General Information

Kalydeco (ivacaftor) is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator. Cystic fibrosis is caused by mutations in a gene that encodes for the CFTR protein that regulates ion (such as chloride) and water transport in the body. The defect in chloride and water transport results in the formation of thick mucus that builds up in the lungs, digestive tract and other parts of the body leading to severe respiratory and digestive problems.

Kalydeco was specifically approved for the treatment of cystic fibrosis in patients age 6 years and older who have a G551D mutation in the CFTR gene. If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of the G551D mutation. Kalydeco was subsequently approved use in children with cystic fibrosis (CF) ages one month and older who have at least one mutation in their cystic fibrosis transmembrane conductance regulator (CFTR) gene that is responsive to Kalydeco based on clinical and/or in vitro assay data. The indication was expanded in December of 2020 to include 59 additional responsive mutations in people with CF ages 6 years and older and age 4 months and older, respectively. 

Kalydeco is supplied as a tablet for oral administration. The recommended dose of Kalydeco for both adults and pediatric patients age 6 years and older is one 150 mg tablet taken orally every 12 hours (300 mg total daily dose). Kalydeco is supplied as 25 mg, 50 mg and 75 mg granules for pediatric patients ages 6 months to less than 6 years.

Mechanism of Action

Kalydeco (ivacaftor) is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator. The CFTR protein is a chloride channel present at the surface of epithelial cells in multiple organs. Ivacaftor facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the G551D-CFTR protein. Cystic fibrosis is caused by mutations in a gene that encodes for the CFTR protein that regulates ion (such as chloride) and water transport in the body. The defect in chloride and water transport results in the formation of thick mucus that builds up in the lungs, digestive tract and other parts of the body leading to severe respiratory and digestive problems.

Side Effects

Adverse events associated with the use of Kalydeco may include, but are not limited to, the following:

• headache
• oropharyngeal pain
• upper respiratory tract infection
• nasal congestion
• abdominal pain
• nasopharyngitis
• diarrhea
• rash
• nausea
• dizziness

Clinical Trial Results

The FDA approval of Kalydeco was based on the following trials:

Dose Ranging:

• A double-blind, placebo-controlled, cross-over trial enrolled 39 adult subjects. Twenty subjects with median predicted FEV1 at baseline of 56% received Kalydeco 25, 75, 150 mg or placebo every 12 hours for 14 days and 19 subjects with median predicted FEV1 at baseline of 69% received Kalydeco 150, 250 mg or placebo every 12 hours for 28 days. The optimal dose was determined to be 150 mg every 12 hours.

Efficacy:

• Two randomized, double-blind, placebo- controlled clinical trials enrolled 213 clinically stable subjects who received Kalydeco 150 mg twice daily or placebo every 12 hours with food containing fat for 48 weeks in addition to their prescribed CF therapies. Trial 1 enrolled 161 subjects who were 12 years of age or older with baseline FEV1 between 40-90% predicted. Trial 2 evaluated 52 subjects who were 6 to 11 years of age with baseline FEV1 between 40-105% predicted. The primary efficacy endpoint in both studies was improvement in lung function as determined by the mean absolute change from baseline in percent predicted pre-dose FEV1 through 24 weeks of treatment. In both studies, treatment with Kalydeco resulted in a significant improvement in FEV1. The treatment difference between Kalydeco and placebo for the mean absolute change in percent predicted FEV1 from baseline through Week 24 was 10.6 percentage points (P < 0.0001) in Trial 1 and 12.5 percentage points (P < 0.0001) in Trial 2. These changes persisted through 48 weeks.

The FDA approval of Kalydeco for use in patients 6 months to less than 12 months was based on data from a 24-week Phase 3 open-label safety cohort (ARRIVAL) of 11 children with CF aged six months to less than 12 months who have one of 10 mutations in the CFTR gene (G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, G1349D or R117H). The study demonstrated a safety profile similar to that observed in previous Phase 3 studies of older children and adults; most adverse events were mild or moderate in severity, and no patient discontinued therapy due to adverse events. Mean baseline sweat chloride for the children in this cohort was 101.5 mmol/L (n=11). Following 24 weeks of treatment with Kalydeco, the mean sweat chloride level was 43.1 mmol/L (n=6). In the six subjects with paired sweat chloride samples at baseline and week 24, there was a mean absolute change of -58.6 mmol/L.