"The U.S. Food and Drug Administration yesterday approved Ruconest, the first recombinant C1-Esterase Inhibitor product for the treatment of acute attacks in adult and adolescent patients with hereditary angioedema (HAE).
Mechanism Of Action
Ivacaftor is a potentiator of the CFTR protein. 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 CFTR protein.
In vitro, ivacaftor increased CFTR-mediated transepithelial current (IT) in rodent cells expressing the G551D-CFTR protein following addition of a cyclic adenosine monophosphate (cAMP) agonist with an EC50 of 100 ± 47 nM; however, ivacaftor did not increase IT in the absence of cAMP agonist. Ivacaftor also increased IT in human bronchial epithelial cells expressing G551D-CFTR protein following addition of a cAMP agonist by 10-fold with an EC50 of 236 ± 200 nM. Ivacaftor increased the open probability of G551D-CFTR protein in single channel patch clamp experiments using membrane patches from rodent cells expressing G551D-CFTR protein by 6-fold versus untreated cells after addition of PKA and ATP. In addition to G551D-CFTR, ivacaftor increased the channel-open probability of other mutant CFTR forms expressed in rodent cells, resulting in enhanced CFTR-mediated IT. These mutant CFTR forms included G178R-, S549N-, S549R-, G551S-, G970R-, G1244E-, S1251N-, S1255P-, and G1349D-CFTR. In vitro responses do not necessarily correspond to in vivo pharmacodynamic response or clinical benefit.
Sweat Chloride Evaluation
Changes in sweat chloride response to KALYDECO were evaluated in four clinical trials. In two randomized, double-blind, placebo-controlled clinical trials in patients with a G551D mutation in the CFTR gene, one in patients 12 and older (Trial 1) and the other in patients 6-11 years of age (Trial 2), the treatment difference (between KALYDECO and placebo) in mean change in sweat chloride from baseline through Week 24 was -48 mmol/L (95% CI -51, -45) and 54 mmol/L (95% CI -62, -47), respectively. These changes persisted through 48 weeks. In a 16-week randomized, double-blind, placebo-controlled, parallel-group clinical trial in patients with CF age 12-years and older who were homozygous for the F508del mutation in the CFTR gene (Trial 3), the treatment difference in mean change in sweat chloride from baseline through 8 weeks of treatment was -3 mmol/L (95% CI -6, -0.2). In a two-part, randomized, double-blind, placebo-controlled, crossover clinical trial in patients with CF who had a G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, or S549R mutation in the CFTR gene (Trial 4), the treatment difference in mean change in sweat chloride from baseline through 8 weeks of treatment was -49 mmol/L (95% CI -57, -41). In Trial 4, mean changes in sweat chloride for the mutations for which KALYDECO is indicated ranged from -51 to -78, whereas the range for individual subjects with the G970R mutations was -1 to -11 mmol/L.
There was no direct correlation between decrease in sweat chloride levels and improvement in lung function (FEV1).
The effect of multiple doses of ivacaftor 150 mg and 450 mg twice daily on QTc interval was evaluated in a randomized, placebo-and active-controlled (moxifloxacin 400 mg) four-period crossover thorough QT study in 72 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on Fridericia's correction method (QTcF) was below 10 ms, the threshold for regulatory concern.
The pharmacokinetics of ivacaftor is similar between healthy adult volunteers and patients with CF.
After oral administration of a single 150 mg dose to healthy volunteers in a fed state, peak plasma concentrations (Tmax) occurred at approximately 4 hours, and the mean (±SD) for AUC and Cmax were 10600 (5260) ng*hr/mL and 768 (233) ng/mL, respectively.
After every 12-hour dosing, steady-state plasma concentrations of ivacaftor were reached by days 3 to 5, with an accumulation ratio ranging from 2.2 to 2.9.
The exposure of ivacaftor increased approximately 2-to 4-fold when given with food containing fat. Therefore, KALYDECO should be administered with fat-containing food. Examples of fat-containing foods include eggs, butter, peanut butter, and cheese pizza. The median (range) Tmax is approximately 4.0 (3.0; 6.0) hours in the fed state.
The mean apparent volume of distribution (Vz/F) of ivacaftor after a single dose of 275 mg of KALYDECO in the fed state was similar for healthy subjects and patients with CF. After oral administration of 150 mg every 12 hours for 7 days to healthy volunteers in a fed state, the mean (±SD) for apparent volume of distribution was 353 (122) L.
Ivacaftor is extensively metabolized in humans. In vitro and clinical studies indicate that ivacaftor is primarily metabolized by CYP3A. M1 and M6 are the two major metabolites of ivacaftor in humans. M1 has approximately one-sixth the potency of ivacaftor and is considered pharmacologically active. M6 has less than one-fiftieth the potency of ivacaftor and is not considered pharmacologically active.
Following oral administration, the majority of ivacaftor (87.8%) is eliminated in the feces after metabolic conversion. The major metabolites M1 and M6 accounted for approximately 65% of the total dose eliminated with 22% as M1 and 43% as M6. There was negligible urinary excretion of ivacaftor as unchanged parent. The apparent terminal half-life was approximately 12 hours following a single dose. The mean apparent clearance (CL/F) of ivacaftor was similar for healthy subjects and patients with CF. The CL/F (SD) for the 150 mg dose was 17.3 (8.4) L/hr in healthy subjects.
Patients with moderately impaired hepatic function (Child-Pugh Class B, score 7 to 9) had similar ivacaftor Cmax, but an approximately two-fold increase in ivacaftor AUC0-∞ compared with healthy subjects matched for demographics. Based on simulations of these results, a reduced KALYDECO dose of 150 mg once daily is recommended for patients with moderate hepatic impairment. The impact of mild hepatic impairment (Child-Pugh Class A) on pharmacokinetics of ivacaftor has not been studied, but the increase in ivacaftor AUC0-∞ is expected to be less than two-fold. Therefore, no dose adjustment is necessary for patients with mild hepatic impairment. The impact of severe hepatic impairment (Child-Pugh Class C, score 10-15) on pharmacokinetics of ivacaftor has not been studied. The magnitude of increase in exposure in these patients is unknown but is expected to be substantially higher than that observed in patients with moderate hepatic impairment. When benefits are expected to outweigh the risks, KALYDECO should be used with caution in patients with severe hepatic impairment at a dose of 150 mg given once daily or less frequently.
KALYDECO has not been studied in patients with mild, moderate or severe renal impairment (creatinine clearance less than or equal to 30 mL/min) or in patients with end-stage renal disease. No dose adjustments are recommended for mild and moderate renal impairment patients because of minimal elimination of ivacaftor and its metabolites in urine (only 6.6% of total radioactivity was recovered in the urine in a human PK study); however, caution is recommended when administering KALYDECO to patients with severe renal impairment or end-stage renal disease.
The effect of gender on KALYDECO pharmacokinetics was evaluated using population pharmacokinetics of data from clinical studies of KALYDECO. No dose adjustments are necessary based on gender.
Drug interaction studies were performed with KALYDECO and other drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interaction studies [see DRUG INTERACTIONS].
Dosing recommendations based on clinical studies or potential drug interactions with KALYDECO are presented below.
Potential for Ivacaftor to Affect Other Drugs
Based on in vitro results, ivacaftor and metabolite M1 have the potential to inhibit CYP3A and P-gp. Clinical studies showed that KALYDECO is a weak inhibitor of CYP3A and P-gp, but not an inhibitor of CYP2C8. In vitro studies suggest that ivacaftor and M1 may inhibit CYP2C9. In vitro, ivacaftor, M1, and M6 were not inducers of CYP isozymes. Dosing recommendations for co-administered drugs with KALYDECO are shown in Figure 1.
Figure 1 : Impact of KALYDECO on Other Drugs
Note: The data obtained with substrates but without co-administration of KALYDECO are used as reference.
*NE: Norethindrone; **EE: Ethinyl Estradiol The vertical lines are at 0.8, 1.0 and 1.25, respectively.
Potential for Other Drugs to Affect Ivacaftor
In vitro studies showed that ivacaftor and metabolite M1 were substrates of CYP3A enzymes (i.e., CYP3A4 and CYP3A5). Exposure to ivacaftor is reduced by concomitant CYP3A inducers and increased by concomitant CYP3A inhibitors [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS]. KALYDECO dosing recommendations for co-administration with CYP3A inhibitors or inducers are shown in Figure 2.
Figure 2: Impact of Other Drugs on KALYDECO
Note: The data obtained for KALYDECO without co-administration of inducers or inhibitors are used as reference.
The vertical lines are at 0.8, 1.0 and 1.25, respectively.
Animal Toxicology And/Or Pharmacology
Cataracts were seen in juvenile rats dosed with ivacaftor from postnatal day 7-35 at dose levels of 10 mg/kg/day and higher (approximately 0.12 times the MRHD based on summed AUCs of ivacaftor and its metabolites). This finding has not been observed in older animals.
Trials In Patients With CF Who Have A G551D Mutation In The CFTR Gene
Dose ranging for the clinical program consisted primarily of one double-blind, placebo-controlled, crossover trial in 39 adult (mean age 31 years) Caucasian patients with CF who had FEV1 ≥ 40% predicted. Twenty patients with median predicted FEV1 at baseline of 56% (range: 42% to 109%) received KALYDECO 25, 75, 150 mg or placebo every 12 hours for 14 days and 19 patients with median predicted FEV1 at baseline of 69% (range: 40% to 122%) received KALYDECO 150, 250 mg or placebo every 12 hours for 28 days. The selection of the 150 mg every 12 hours dose was primarily based on nominal improvements in lung function (pre-dose FEV1) and changes in pharmacodynamic parameters (sweat chloride and nasal potential difference). The twice-daily dosing regimen was primarily based on an apparent terminal plasma half-life of approximately 12 hours. Selection of the 150 mg dose of KALYDECO for children 6 to 11 years of age was based on achievement of comparable pharmacokinetics as those observed for adult patients.
The efficacy of KALYDECO in patients with CF who have a G551D mutation in the CFTR gene was evaluated in two randomized, double-blind, placebo-controlled clinical trials in 213 clinically stable patients with CF (109 receiving KALYDECO 150 mg twice daily). All eligible patients from these trials were rolled over into an open-label extension study.
Trial 1 evaluated 161 patients with CF who were 12 years of age or older (mean age 26 years) with FEV1 at screening between 40-90% predicted [mean FEV1 64% predicted at baseline (range: 32% to 98%)]. Trial 2 evaluated 52 patients who were 6 to 11 years of age (mean age 9 years) with FEV1 at screening between 40-105% predicted [mean FEV1 84% predicted at baseline (range: 44% to 134%)]. Patients who had persistent Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium abscessus isolated from sputum at screening and those with abnormal liver function defined as 3 or more liver function tests (ALT, AST, AP, GGT, total bilirubin) ≥ 3 times the upper limit of normal were excluded.
Patients in both trials were randomized 1:1 to receive either 150 mg of KALYDECO or placebo every 12 hours with food containing fat for 48 weeks in addition to their prescribed CF therapies (e.g., tobramycin, dornase alfa). The use of inhaled hypertonic saline was not permitted.
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 (Figure 3). These changes persisted through 48 weeks. Improvements in percent predicted FEV1 were observed regardless of age, disease severity, sex, and geographic region.
Figure 3: Mean Absolute
Change from Baseline in Percent Predicted FEV1 *
*Primary endpoint was assessed at the 24-week time point.
Other efficacy variables included absolute change in sweat chloride from baseline to Week 24, time to first pulmonary exacerbation through Week 48 (Trial 1 only), absolute change in weight from baseline to Week 48, and improvement in cystic fibrosis symptoms including relevant respiratory symptoms such as cough, sputum production, and difficulty breathing. For the purpose of the study, a pulmonary exacerbation was defined as a change in antibiotic therapy (IV, inhaled, or oral) as a result of 4 or more of 12 pre-specified sino-pulmonary signs/symptoms. Patients treated with KALYDECO demonstrated statistically significant improvements in risk of pulmonary exacerbations, CF symptoms (in Trial 1 only), and gain in body weight (Table 2). Weight data, when expressed as body mass index normalized for age and sex in patients < 20 years of age, was consistent with absolute change from baseline in weight.
Table 2: Effect of KALYDECO on Other Efficacy
Endpoints in Trials 1 and 2
|Endpoint||Trial 1||Trial 2|
|Treatment differencea (95% CI)||P value||Treatment differencea (95% CI)||P value|
|Mean absolute change from baseline in CF symptom score (points)|
|Through Week24||8.1 (4.7, 11.4)||< 0.0001||6.1 (-1.4, 13.5)||0.1092|
|Through Week 48||8.6 (5.3, 11.9)||< 0.0001||5.1 (-1.6, 11.8)||0.1354|
|Relative risk of pulmonary exacerbation|
|Through Week 24||0.40b||0.0016||NA||NA|
|Through Week 48||0.46b||0.0012||NA||NA|
|Mean absolute change from baseline in body weight (kg)|
|At Week24||2.8 (1.8, 3.7)||< 0.0001||1.9 (0.9, 2.9)||0.0004|
|At Week48||2.7 (1.3, 4.1)||0.0001||2.8 (1.3, 4.2)||0.0002|
|CI: confidence interval; NA: not analyzed due to low
incidence of events
aTreatment difference = effect of KALYDECO – effect of Placebo
bHazard ratio for time to first pulmonary exacerbation
Trial In Patients With A G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, Or S549R Mutation In The CFTR Gene
The efficacy and safety of KALYDECO in patients with CF who have a G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, or S549R mutation in the CFTR gene were evaluated in a two-part, randomized, double-blind, placebo-controlled, crossover design clinical trial in 39 patients with CF (Trial 4). Patients who completed Part 1 of this trial continued into the 16-week open-label Part 2 of the study. The mutations studied were G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P, and G1349D. See Clinical Studies for efficacy in patients with a G551D mutation.
Patients were 6 years of age or older (mean age 23 years) with FEV1 ≥ 40% at screening [mean FEV1 at baseline 78% predicted (range: 43% to 119%)]. Patients with evidence of colonization with Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium abscessus and those with abnormal liver function defined as 3 or more liver function tests (ALT, AST, AP, GGT, total bilirubin) ≥ 3 times the upper limit of normal at screening were excluded.
Patients were randomized 1:1 to receive either 150 mg of KALYDECO or placebo every 12 hours with food containing fat for 8 weeks in addition to their prescribed CF therapies during the first treatment period and crossed over to the other treatment for the second 8 weeks. The two 8-week treatment periods were separated by a 4-to 8-week washout period. The use of inhaled hypertonic saline was not permitted.
The primary efficacy endpoint was improvement in lung function as determined by the mean absolute change from baseline in percent predicted FEV1 through 8 weeks of treatment. Other efficacy variables included absolute change from baseline in sweat chloride through 8 weeks of treatment, absolute change from baseline in body mass index (BMI) at 8 weeks of treatment (including body weight at 8 weeks), and improvement in cystic fibrosis symptoms (including relevant respiratory symptoms such as cough, sputum production, and difficulty breathing) through 8 weeks of treatment. For the overall population of the 9 mutations studied, treatment with KALYDECO compared to placebo resulted in significant improvement in percent predicted FEV1 [10.7 through Week 8 (P < 0.0001)], BMI [0.66 kg/m² at Week 8 (P < 0.0001)], and cystic fibrosis respiratory symptom score [9.6 through Week 8 (P = 0.0004)]; however, there was a high degree of variability of efficacy responses among the 9 mutations (Table 3). Based on clinical and pharmacodynamic (sweat chloride) responses to ivacaftor, efficacy in patients with the G970R mutation could not be established.
Table 3: Effect of KALYDECO for Efficacy Variables in
the Overall Populations and for Specific CFTR Mutations
|Mutation (n)||Absolute change in percent predicted FEV1||BMI (kg/m²)||CF Respiratory Symptom Score (points)|
|At Week 2||At Week 4||At Week 8||At Week 8||At Week 8|
|All patients (n=39)
Results shown as mean (95% CI) change from baseline KALYDECO vsplacebo-treated patients:
|8.3 (4.5, 12.1)||10.0 (6.2, 13.8)||13.8 (9.9, 17.6)||0.66†(0.34, 0.99)||12.8 (6.7, 18.9)|
|Patients grouped under mutation types (n)|
|Results shown as mean (minimum, maximum) for change from baseline for KALYDECO-treated patients*:|
|G1244E (5)||11 (-5, 25)||6 (-5, 13)||8 (-1, 18)||0.63 (0.34, 1.32)||3.3 (-27.8, 22.2)|
|G1349D (2)||19 (5, 33)||18 (2, 35)||20 (3, 36)||1.15 (1.07, 1.22)||16.7 (-11.1, 44.4)|
|G178R (5)||7 (1, 17)||10 (-2, 21)||8 (-1, 18)||0.85 (0.33, 1.46)||20.0 (5.6, 50.0)|
|G551S (2)||0 (-5, 5)||0.3 (-5, 6)||3††||0.16††||16.7††|
|G970R (4)||7(1, 13)||7 (1, 14)||3 (-1, 5)||0.48 (-0.38, 1.75)||1.4 (-16.7, 16.7)|
|S1251N (8)||2 (-23, 20)||8 (-13, 26)||9 (-20, 21)||0.73 (0.08, 1.83)||23.3 (5.6, 50.0)|
|S1255P (2)||11 (8, 14)||9 (5, 13)||3 (-1, 8)||1.62 (1.39, 1.84)||8.3 (5.6, 11.1)|
|S549N (6)||11 (5, 16)||8 (-9, 19)||11 (-2, 20)||0.79 (0.00, 1.91)||8.8 (-8.3, 27.8)|
|S549R (4)||3 (-4, 8)||4 (-4, 10)||5 (-3, 13)||0.53 (0.33, 0.80)||6.9 (0.0, 11.1)|
|* Statistical testing was not
performed due to small numbers for individual mutations.
† Result for weight gain as a component of body mass index was consistent with BMI.
†† Reflects results from the one patient with the G551S mutation with data at the 8-week time point.
Trial In Patients Homozygous For The F508del Mutation In The CFTR Gene
Trial 3 was a 16-week randomized, double-blind, placebo-controlled, parallel-group trial in 140 patients with CF age 12 years and older who were homozygous for the F508del mutation in the CFTR gene and who had FEV1 ≥ 40% predicted. Patients were randomized 4:1 to receive KALYDECO 150 mg (n=112) every twelve hours or placebo (n=28) in addition to their prescribed CF therapies. The mean age of patients enrolled was 23 years and the mean baseline FEV1 was 79% predicted (range 40% to 129%). As in Trials 1 and 2, patients who had persistent Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium abscessus isolated from sputum at screening and those with abnormal liver function defined as 3 or more liver function tests (ALT, AST, AP, GGT, total bilirubin) ≥ 3 times the upper limit of normal were excluded. The use of inhaled hypertonic saline was not permitted.
The primary endpoint was improvement in lung function as determined by the mean absolute change from baseline through Week 16 in percent predicted FEV1. Treatment with KALYDECO resulted in no improvement in FEV1 relative to placebo in patients with CF homozygous for the F508del mutation in the CFTR gene [mean absolute change from baseline through Week 16 in percent predicted FEV1 was 1.5% and -0.2% for patients in the KALYDECO and placebo-treated groups, respectively (P = 0.15)]. There were no meaningful differences between patients treated with KALYDECO compared to placebo for secondary endpoints (change in CF symptoms, change in weight, or change in sweat chloride concentration).
Last reviewed on RxList: 7/15/2014
This monograph has been modified to include the generic and brand name in many instances.
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