ORKAMBI: Studied in Over 250 Patients Age 6 Through 11 Years

TRIAL 31-3
Phase 3, Open-label Safety Study
TRIAL 44,5
Phase 3, Double-blind, Placebo-controlled Efficacy and Safety Study
24 WEEKS
(WITH 2-WEEK WASHOUT)
24 WEEKS
ORKAMBI
lumacaftor 200 mg/ivacaftor 250 mg q12h + currently prescribed CF therapies (n=58)
WASHOUT
Currently prescribed CF therapies only
ORKAMBI
lumacaftor 200 mg/ivacaftor 250 mg q12h + currently prescribed CF therapies (n=103)
Placebo
q12h + currently prescribed CF therapies
GEOGRAPHIC LOCATIONS
  • North America
  • North America, Europe, Australia
KEY INCLUSION CRITERIA
  • Confirmed CF diagnosis, F508del homozygous, clinically stable, 6 through 11 years of age
  • Percent predicted FEV1 ≥40%
  • Screening LCI2.5 score ≥7.5
  • Percent predicted FEV1 ≥70%
KEY EXCLUSION CRITERIA
  • History of colonization with organisms such as Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium abscessus
  • 3 or more abnormal liver function tests (ALT, AST, AP, GGT ≥3 x ULN, or total bilirubin ≥2 x ULN), ALT or AST >5 x ULN, or bilirubin >2 x ULN
  • 2 or more abnormal liver function tests (AST, ALT, GGT, AP ≥3 x ULN), ALT or AST >5 x ULN, or bilirubin >2 x ULN
PRIMARY ENDPOINT
  • Safety and tolerability, including assessments of adverse events, clinical laboratory values, and spirometry (FEV1) up to 24 weeks
  • Absolute change in LCI2.5 from baseline through Week 24
ADDITIONAL ASSESSMENTS
  • Absolute change from baseline in sweat chloride at Day 15 and at Week 24
  • Absolute change in sweat chloride from Week 24 at Week 26 (washout period)
Key Secondary Endpoints
  • Average absolute change in sweat chloride from baseline at Day 15 and at Week 4
  • Absolute change in BMI from baseline at Week 24
  • Absolute change in CFQ-R Respiratory Domain score from baseline through Week 24
Other Secondary Endpoints (selected)
  • Absolute change in ppFEV1 from baseline through Week 24
  • Absolute change in BMI z-score from baseline at Week 24
AP, alkaline phosphatase; FEV1, forced expiratory volume exhaled in 1 second; GGT, gamma-glutamyl transpeptidase.
  • These trials were conducted in different patient populations and are not meant to be comparative
BASELINE
CHARACTERISTICS
TRIAL 31,3,6 TRIAL 47
  ORKAMBI (n=58) ORKAMBI (n=103) Placebo (n=101)
Sex, female, % 53.4 61.2 57.4
Mean age, years (range) 9.1 (6-12) 8.7 (6-12) 8.9 (6-12)
Mean percent predicted FEV1 (range) 91.4 (55.0-122.7) 88.8 (48.6-119.6) 90.7 (79.0-114.7)
Mean sweat chloride, mmol/L (range) 105.9 (57.0-121.3) 102.6 (46.0-119.0) 103.4 (64.5-123.0)
Mean LCI2.5 score (range) 10.3 (7.10-16.38) 10.26 (6.55-15.82)
Mean BMI z-score (range) 0.01 (-1.93 to 2.35)8 -0.14 (-3.24 to 1.54) -0.14 (-2.51 to 1.73)
  • At baseline in Trial 4, 97.1% of patients treated with ORKAMBI had abnormal LCI2.5 (7.5); mean percent predicted FEV1 was 88.85,7
MAINTENANCE USE
OF PULMONARY OR
RESPIRATORY THERAPY
AT BASELINEa
TRIAL 33,9 TRIAL 44,10
  ORKAMBI (n=58)
n (%)
ORKAMBI (n=103)
n (%)
Placebo (n=101)
n (%)
Bronchodilatorsb 57 (98.3) 85 (83) 82 (81)
Dornase alfa 50 (86.2) 88 (85) 88 (87)
Inhaled hypertonic saline 44 (75.9) 67 (65) 54 (54)
Inhaled corticosteroids 25 (43.1) 38 (37) 47 (47)
Azithromycin 20 (35.0)9 35 (34)10 36 (36)10
Inhaled antibiotics 14 (24.1) 20 (19) 30 (30)
a This is not an exhaustive list of all concomitant medications taken by patients in Trial 3.9,10
b The majority were short-acting bronchodilators.9,10

Limitations of Trial 3

  • The study was open label and not placebo-controlled; therefore, hypothesis testing cannot determine whether within-arm changes were due to drug effect3

Additional Disclosures

  • Trial 4 efficacy results are not included in the approved full Prescribing Information, and the FDA did not consider this study in approving ORKAMBI
  • Trial 3 may not meet the FDA definition of an adequate and well-controlled study due to its study design
 
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INDICATION

ORKAMBI® (lumacaftor/ivacaftor) is a combination of lumacaftor and ivacaftor indicated for the treatment of cystic fibrosis (CF) in patients age 6 years and older who are homozygous for the F508del 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 F508del mutation on both alleles of the CFTR gene.


Limitations of Use

The efficacy and safety of ORKAMBI have not been established in patients with CF other than those homozygous for the F508del mutation.

IMPORTANT SAFETY INFORMATION

Use in Patients With Advanced Liver Disease

  • Worsening of liver function, including hepatic encephalopathy, in patients with advanced liver disease has been reported. Liver function decompensation, including liver failure leading to death, has been reported in CF patients with pre-existing cirrhosis with portal hypertension while receiving ORKAMBI
  • Use ORKAMBI with caution in patients with advanced liver disease and only if the benefits are expected to outweigh the risks. If ORKAMBI is used in these patients, they should be closely monitored after the initiation of treatment and the dose should be reduced

Liver-related Events

  • Serious adverse reactions related to elevated transaminases have been reported in patients with CF receiving ORKAMBI. In some instances, these elevations have been associated with concomitant elevations in total serum bilirubin
  • It is recommended that ALT, AST, and bilirubin be assessed prior to initiating ORKAMBI, every 3 months during the first year of treatment, and annually thereafter. For patients with a history of ALT, AST, or bilirubin elevations, more frequent monitoring should be considered. Patients who develop increased ALT, AST, or bilirubin should be closely monitored until the abnormalities resolve
  • Dosing should be interrupted in patients with ALT or AST greater than 5 x upper limit of normal (ULN) when not associated with elevated bilirubin. Dosing should also be interrupted in patients with ALT or AST elevations greater than 3 x ULN when associated with bilirubin elevations greater than 2 x ULN. Following resolution of transaminase elevations, consider the benefits and risks of resuming dosing

Respiratory Events

  • Respiratory events (e.g., chest discomfort, dyspnea, and respiration abnormal) were observed more commonly in patients during initiation of ORKAMBI compared to those who received placebo. These events have led to drug discontinuation and can be serious, particularly in patients with advanced lung disease (percent predicted FEV1 (ppFEV1) <40). Clinical experience in patients with ppFEV1 <40 is limited, and additional monitoring of these patients is recommended during initiation of therapy

Effect on Blood Pressure

  • Increased blood pressure has been observed in some patients treated with ORKAMBI. Blood pressure should be monitored periodically in all patients being treated with ORKAMBI

Drug Interactions

Substrates of CYP3A

  • Lumacaftor is a strong inducer of CYP3A. Administration of ORKAMBI may decrease systemic exposure of medicinal products that are substrates of CYP3A, which may decrease therapeutic effect. Co-administration with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index is not recommended
  • ORKAMBI may substantially decrease hormonal contraceptive exposure, reducing their effectiveness and increasing the incidence of menstruation-associated adverse reactions, e.g., amenorrhea, dysmenorrhea, menorrhagia, menstrual irregular. Hormonal contraceptives, including oral, injectable, transdermal, and implantable, should not be relied upon as an effective method of contraception when co-administered with ORKAMBI

Strong CYP3A Inducers

  • Ivacaftor is a substrate of CYP3A4 and CYP3A5 isoenzymes. Use of ORKAMBI with strong CYP3A inducers, such as rifampin, significantly reduces ivacaftor exposure, which may reduce the therapeutic effectiveness of ORKAMBI. Therefore, co-administration with strong CYP3A inducers is not recommended

Cataracts

  • Cases of non-congenital lens opacities have been reported in pediatric patients treated with ORKAMBI and ivacaftor, a component of ORKAMBI. Although other risk factors were present in some cases (such as corticosteroid use and exposure to radiation), a possible risk attributable to ivacaftor cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating treatment with ORKAMBI

Adverse Reactions

  • Serious adverse reactions, whether considered drug-related or not by the investigators, that occurred more frequently in patients treated with ORKAMBI included pneumonia, hemoptysis, cough, increased blood creatine phosphokinase, and transaminase elevations. These occurred in 1% or less of patients
  • The most common adverse reactions in patients age 12 years and older in Phase 3 trials (Trials 1 and 2) occurring in ≥5% of patients treated with ORKAMBI (N=369) vs placebo (N=370) and at a rate higher than placebo were dyspnea, nasopharyngitis, nausea, diarrhea, upper respiratory tract infection, fatigue, respiration abnormal, blood creatine phosphokinase increased, rash, flatulence, rhinorrhea, and influenza
  • The safety profile in patients age 6 through 11 years from an open-label Phase 3 trial (Trial 3; N=58) and a placebo-controlled Phase 3 trial (Trial 4; patients treated with ORKAMBI, N=103 vs placebo, N=101) was similar to that observed in Trials 1 and 2. Additional common adverse reactions were reported in Trial 4, but were not reported in Trials 1 and 2. The adverse reactions in Trial 4 that occurred in ≥5% of patients treated with ORKAMBI with an incidence of ≥3% higher than placebo included: productive cough, nasal congestion, headache, abdominal pain upper, and sputum increased

Click here to access full Prescribing Information.

×
+

INDICATION

ORKAMBI® (lumacaftor/ivacaftor) is a combination of lumacaftor and ivacaftor indicated for the treatment of cystic fibrosis (CF) in patients age 6 years and older who are homozygous for the F508del 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 F508del mutation on both alleles of the CFTR gene.


Limitations of Use

The efficacy and safety of ORKAMBI have not been established in patients with CF other than those homozygous for the F508del mutation.

IMPORTANT SAFETY INFORMATION

Use in Patients With Advanced Liver Disease

  • Worsening of liver function, including hepatic encephalopathy, in patients with advanced liver disease has been reported. Liver function decompensation, including liver failure leading to death, has been reported in CF patients with pre-existing cirrhosis with portal hypertension while receiving ORKAMBI
  • Use ORKAMBI with caution in patients with advanced liver disease and only if the benefits are expected to outweigh the risks. If ORKAMBI is used in these patients, they should be closely monitored after the initiation of treatment and the dose should be reduced

Liver-related Events

  • Serious adverse reactions related to elevated transaminases have been reported in patients with CF receiving ORKAMBI. In some instances, these elevations have been associated with concomitant elevations in total serum bilirubin
  • It is recommended that ALT, AST, and bilirubin be assessed prior to initiating ORKAMBI, every 3 months during the first year of treatment, and annually thereafter. For patients with a history of ALT, AST, or bilirubin elevations, more frequent monitoring should be considered. Patients who develop increased ALT, AST, or bilirubin should be closely monitored until the abnormalities resolve
  • Dosing should be interrupted in patients with ALT or AST greater than 5 x upper limit of normal (ULN) when not associated with elevated bilirubin. Dosing should also be interrupted in patients with ALT or AST elevations greater than 3 x ULN when associated with bilirubin elevations greater than 2 x ULN. Following resolution of transaminase elevations, consider the benefits and risks of resuming dosing

Respiratory Events

  • Respiratory events (e.g., chest discomfort, dyspnea, and respiration abnormal) were observed more commonly in patients during initiation of ORKAMBI compared to those who received placebo. These events have led to drug discontinuation and can be serious, particularly in patients with advanced lung disease (percent predicted FEV1 (ppFEV1) <40). Clinical experience in patients with ppFEV1 <40 is limited, and additional monitoring of these patients is recommended during initiation of therapy

Effect on Blood Pressure

  • Increased blood pressure has been observed in some patients treated with ORKAMBI. Blood pressure should be monitored periodically in all patients being treated with ORKAMBI

Drug Interactions

Substrates of CYP3A

  • Lumacaftor is a strong inducer of CYP3A. Administration of ORKAMBI may decrease systemic exposure of medicinal products that are substrates of CYP3A, which may decrease therapeutic effect. Co-administration with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index is not recommended
  • ORKAMBI may substantially decrease hormonal contraceptive exposure, reducing their effectiveness and increasing the incidence of menstruation-associated adverse reactions, e.g., amenorrhea, dysmenorrhea, menorrhagia, menstrual irregular. Hormonal contraceptives, including oral, injectable, transdermal, and implantable, should not be relied upon as an effective method of contraception when co-administered with ORKAMBI

Strong CYP3A Inducers

  • Ivacaftor is a substrate of CYP3A4 and CYP3A5 isoenzymes. Use of ORKAMBI with strong CYP3A inducers, such as rifampin, significantly reduces ivacaftor exposure, which may reduce the therapeutic effectiveness of ORKAMBI. Therefore, co-administration with strong CYP3A inducers is not recommended

Cataracts

  • Cases of non-congenital lens opacities have been reported in pediatric patients treated with ORKAMBI and ivacaftor, a component of ORKAMBI. Although other risk factors were present in some cases (such as corticosteroid use and exposure to radiation), a possible risk attributable to ivacaftor cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating treatment with ORKAMBI

Adverse Reactions

  • Serious adverse reactions, whether considered drug-related or not by the investigators, that occurred more frequently in patients treated with ORKAMBI included pneumonia, hemoptysis, cough, increased blood creatine phosphokinase, and transaminase elevations. These occurred in 1% or less of patients
  • The most common adverse reactions in patients age 12 years and older in Phase 3 trials (Trials 1 and 2) occurring in ≥5% of patients treated with ORKAMBI (N=369) vs placebo (N=370) and at a rate higher than placebo were dyspnea, nasopharyngitis, nausea, diarrhea, upper respiratory tract infection, fatigue, respiration abnormal, blood creatine phosphokinase increased, rash, flatulence, rhinorrhea, and influenza
  • The safety profile in patients age 6 through 11 years from an open-label Phase 3 trial (Trial 3; N=58) and a placebo-controlled Phase 3 trial (Trial 4; patients treated with ORKAMBI, N=103 vs placebo, N=101) was similar to that observed in Trials 1 and 2. Additional common adverse reactions were reported in Trial 4, but were not reported in Trials 1 and 2. The adverse reactions in Trial 4 that occurred in ≥5% of patients treated with ORKAMBI with an incidence of ≥3% higher than placebo included: productive cough, nasal congestion, headache, abdominal pain upper, and sputum increased

Click here to access full Prescribing Information.