Kalydeco Drug Information
Generic name: IVACAFTOR
Cystic Fibrosis Transmembrane Conductance Regulator Potentiator [EPC]
Uses of Kalydeco
is indicated for the treatment of cystic fibrosis (CF) in patients aged 1 month and older who have at least one mutation in the CFTR gene that is responsive to ivacaftor potentiation based on clinical and/or in vitro assay data . If the patient's genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of a CFTR mutation followed by verification with bi-directional sequencing when recommended by the mutation test instructions for use. KALYDECO is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator indicated for the treatment of cystic fibrosis (CF) in patients aged 1 month and older who have at least one mutation in the CFTR gene that is responsive to ivacaftor based on clinical and/or in vitro assay data. If the patient's genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of a CFTR mutation followed by verification with bi-directional sequencing when recommended by the mutation test instructions for use.
Dosage & Administration of Kalydeco
| 1 month to less than 2 months | 3 kg or greater |
|---|---|
| 2 months to less than 4 months | 3 kg or greater |
| 4 months to less than 6 months | 5 kg or greater |
| 6 months to less than 6 years | 5 kg to less than 7 kg |
| 7 kg to less than 14 kg | One 50 mg packet every 12 hours |
| 14 kg or greater | One 75 mg packet every 12 hours |
| 6 years and older | - |
Side Effects of Kalydeco
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The overall safety profile of KALYDECO is based on pooled data from three placebo-controlled clinical trials conducted in 353 patients 6 years of age and older with CF who had a G551D mutation in the CFTR gene (Trials 1 and 2) or were homozygous for the F508del mutation (Trial 3). In addition, the following clinical trials have also been conducted : An 8-week, crossover design trial (Trial 4) involving 39 patients between the ages of 6 and 57 years with a G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, or S549R mutation in the CFTR gene. A 24-week, placebo-controlled trial (Trial 5) involving 69 patients between the ages of 6 and 68 years with an R117H mutation in the CFTR gene.
A 24-week, open-label trial (Trial 6) in 34 patients 2 to less than 6 years of age. Patients eligible for Trial 6 were those with the G551D, G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, or S549R mutation in the CFTR gene. Of 34 patients enrolled, 32 had the G551D mutation and 2 had the S549N mutation.
An 8-week, crossover design trial (Trial 7) involving patients between the ages of 12 and 72 years who were heterozygous for the F508del mutation and a second CFTR mutation predicted to be responsive to ivacaftor. A total of 156 patients were randomized to and received KALYDECO. A 24-week open-label clinical trial in patients with CF aged less than 24 months (Trial 8) including a cohort of 19 patients aged 12 months to less than 24 months, a cohort of 11 patients aged 6 months to less than 12 months, a cohort of 6 patients aged 4 months to less than 6 months, and a cohort of 7 patients aged 1 month to less than 4 months. Patients with a gating mutation or R117H mutation were eligible for the first three cohorts of this study.
Patients with any ivacaftor-responsive mutation were eligible for the cohort aged 1 to less than 4 months. Of the 353 patients included in the pooled analyses of patients with CF who had either a G551D mutation or were homozygous for the F508del mutation in the CFTR gene, 50% of patients were female and 97% were Caucasian; 221 received KALYDECO, and 132 received placebo for 16 to 48 weeks. The proportion of patients who prematurely discontinued study drug due to adverse reactions was 2% for KALYDECO-treated patients and 5% for placebo-treated patients.
Serious adverse reactions, whether considered drug-related or not by the investigators, that occurred more frequently in KALYDECO-treated patients, included abdominal pain, increased hepatic enzymes, and hypoglycemia. The most common adverse reactions in the 221 patients treated with KALYDECO were headache (17%), upper respiratory tract infection (16%), nasal congestion (16%), nausea (10%), rash (10%), rhinitis (6%), dizziness (5%), arthralgia (5%), and bacteria in sputum (5%). The incidence of adverse reactions below is based upon two double-blind, placebo-controlled, 48-week clinical trials (Trials 1 and 2) in a total of 213 patients with CF ages 6 to 53 who have a G551D mutation in the CFTR gene and who were treated with KALYDECO 150 mg orally or placebo twice daily. Table 2 shows adverse reactions occurring in ≥8% of KALYDECO-treated patients with CF who have a G551D mutation in the CFTR gene that also occurred at a higher rate than in the placebo-treated patients in the two double-blind, placebo-controlled trials.
Table 2: Incidence of Adverse Drug Reactions in ≥8% of KALYDECO-Treated Patients with a G551D Mutation in the CFTR Gene and Greater than Placebo in 2 Placebo-Controlled Phase 3 Clinical Trials of 48 Weeks Duration Adverse Reaction (Preferred Term) Incidence: Pooled 48-Week Trials KALYDECO N=109 n (%) Placebo N=104 n (%) Headache 26 17 Oropharyngeal pain 24 19 Upper respiratory tract infection 24 14 Nasal congestion 22 16 Abdominal pain 17 13 Nasopharyngitis 16 12 Diarrhea 14 10 Rash 14 7 Nausea 13 11 Dizziness 10 1 Adverse reactions in the 48-week clinical trials that occurred in the KALYDECO group at a frequency of 4 to 7% where rates exceeded that in the placebo group include: Infections and infestations : rhinitis Investigations: aspartate aminotransferase increased, bacteria in sputum, blood glucose increased, hepatic enzyme increased Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal chest pain, myalgia Nervous system disorders: sinus headache Respiratory, thoracic and mediastinal disorders: pharyngeal erythema, pleuritic pain, sinus congestion, wheezing Skin and subcutaneous tissue disorders: acne The safety profile for the CF patients enrolled in the other clinical trials (Trials 3-8) was similar to that observed in the 48-week, placebo-controlled trials (Trials 1 and 2). Laboratory Abnormalities Transaminase Elevations: In Trials 1, 2, and 3 the incidence of maximum transaminase (ALT or AST) >8, >5, or >3 × ULN was 2%, 2%, and 6% in KALYDECO-treated patients and 2%, 2%, and 8% in placebo-treated patients, respectively. Two patients (2%) on placebo and 1 patient (0.5%) on KALYDECO permanently discontinued treatment for elevated transaminases, all >8 × ULN. Two patients treated with KALYDECO were reported to have serious adverse reactions of elevated liver transaminases compared to none on placebo. Transaminase elevations were more common in patients with a history of transaminase elevations.
During the 24-week, open-label, clinical trial in 34 patients ages 2 to less than 6 years (Trial 6), where patients received either 50 mg (less than 14 kg) or 75 mg (14 kg or greater) ivacaftor granules twice daily, the incidence of patients experiencing transaminase elevations (ALT or AST) >3 × ULN was 14.7% (5/34). All 5 patients had maximum ALT or AST levels >8 × ULN, which returned to baseline levels following interruption of KALYDECO dosing. Transaminase elevations were more common in patients who had abnormal transaminases at baseline. KALYDECO was permanently discontinued in one patient.
During the 24-week, open-label, clinical trial in patients aged less than 24 months (Trial 8), the incidence of patients experiencing transaminase elevations (ALT or AST) >3, >5, and >8 × ULN in the cohort of patients aged 12 months to less than 24 months (N=19) was 27.8% (5/18), 11.1% (2/18) and 11.1% (2/18), respectively. In the cohort of patients aged 6 months to less than 12 months (N=11) one patient (9.1%) had elevated ALT of >3 to ≤5 × ULN. In the cohort of patients aged 4 months to less than 6 months (N=6), no patients had elevated ALT or AST (>3× ULN). In the cohort of patients aged 1 month to less than 4 months (N=7), 1 patient (14.3%) had maximum ALT or AST >3 × ULN (ALT >8 × ULN and AST of >3 to ≤5 × ULN); the patient discontinued ivacaftor treatment .
Postmarketing Experience
The following adverse reactions have been identified during post approval use of KALYDECO or drugs containing the same or similar active ingredient as KALYDECO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System Disorders : anaphylaxis Nervous System Disorders : intracranial hypertension Psychiatric Disorders: anxiety, depression, suicidal ideation and behavior, insomnia
Warnings & Cautions for Kalydeco
Transaminase (ALT or
AST) Elevations Elevated transaminases have been reported in patients with CF receiving KALYDECO. ALT and AST should be assessed prior to initiating KALYDECO, every 3 months during the first year of treatment, and annually thereafter. For patients with a history of transaminase elevations, consider more frequent monitoring of liver function tests. Patients who develop increased transaminase levels should be closely monitored until the abnormalities resolve.
Dosing should be interrupted in patients with ALT or AST of greater than 5 times the upper limit of normal (ULN). Following resolution of transaminase elevations, consider the benefits and risks of resuming KALYDECO .
Hypersensitivity Reactions, Including Anaphylaxis Hypersensitivity reactions, including cases of anaphylaxis, have been
reported in the postmarketing setting . If signs or symptoms of serious hypersensitivity reactions develop during treatment, discontinue KALYDECO and institute appropriate therapy. Consider the benefits and risks for the individual patient to determine whether to resume treatment with KALYDECO.
Intracranial Hypertension Cases of intracranial hypertension (IH) have been reported in the
postmarketing setting with the use of drugs containing the same or similar active ingredients as KALYDECO . Clinical manifestations of IH include headache, blurred vision, diplopia, and potential vision loss; papilledema can be found on fundoscopy. If an unusual headache or visual disturbances occur during treatment, and IH is suspected, interrupt KALYDECO and refer for prompt medical evaluation. Consider the benefits and risks for the individual patient to determine whether to resume treatment with KALYDECO. Patients should be monitored until IH resolution and for recurrence.
Patients with elevated vitamin A levels may be at increased risk.
Neuropsychiatric Events, Including Suicidal Thoughts and Behaviors Serious neuropsychiatric events, including symptoms
of anxiety, depression, suicidal ideation and behavior, and sleep disturbances, have been reported in the postmarketing setting in patients taking KALYDECO or drugs containing the same or similar active ingredient . The events were reported in adult and pediatric patients with and without a previous history of neuropsychiatric symptoms. Symptoms may occur within the first three months of treatment initiation. Assess patients for baseline neuropsychiatric symptoms and monitor for new or worsening symptoms of anxiety, depression, suicidal ideation or behavior, or sleep disturbances.
Consider the benefits and risks for the individual patient to determine if therapy with KALYDECO should be interrupted at the occurrence of neuropsychiatric symptoms and whether to resume therapy with symptom improvement.
Concomitant Use with
CYP3A Inducers Use of KALYDECO with strong CYP3A inducers, such as rifampin, substantially decreases the exposure of ivacaftor, which may reduce the therapeutic effectiveness of KALYDECO. Therefore, co-administration of KALYDECO with strong CYP3A inducers (e.g., rifampin, St. John's wort) is not recommended.
Cataracts Cases of non-congenital lens opacities/cataracts have been reported in pediatric patients
treated with KALYDECO. Although other risk factors were present in some cases (such as corticosteroid use and/or exposure to radiation), a possible risk attributable to KALYDECO cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating KALYDECO treatment.
Drug Interactions with Kalydeco
Inhibitors of
CYP3A Ivacaftor is a sensitive CYP3A substrate. Co-administration with ketoconazole, a strong CYP3A inhibitor, significantly increased ivacaftor exposure by 8.5-fold. Based on simulations of these results, a reduction of the KALYDECO dosage is recommended for patients aged 6 months and older taking concomitant strong CYP3A inhibitors, such as ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, and clarithromycin.
KALYDECO is not recommended for patients less than 6 months of age taking strong CYP3A inhibitors . Co-administration with fluconazole, a moderate inhibitor of CYP3A, increased ivacaftor exposure by 3-fold. Therefore, a reduction of the KALYDECO dosage is recommended for patients aged 6 months and older taking concomitant moderate CYP3A inhibitors, such as fluconazole and erythromycin. KALYDECO is not recommended for patients less than 6 months of age taking moderate CYP3A inhibitors . Co-administration of KALYDECO with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure of ivacaftor.
Therefore, avoid food or drink containing grapefruit during treatment with KALYDECO.
Inducers of
CYP3A Co-administration with rifampin, a strong CYP3A inducer, significantly decreased ivacaftor exposure (AUC) by approximately 9-fold. Therefore, co-administration with strong CYP3A inducers, such as rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, and St. John's wort is not recommended.
Ciprofloxacin Co-administration of
KALYDECO with ciprofloxacin had no effect on the exposure of ivacaftor. Therefore, no dosage adjustment is necessary during concomitant administration of KALYDECO with ciprofloxacin. Potential for ivacaftor to affect other drugs
CYP2C9 Substrates Ivacaftor may inhibit
CYP2C9; therefore, monitoring of the international normalized ratio (INR) during co-administration of KALYDECO with warfarin is recommended. Other therapeutic products for which exposure may be increased by KALYDECO include glimepiride and glipizide; these therapeutic products should be used with caution .
CYP3A and/or P-gp Substrates Ivacaftor and its M1 metabolite have the potential
to inhibit CYP3A and P-gp. Co-administration with oral midazolam, a sensitive CYP3A substrate, increased midazolam exposure 1.5-fold, consistent with weak inhibition of CYP3A by ivacaftor. Co-administration with digoxin, a sensitive P-gp substrate, increased digoxin exposure by 1.3-fold, consistent with weak inhibition of P-gp by ivacaftor.
Administration of KALYDECO may increase systemic exposure of drugs that are substrates of CYP3A and/or P-gp, which may increase or prolong their therapeutic effect and adverse events. Therefore, caution and appropriate monitoring are recommended when co-administering KALYDECO with sensitive CYP3A and/or P-gp substrates, such as digoxin, cyclosporine, and tacrolimus.
Pregnancy Safety for Kalydeco
Pregnancy Risk Summary There are limited and incomplete human data from clinical trials and postmarketing reports on use of KALYDECO in pregnant women. In animal reproduction studies, oral administration of ivacaftor to pregnant rats and rabbits during organogenesis demonstrated no teratogenicity or adverse effects on fetal development at doses that produced maternal exposures up to approximately 5 (rats) and 11 (rabbits) times the exposure at the maximum recommended human dose (MRHD). No adverse developmental effects were observed after oral administration of ivacaftor to pregnant rats from organogenesis through lactation at doses that produced maternal exposures approximately 3 times the exposures at the MRHD, respectively ( see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects is 2% to 4% and miscarriage is 15% to 20% in clinically recognized pregnancies.
Data Animal Data In an embryo-fetal development study, pregnant rats were administered ivacaftor at oral doses of 50, 100, or 200 mg/kg/day during the period of organogenesis from gestation days 7-17. Ivacaftor did not affect fetal survival at exposures up to 5 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at maternal oral doses up to 200 mg/kg/day). Maternal toxicity was observed at 100 and 200 mg/kg/day (3 and 5 times the exposure at the MRHD) and was associated with a decrease in fetal body weights at a maternal dose of 200 mg/kg/day (5 times the MRHD). In an EFD study, pregnant rabbits were administered ivacaftor at oral doses of 25, 50, or 100 mg/kg/day during the period of organogenesis from gestation days 7-19. Ivacaftor did not affect fetal development or survival at exposures up to 11 times the MRHD (on an ivacaftor AUC basis at maternal oral doses up to 100 mg/kg/day). Maternal toxicity (i.e., death, decreased food consumption, decreased mean body weight and body weight gain, decreased clinical condition, abortions) was observed at doses greater than or equal to 50 mg/kg/day (approximately 5 times the MRHD). In a pre- and post-natal development study, pregnant female rats were administered ivacaftor at oral doses of 50, 100, or 200 mg/kg/day from gestation day 7 through lactation day 20. Ivacaftor had no effects on delivery or growth and development of offspring at exposures up to 3 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at maternal oral doses up to 100 mg/kg/day). Decreased fetal body weights were observed at a maternally toxic dose that produced exposures 5 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at a maternal oral dose of 200 mg/kg/day). Placental transfer of ivacaftor was observed in pregnant rats and rabbits.
Pediatric Use of Kalydeco
Pediatric Use The safety and effectiveness of KALYDECO for the treatment of CF have been established in pediatric patients 1 month to 17 years of age who have at least one mutation in the CFTR gene that is responsive to ivacaftor potentiation based on clinical and/or in vitro assay data. The use of KALYDECO for this indication is supported by evidence from placebo-controlled clinical trials in the following pediatric patients with CF: 12 to 17 years of age who are heterozygous for the F508del mutation and a second mutation predicted to be responsive to ivacaftor . 6 to 17 years of age with a G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, or R117H mutation in the CFTR gene . The effectiveness of KALYDECO in patients aged 2 to less than 6 years was extrapolated from patients 6 years of age and older with support from population pharmacokinetic analyses showing similar drug exposure levels in adults and pediatric patients 2 to less than 6 years of age . Safety of KALYDECO in this population was derived from a 24-week, open-label clinical trial in 34 patients ages 2 to less than 6 years (mean age 3 years) administered either 50 mg or 75 mg of ivacaftor granules twice daily (Trial 6). The type and frequency of adverse reactions in this trial were similar to those in patients aged 6 years and older. Transaminase elevations were more common in patients who had abnormal transaminases at baseline . The effectiveness of KALYDECO in patients aged 1 month to less than 24 months was extrapolated from patients 6 years of age and older with support from population pharmacokinetic analyses showing that the exposure of ivacaftor in pediatric patients 1 month to less than 24 months of age is within the range of exposure in adults and pediatric patients 6 years of age and older.
Safety of KALYDECO in this population was derived from a cohort of 7 patients aged 1 month to less than 4 months (mean age 1.9 months at baseline), a cohort of 6 patients aged 4 months to less than 6 months (mean age 4.5 months at baseline), a cohort of 11 patients aged 6 months to less than 12 months (mean age 9.0 months at baseline), and a cohort of 19 patients aged 12 months to less than 24 months (mean age 15.2 months at baseline) in a 24-week, open-label clinical trial, administered 5.8 mg, 11.4 mg, 17.1 mg, 22.8 mg, 25 mg, 50 mg, or 75 mg (11.4 mg, 17.1 mg, and 22.8 mg are not recommended dosages) of ivacaftor granules twice daily (Trial 8). The safety profile of patients in this trial was similar to that observed in patients aged 2 years and older. Safety of KALYDECO in patients aged 1 month and older was evaluated in a 96-week, open-label study (Trial 9) in 86 patients (38 rolled over from Trial 8, and 48 KALYDECO-naïve). Adverse reactions from Trial 9 were generally similar to those reported in Trial 8. The safety and effectiveness of KALYDECO in pediatric patients with CF younger than 1 month of age have not been established. Juvenile Animal Toxicity Data In a juvenile toxicology study in which ivacaftor was administered to rats from postnatal days 7 to 35, cataracts were observed at all dose levels, ranging from 0.1 to 0.8 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at oral doses of 10-50 mg/kg/day). This finding has not been observed in older animals.
Overdosage Information for Kalydeco
There have been no reports of overdose with KALYDECO. No specific antidote is available for overdose with KALYDECO. Treatment of overdose with KALYDECO consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.
Clinical Studies of Kalydeco
Trials in Patients with CF who have a G551D Mutation in the
CFTR Gene Dose Ranging: 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 FEV 1 ≥40% predicted. Twenty patients with median predicted FEV 1 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 FEV 1 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 FEV 1 ) 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.
Efficacy: 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 FEV 1 at screening between 40-90% predicted. Trial 2 evaluated 52 patients who were 6 to 11 years of age (mean age 9 years) with FEV 1 at screening between 40-105% predicted.
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 ULN were excluded. Patients in both trials were randomized 1:1 to receive either 150 mg of KALYDECO or placebo every 12 hours with fat-containing food 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 FEV 1 through 24 weeks of treatment.
In both studies, treatment with KALYDECO resulted in a significant improvement in FEV 1. The treatment difference between KALYDECO and placebo for the mean absolute change in percent predicted FEV 1 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 FEV 1 were observed regardless of age, disease severity, sex, and geographic region. Figure 3: Mean Absolute Change from Baseline in Percent Predicted FEV 1 Primary endpoint was assessed at the 24-week time point.
Other efficacy variables included absolute change from baseline in sweat chloride, time to first pulmonary exacerbation (Trial 1 only), absolute change from baseline in weight, and improvement from baseline in Cystic Fibrosis Questionnaire Revised (CFQ-R) respiratory domain score, a measure of respiratory symptoms relevant to patients with CF 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 5). Weight data, when expressed as body mass index normalized for age and sex in patients <20 years of age, were consistent with absolute change from baseline in weight.
Table 5: Effect of KALYDECO on Other Efficacy Endpoints in Trials 1 and 2 Trial 1 Trial 2 Endpoint Treatment difference Treatment difference = effect of KALYDECO – effect of Placebo. (95% CI) P value Treatment difference (95% CI) P value CI: confidence interval; NA: not analyzed due to low incidence of events. Mean absolute change from baseline in CFQ-R respiratory domain score (points) Through Week 24 8.1 <0.0001 6.1 (-1.4, 13.5) 0.1092 Through Week 48 8.6 <0.0001 5.1 (-1.6, 11.8) 0.1354 Relative risk of pulmonary exacerbation Through Week 24 0.40 Hazard ratio for time to first pulmonary exacerbation. 0.0016 NA NA Through Week 48 0.46 0.0012 NA NA Mean absolute change from baseline in body weight (kg) At Week 24 2.8 <0.0001 1.9 0.0004 At Week 48 2.7 0.0001 2.8 0.0002 Absolute change in sweat chloride (mmol/L) Through Week 24 -48 (-51, -45) <0.0001 -54 (-62, -47) <0.0001 Through Week 48 -48 (-51, -45) <0.0001 -53 (-61, -46) <0.0001 Figure 3
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 FEV 1 ≥40% at screening.
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 ULN at screening were excluded. Patients were randomized 1:1 to receive either 150 mg of KALYDECO or placebo every 12 hours with fat-containing food 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 FEV 1 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 CFQ-R respiratory domain score 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 FEV 1, BMI, and CFQ-R respiratory domain score ; however, there was a high degree of variability of efficacy responses among the 9 mutations (Table 6). Table 6: Effect of KALYDECO for Efficacy Variables in the Overall Populations and for Specific CFTR Mutations Mutation (n) Absolute change in percent predicted FEV 1 BMI (kg/m 2 ) CFQ-R Respiratory Domain Score (Points) Absolute Change in Sweat Chloride (mmol/L) At Week 2 At Week 4 At Week 8 At Week 8 At Week 8 At Week 8 All patients (n=39) Results shown as mean (95% CI) change from baseline KALYDECO vs. placebo-treated patients: 8.3 10.0 13.8 0.66 Result for weight gain as a component of body mass index was consistent with BMI. 12.8 -50 (-58, -41) n=36 for the analysis of absolute change in sweat chloride. Patients grouped under mutation types (n) Results shown as mean (minimum, maximum) for change from baseline for KALYDECO-treated patients: Statistical testing was not performed due to small numbers for individual mutations. G1244E 11 (-5, 25) 6 (-5, 13) 8 (-1, 18) 0.63 3.3 (-27.8, 22.2) -55 (-75, -34) G1349D 19 18 20 1.15 16.7 (-11.1, 44.4) -80 (-82, -79) G178R 7 10 (-2, 21) 8 (-1, 18) 0.85 20.0 -53 (-65, -35) G551S 0 (-5, 5) 0.3 (-5, 6) 3 Reflects results from the one patient with the G551S mutation with data at the 8-week time point. 0.16 16.7 -68 G970R 7 7 3 (-1, 5) 0.48 (-0.38, 1.75) 1.4 (-16.7, 16.7) -6 (-16, -2) S1251N 2 (-23, 20) 8 (-13, 26) 9 (-20, 21) 0.73 23.3 -54 (-84, -7) S1255P 11 9 3 (-1, 8) 1.62 8.3 -78 (-82, -74) S549N 11 8 (-9, 19) 11 (-2, 20) 0.79 8.8 (-8.3, 27.8) -74 (-93, -53) S549R 3 (-4, 8) 4 (-4, 10) 5 (-3, 13) 0.53 6.9 -61 n=3 for the analysis of absolute change in sweat chloride. (-71, -54)
Trial in Patients with CF who have an R117H Mutation in the
CFTR Gene The efficacy and safety of KALYDECO in patients with CF who have an R117H mutation in the CFTR gene were evaluated in a randomized, double-blind, placebo-controlled, parallel-group clinical trial (Trial 5). Fifty-nine of 69 patients completed 24 weeks of treatment. Two patients discontinued and 8 patients did not complete treatment due to study termination. Trial 5 evaluated 69 clinically stable patients with CF who were 6 years of age or older (mean age 31 years). Patients who were aged 12 years and older had FEV 1 at screening between 40-90% predicted, and patients who were 6-11 years of age had FEV 1 at screening between 40-105% predicted.
The overall mean FEV 1 was 73% predicted at baseline (range: 33% to 106%). The patients had well preserved BMIs (mean overall: 23.76 kg/m 2 ) and a high proportion were pancreatic sufficient as assessed by a low rate of pancreatic enzyme replacement therapy use (pancreatin: 11.6%; pancrelipase: 5.8%). 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 ULN, were excluded. Patients were randomized 1:1 to receive either 150 mg of KALYDECO (n=34) or placebo (n=35) every 12 hours with fat-containing food for 24 weeks in addition to their prescribed CF therapies. The primary efficacy endpoint was improvement in lung function as determined by the mean absolute change from baseline in percent predicted FEV 1 through 24 weeks of treatment.
The treatment difference for absolute change in percent predicted FEV 1 through Week 24 was 2.1 percentage points (analysis conducted with the full analysis set which included all 69 patients) and did not reach statistical significance (Table 7). Other efficacy variables that were analyzed included absolute change in sweat chloride from baseline through Week 24, improvement in cystic fibrosis respiratory symptoms through Week 24 as assessed by the CFQ-R respiratory domain score (Table 7), absolute change in body mass index (BMI) at Week 24, and time to first pulmonary exacerbation. The overall treatment difference for the absolute change from baseline in BMI at Week 24 was 0.3 kg/m 2 and the calculated hazard ratio for time to first pulmonary exacerbation was 0.93, which were not statistically significant. Statistically significant improvements in clinical efficacy (FEV 1, CFQ-R respiratory domain score) were seen in several subgroup analyses and decreases in sweat chloride were observed in all subgroups.
The mean baseline sweat chloride for all patients was 70 mmol/L. Subgroups analyzed included those based on age, lung function, and poly-T status (Table 7). Table 7: Effect of KALYDECO on Overall Population (Percent Predicted FEV 1, CFQ-R Respiratory Domain Score, and Sweat Chloride) and in Relevant Subgroups Through 24 Weeks Absolute Change through Week 24 MMRM analysis with fixed effects for treatment, age, week, baseline value, treatment by week, and subject as a random effect. - All Randomized Patients % Predicted FEV 1 (Percentage Points) CFQ-R Respiratory Domain Score (Points) Sweat Chloride (mmol/L) Subgroup Parameter Study Drug n Mean Treatment Difference (95% CI) n Mean Treatment Difference (95% CI) n Mean Treatment Difference (95% CI) R117H–All Patients Placebo KALYDECO 35 34 0.5 2.6 2.1 (-1.1, 5.4) 34 33 -0.8 7.6 8.4 35 32 -2.3 -26.3 -24.0 (-28.0, -19.9) Subgroup by Age 6-11 Placebo KALYDECO 8 9 3.5 -2.8 -6.3 (-12.0, -0.7) 7 8 -1.6 -7.7 -6.1 (-15.7, 3.4) 8 8 1.0 -26.6 -27.6 (-37.2, -18.1) 12-17 Placebo KALYDECO 1 1 --- --- 1 1 --- --- 1 1 --- --- ≥18 Placebo KALYDECO 26 24 -0.5 4.5 5.0 26 24 -0.5 12.2 12.6 26 23 -4.0 -25.9 -21.9 (-26.5, -17.3) Subgroup by Poly-T Status (n=54) Poly-T status confirmed by genotyping. 5T Placebo KALYDECO 24 14 0.7 6.0 5.3 24 14 -0.6 14.7 15.3 24 13 -4.6 -28.7 -24.2 (-30.2, -18.2) 7T Placebo KALYDECO 5 11 -0.9 -0.7 0.2 (-8.1, 8.5) 5 11 -6.0 -0.7 5.2 (-13.0, 23.4) 5 10 3.9 -20.2 -24.1 (-33.9, -14.3) Subgroup by Baseline FEV 1 % Predicted <70% Placebo KALYDECO 15 13 0.4 4.5 4.0 (-2.1, 10.1) 15 13 3.0 14.4 11.4 15 12 -3.8 -29.3 -25.5 (-31.8, -19.3) 70-90% Placebo KALYDECO 14 14 0.2 2.8 2.6 (-2.3, 7.5) 13 14 -3.6 5.2 8.8 (-2.6, 20.2) 14 14 -3.1 -23.0 -20.0 (-26.9, -12.9) >90% Placebo KALYDECO 6 7 2.2 -2.1 -4.3 (-9.9, 1.3) 6 6 -2.5 -3.2 -0.7 (-10.4, 9.0) 6 6 1.0 -25.9 -26.8 (-39.5, -14.1)
Trial in Patients with CF Heterozygous for the F508del Mutation and a
Second Mutation Predicted to be Responsive to Ivacaftor The efficacy and safety of KALYDECO and an ivacaftor-containing combination product in 246 patients with CF was evaluated in a randomized, double-blind, placebo-controlled, 2-period, 3-treatment, 8-week crossover design clinical trial (Trial 7). Mutations predicted to be responsive to ivacaftor were selected for the study based on the clinical phenotype (pancreatic sufficiency), biomarker data (sweat chloride), and in vitro responsiveness to ivacaftor. Eligible patients were heterozygous for the F508del mutation with a second mutation predicted to be responsive to ivacaftor. Of the 244 patients included in the efficacy analysis, who were randomized and dosed, 146 patients had a splice mutation and 98 patients had a missense mutation, as the second allele. 156 patients received KALYDECO and 161 patients received placebo.
Patients were aged 12 years and older (mean age 35 years ) and had a percent predicted FEV 1 at screening between 40-90. Patients with evidence of colonization with organisms associated with a more rapid decline in pulmonary status (e.g., Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium abscessus ) and those with abnormal liver function at screening were excluded. Abnormal liver function was defined as 2 or more liver function tests (ALT, AST, ALP, GGT) ≥3 times the ULN or total bilirubin ≥2 times the ULN, or a single increase in ALT/AST ≥5 times the ULN. The primary efficacy endpoint was the mean absolute change from study baseline in percent predicted FEV 1 averaged at Weeks 4 and 8 of treatment. The key secondary efficacy endpoint was absolute change in CFQ-R respiratory domain score from study baseline averaged at Weeks 4 and 8 of treatment.
For the overall population, treatment with KALYDECO compared to placebo resulted in significant improvement in ppFEV 1 and CFQ-R respiratory domain score. Statistically significant improvements compared to placebo were also observed in the subgroup of patients with splice mutations and missense mutations (Table 8). Table 8: Effect of KALYDECO for Efficacy Variables Mutation (n) Absolute Change in percent predicted FEV 1 Average of Week 4 and 8 values. Absolute change in ppFEV 1 by individual mutations is an ad hoc analysis.
Absolute Change in CFQ-R Respiratory Domain Score (Points) Absolute change in CFQ-R respiratory domain score and absolute change in sweat chloride by mutation subgroups and by individual mutations are ad hoc analyses. Absolute Change in Sweat Chloride (mmol/L) Splice mutations (n=94 for IVA and n=97 for PBO) Results shown as difference in mean (95% CI) change from study baseline for KALYDECO vs. placebo-treated patients: 5.4 8.5 -2.4 (-5.0, 0.3) By individual splice mutation (n). Results shown as mean (minimum, maximum) for change from study baseline for KALYDECO-treated patients 2789+5G→A 5.1 (-7.1, 17.0) 8.6 (-5.6, 27.8) 0.4 (-7.5, 8.8) 3272-26A→G 3.5 (-9.1, 16.0) 8.0 (-11.1, 27.8) -2.3 (-25.0, 11.8) 3849+10kbC→T 5.1 (-6.8, 16.2) 7.5 (-30.6, 55.6) -4.6 (-80.5, 23.0) 711+3A→G 9.2 -8.3 (-13.9, -2.8) -9.9 (-13.5, -6.3) E831X 7.1 0.0 -7.8 (-7.8, -7.8) Missense mutations (n=62 for IVA and n=63 for PBO) Results shown as difference in mean (95% CI) change from study baseline for KALYDECO vs. placebo-treated patients: 3.6 11.5 -7.8 (-11.2, -4.5) By individual missense mutation (n). Results shown as mean (minimum, maximum) for change from study baseline for KALYDECO-treated patients D579G 13.3 15.3 (-2.8, 33.3) -30.8 (-36.0, -25.5) D1152H 2.4 (-5.0, 10.2) 13.7 (-16.7, 50.0) -4.8 (-22.0, 3.0) A455E 3.7 (-6.6, 19.7) 6.8 (-13.9, 33.3) 7.5 (-16.8, 16.0) L206W 4.2 12.5 (-5.6, 30.6) 3.9 (-8.3, 16.0) P67L 4.3 (-2.5, 25.7) 10.8 (-12.5, 36.1) -10.5 (-34.8, 9.8) R1070W 2.9 44.4
R117C 3.5 22.2 -36.0 (-36.0, -36.0) R347H 2.5 (-0.6, 6.9) 6.5 -19.2
(-25.8, -7.0) R352Q 4.4 9.7 -21.9 (-45.5, 1.8) S945L 8.8 (-0.2, 20.5) 10.6 (-25.0, 27.8) -30.8 (-50.8, -17.3) S977F 4.3 -2.8 (-2.8, -2.8) -19.5 (-19.5, -19.5) In an analysis of BMI at Week 8, an exploratory endpoint, patients treated with KALYDECO had a mean improvement of 0.28 kg/m 2, 0.24 kg/m 2, and 0.35 kg/m 2 versus placebo for the overall, splice, and missense mutation populations of patients, respectively.
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 aged 12 years and older who were homozygous for the F508del mutation in the CFTR gene and who had FEV 1 ≥40% predicted. Patients were randomized 4:1 to receive KALYDECO 150 mg (n=112) every 12 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 FEV 1 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 ULN 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 FEV 1. The treatment difference from placebo for the mean absolute change in percent predicted FEV 1 through Week 16 in patients with CF homozygous for the F508del mutation in the CFTR gene was 1.72 percentage points (1.5% and -0.2% for patients in the KALYDECO and placebo-treated groups, respectively) and did not reach statistical significance (Table 9). Other efficacy variables that were analyzed included absolute change in sweat chloride from baseline through Week 16, change in cystic fibrosis respiratory symptoms through Week 16 as assessed by the CFQ-R respiratory domain score (Table 9), change in weight through Week 16, and rate of pulmonary exacerbation. The overall treatment difference for change from baseline in weight through Week 16 was -0.16 kg (95% CI -1.06, 0.74); the rate ratio for pulmonary exacerbation was 0.677 (95% CI 0.33, 1.37). Table 9: Effect of KALYDECO on Overall Population (Percent Predicted FEV 1, CFQ-R Respiratory Domain Score, and Sweat Chloride) Through 16 Weeks Absolute Change through Week 16 MMRM analysis with fixed effects for treatment, age week, baseline value, treatment by week, and subject as a random effect. - Full Analysis Set % Predicted FEV 1 (Percentage Points) CFQ-R Respiratory Domain Score (Points) Sweat Chloride (mmol/L) Subgroup Parameter Study Drug n Mean Treatment Difference (95% CI) n Mean Treatment Difference (95% CI) n Mean Treatment Difference (95% CI) F508del homozygous Placebo KALYDECO 28 111 -0.2 1.5 1.72 (-0.6, 4.1) 28 111 -1.44 -0.12 1.3 (-2.9, 5.6) 28 109 0.13 -2.74 -2.9 (-5.6, -0.2)
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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