ORKAMBI: Studied in Patients Age 12 Years and Older1-5

TRIAL 1a
Phase 3, Randomized, Double-blind
TRIAL 2a
Phase 3, Randomized, Double-blind
EXTENSION STUDYb
24-WEEK TREATMENT 24-WEEK TREATMENT ADDITIONAL 96-WEEK TREATMENT

ORKAMBI
lumacaftor 400 mg/ivacaftor 250 mg q12h + currently prescribed CF therapies (n=182)

ORKAMBI
(Same dose as Trial 1)
(n=187)

Continued ORKAMBI
(n=340)

Placebo
+ currently prescribed CF therapies (n=184)

Placebo
(n=187)

Started ORKAMBI
(Same dose as Trial 1)
(n=176)

PRIMARY ENDPOINT
  • Absolute change in ppFEV1 from baseline at Week 24
  • Safety of long-term treatment based on adverse events, clinical laboratory values, standard digital electrocardiograms, vital signs, and pulse oximetry
SELECTED SECONDARY ENDPOINTS
Listed in order evaluated by statistical analyses hierarchy:
  • Relative change in ppFEV1, absolute change in BMI, absolute change in CFQ-R Respiratory Domain score, proportion of patients with ≥5% relative change in ppFEV1, and number of pulmonary exacerbations
  • Absolute change from baseline in percent predicted FEV1
  • Absolute change from baseline in BMI
  • Absolute change from baseline in the CFQ-R Respiratory Domain score
  • Number of pulmonary exacerbations
POOLED ANALYSIS ANALYSES
  • The safety of ORKAMBI was evaluated based on a prespecified pooled analysis
  • A separate pooled analysis for efficacy was not prespecified and did not correct for multiple comparisons. Separate analyses of Trials 1 and 2 were conducted to evaluate efficacy
  • The primary analysis of the Extension Study included data through 72 weeks. A sensitivity analysis was performed including data through 96 weeks
  • For the ORKAMBI-to-ORKAMBI group in the Extension Study, baseline from Trials 1 and 2 was used. For the placebo-to-ORKAMBI group, baseline from treatment initiation in the Extension Study was used
KEY INCLUSION CRITERIA
  • ≥12 years old
  • Confirmed CF diagnosis
  • Clinically stable
  • F508del homozygous
  • Percent predicted FEV1 (ppFEV1) 40 to 90 at screening
  • Completed Trial 1 or Trial 2
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 × ULN, or total bilirubin ≥2 × ULN)
  • Any comorbidity or laboratory abnormality that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering the study drug to the participant
  • History of drug intolerance
  • History of poor compliance with the study drug
RATE OF CHANGE ANALYSIS2
Cohort treated with ORKAMBI
(n=455)c
Cohorts
  • Patients receiving ORKAMBI in Trial 1, Trial 2, and Extension Study
  • Propensity-score matched control patients homozygous for the F508del mutation based on observational data from the US CFFPR
Propensity-score matched controls
(n=1588)
Objective
  • To evaluate whether treatment with ORKAMBI affects the rate of change in pulmonary function in patients 12 years and older who are homozygous for the F508del mutation
  • A matched cohort of 1588 patients from the US CFFPR was used as the comparator because there was no placebo group in the Extension Study2
  • A propensity-score approach was used to match the two groups on known predictors of disease progression2
    • Propensity scoring is a statistical matching technique used in observational research that attempts to balance the study groups to make them as similar as possible6
  • Patients contributed the following amount of data7:
    • ORKAMBI: 436 (95.8%) patients had ≥48 weeks of data; 407 (89.5%) had ≥72 weeks of data; 276 (60.7%) had ≥96 weeks of data
    • CONTROL: 1570 (98.9%) patients had ≥48 weeks of data; 1518 (95.6%) had ≥72 weeks of data; 1035 (65.2%) had ≥96 weeks of data

CFFPR, Cystic Fibrosis Foundation Patient Registry.

a 368 patients received lumacaftor 600 mg qd/ivacaftor 250 mg q12h.2
b At the start of the Extension Study, patients who received placebo during Trials 1 and 2 were randomized 1:1 to ORKAMBI or lumacaftor 600 mg qd/ivacaftor 250 mg q12h. 334 patients continued to receive lumacaftor 600 mg qd/ivacaftor 250 mg q12h, and 179 rolled over from receiving placebo to lumacaftor 600 mg qd/ivacaftor 250 mg q12h.2
c 24 patients taking ORKAMBI had no identified match among CFFPR controls and therefore were not included in the analysis. Nearly half of the patients taking ORKAMBI (n=213, 46.8%) were matched to 5 control patients.8
  • The focus of the data is the approved dose of ORKAMBI: lumacaftor 400 mg/ivacaftor 250 mg q12h

Limitations and Disclosures

Limitations of the Extension Study

  • Enrollment was limited only to those patients who met strict inclusion criteria, completed Trials 1 and 2, and elected to enroll in the Extension Study2,4
  • The Extension Study was not a placebo-controlled study2
  • All patients in the Extension Study knew they were on active drug, which may have introduced bias related to awareness of treatment2
  • Trials 1 and 2 required patients to remain on their usual prescribed CF regimen. In the Extension Study, patients may have had changes in their stable medication regimen, but the data set was not large enough to assess the effect that changes in concomitant drugs could have had on the efficacy and safety profile of ORKAMBI2
  • Although a relatively large study over a 96-week period, rare adverse events might not have been detected
  • In patients with CF, pulmonary exacerbations and ppFEV1 are interdependent. There are known methodological limitations in outcome stratification by covariates affected by treatment allocation; to address this issue, the earliest post-baseline ppFEV1 measure was used in the analyses of pulmonary exacerbations9

Additional disclosures for the Extension Study

  • This study is not included in the approved full Prescribing Information, and the FDA did not consider these data in approving ORKAMBI
  • This study may not meet the FDA definition of an adequate and well-controlled study due to its study design

Limitations of the Rate of Change Analysis

  • Rates of clinical trial participation may have affected results
    • Patients who participate in clinical trials may differ systematically from those who do not and could have experienced a reduced rate of decline in lung function relative to those who do not2
    • All of the patients treated with ORKAMBI were clinical trial participants4
    • 21% of the patients in the matched control group were in a clinical trial in either 2013 or 2014. Some of these patients may have been treated with ORKAMBI in the clinical studies2
  • Not all variables affecting lung function decline may have been captured in propensity-score matching
    • The analysis is limited to the variables captured in the clinical study and collected in the registry, limiting the ability to match on all reported risk factors for lung function decline2
  • Geographic location of patients may have affected results
    • The CFFPR only includes data from US patients with CF, whereas the ORKAMBI trials included in this analysis were conducted throughout the US, Canada, Europe, and Australia where lung function of the CF populations may differ2
  • Causality is not definitively established
    • This is not a randomized controlled trial; although the finding of differential rates of lung function decline is likely related to treatment with ORKAMBI, causality cannot be definitively established in the context of this analysis2
  • Differences in unmeasured characteristics may have affected results
    • Although the propensity-score matching produced a comparison group similar to the ORKAMBI cohort, there may be differences in unmeasured characteristics2
  • Patients contributed different amounts of data to the analysis
    • Estimations of average annual rate of decline are based on FEV1 measurements spanning different lengths of observation for different patients with more patients contributing information about the rate of change in the first year than in the second year2,7
  • Model assumptions
    • The model assumes that the rate of decline in FEV1 is constant over the observation period for each individual2

Additional disclosures for the Rate of Change Analysis

  • This analysis is not included in the approved full Prescribing Information and the FDA did not consider this analysis in approving ORKAMBI
  • This analysis may not meet the FDA definition of an adequate and well-controlled study due to reliance, in part, on data from a study that was not placebo-controlled
 
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ORKAMBI® (lumacaftor/ivacaftor) INDICATIONS AND USAGE

ORKAMBI 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 cystic fibrosis transmembrane conductance regulator (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 in some patients with CF 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. Clinical experience in patients with percent predicted FEV1 (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 for patients age 6 through 11 years in an open-label Phase 3 trial (Trial 3; N=58) was similar to that observed in Trials 1 and 2

Click here to access full Prescribing Information.

×
+

ORKAMBI® (lumacaftor/ivacaftor) INDICATIONS AND USAGE

ORKAMBI 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 cystic fibrosis transmembrane conductance regulator (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 in some patients with CF 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. Clinical experience in patients with percent predicted FEV1 (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 for patients age 6 through 11 years in an open-label Phase 3 trial (Trial 3; N=58) was similar to that observed in Trials 1 and 2

Click here to access full Prescribing Information.