdeko should be taken with fat-containing food. See drug label for dose adjustments in patients with hepatic impairment and for co-administration with moderate inhibitors of CYP3A.

Clinical Results

FDA Approval

The FDA approval of Symdeko for patients with CF aged 12 years and older was based on three Phase III, double-blind, placebo-controlled trials (Trials 1, 2, and 3).

Trial 1: this was a 24-week randomized, double-blind, placebo-controlled, two-arm study in CF patients (n=504) who were homozygous for the F508del mutation in the CFTR gene. The primary efficacy endpoint was change in lung function as determined by absolute change from baseline in ppFEV1 through Week 24. Treatment with Symdeko resulted in a statistically significant improvement in ppFEV1. The treatment difference between Symdeko and placebo for the mean absolute change in ppFEV1 from baseline through Week 24 was 4.0 percentage points (P<0.0001). These changes persisted throughout the 24-week treatment period.

Trial 2: this was a randomized, double-blind, placebo-controlled, 2-period, 3-treatment, 8-week crossover study in CF patients (n=244) who were heterozygous for the F508del mutation and a second mutation predicted to be responsive to tezacaftor/ivacaftor. Mutations predicted to be responsive were selected for the study based on the clinical phenotype (pancreatic sufficiency), biomarker data (sweat chloride), and in vitro responsiveness to tezacaftor/ivacaftor. Patients were randomized to and received sequences of treatment that included Symdeko, ivacaftor, and placebo. The primary efficacy endpoint was the mean absolute change from study baseline in percent predicted FEV1 averaged at Weeks 4 and 8 of treatment. For the overall population, treatment with Symdeko compared to placebo resulted in significant improvement in ppFEV1 (6.8 percentage points; P<0.0001) Treatment difference for ppFEV1 between ivacaftor- and placebo-treated patients was 4.7 percentage points (P<0.0001) and 2.1 percentage points (P<0.0001) between Symdeko- and ivacaftor-treated patients, which were statistically significant.

Trial 3: this was a 12-week randomized, double-blind, placebo-controlled, two-arm study in CF patients who were heterozygous for the F508del mutation and a second CFTR mutation predicted to be unresponsive to tezacaftor/ivacaftor. Mutations predicted to be non-responsive were selected for the study based on biologic plausibility (mutation class), clinical phenotype (pancreatic insufficiency), biomarker data (sweat chloride), and in vitro testing to tezacaftor and/or ivacaftor. The primary efficacy endpoint was change from baseline in absolute ppFEV1 through Week 12. The overall treatment difference between Symdeko and placebo for the mean absolute change in ppFEV1 from baseline through Week 12 was 1.2 percentage points (95% CI: -0.3, 2.6). This study was terminated following the planned interim analysis because the pre-specified futility criteria were met.

The FDA approval of Symdeko tablets for treatment of pediatric patients ages 6 years and older with cystic fibrosis with certain genetic mutations. was based on a 24-week Phase 3 open-label, multicenter study to evaluate the pharmacokinetics, safety, and tolerability of tezacaftor/ivacaftor and ivacaftor in children ages 6 through 11 years in the U.S. and Canada. The regimen was generally well tolerated, and safety data were similar to what was observed in previous studies of patients aged 12 years and older.

Mechanism of Action

Symdeko is a combination of tezacaftor and ivacaftor. Tezacaftor facilitates the cellular processing and trafficking of normal and select mutant forms of CFTR (including F508del-CFTR) to increase the amount of mature CFTR protein delivered to the cell surface. Ivacaftor is a CFTR potentiator that facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR protein at the cell surface. For ivacaftor to function CFTR protein must be present at the cell surface. Ivacaftor can potentiate the CFTR protein delivered to the cell surface by tezacaftor, leading to a further enhancement of chloride transport than either agent alone. The combined effect of tezacaftor and ivacaftor is increased quantity and function of CFTR at the cell surface, resulting in increases in chloride transport.