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Clinical Trials

6-11

Studied in Over 250 Patients Age 6
Through 11 Years

ORKAMBI Indication

ORKAMBI is a combination of lumacaftor and ivacaftor indicated for the treatment of cystic fibrosis (CF) in patients age 2 years and older who are homozygous for the F508del mutation in 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.

Trial 3 | Phase 3, Open-Label Safety Study

Trial 3 was a 24-week, Phase 3, open-label study (N=58) assessing the safety, tolerability, and pharmacokinetics of ORKAMBI in patients age 6 through 11 years with CF who were homozygous for the F508del-CFTR mutation, were clinically stable, and had a percent predicted FEV1 of ≥40%. Patients received ORKAMBI tablets (lumacaftor 200 mg/ivacaftor 250 mg q12h) with fat-containing food and continued to take their prescribed CF therapies (including during the 2-week washout period). Primary endpoints were safety and tolerability, including assessments of adverse events, clinical laboratory values, and spirometry (FEV1) up to 24 weeks.1-3

Trial 4 | Phase 3, Double-Blind, Placebo-Controlled Efficacy and Safety Study

Trial 4 was a 24-week, Phase 3, double-blind, placebo-controlled study assessing the efficacy and safety of ORKAMBI in patients age 6 through 11 years with CF who were homozygous for the F508del-CFTR mutation, were clinically stable, with an LCI2.5 score of ≥7.5, and a percent predicted FEV1 of ≥70%. Patients received either ORKAMBI tablets (lumacaftor 200 mg/ivacaftor 250 mg q12h) or placebo with fat-containing food and continued to take their prescribed CF therapies. Primary endpoint was an absolute change in LCI2.5 from baseline through Week 24.4,5

Trial 3 | Limitations

  • The study was open label and not placebo controlled2; therefore, causality cannot be attributed to drug effect

Additional Disclosures

  • The Trial 4 efficacy results are not included in the approved full Prescribing Information, and the FDA did not consider either study in approving ORKAMBI
  • These trials were conducted in different patient populations and are not meant to be comparative

Safety Profile in Trial 3 and 4 Was Similar to that Observed in Patients Age 12 Years and Older1

Discontinuations due to Adverse Events

  • Trial 3: 3.4% (n=2); due to elevated liver transaminases (1) and rash (1)2
  • Trial 4: 3% (n=3) in the ORKAMBI group vs 2% (n=2) in the placebo group discontinued treatment due to adverse events. These events included
    • 1 case of abnormal respiration and 2 cases of elevated transaminases in the ORKAMBI group
    • 2 cases of elevated transaminases in the placebo group4

Serious Adverse Reactions

  • Trial 3: 6.9% (n=4); included infective pulmonary exacerbation (2), ileus (1), and elevated liver transaminase levels (1)2
  • Trial 4: 13% (n=13) in the ORKAMBI group vs 11% (n=11) in the placebo group experienced serious adverse events. Of these,
    • 2 were treatment related for ORKAMBI (1 drug interaction and 1 obstructive airway disorder)
    • 3 were treatment related for placebo (1 distal intestinal obstruction disorder and 2 elevated aminotransferases)4

Liver-Related Adverse Reactions2,6

Potentially Clinically Significant (PCS) Laboratory Tests

Parameter
PCS/Categorical
Criteria
TRIAL 3: 24 Weeks
n/Na (%)6
TRIAL 4: 24 Weeks
n/Na (%)6
ALT or AST ORKAMBI ORKAMBI Placebo
>8 x ULN 3/57 (5.3) 1/103 (1.0) 2/101 (2.0)
>5 x ULN 5/57 (8.8) 5/103 (4.9) 3/101 (3.0)
>3 x ULN 11/57 (19.3) 13/103 (12.6) 8/101 (7.9)
Discontinuation due to transaminase elevations 1/57 (1.8) 2/103 (1.9) 2/101 (2.0)

aNumber of subjects with at least one measurement during the period from initiation of study drug to 28 days following last dose.2

  • In Trials 3 and 4, no patients had an increase in total bilirubin levels >2 x ULN1,6,7
  • These trials were conducted in different patient populations and are not meant to be comparative

Respiratory Symptom-Related Adverse Reactions1,2,4,6

Incidence of Respiratory Symptom-Related Adverse Reactions

TRIAL 3: 24 Weeks
n/Na (%)1,2
TRIAL 4: 24 Weeks
n/Na (%)4,6
ORKAMBI ORKAMBI Placebo
Total Incidence 2/58 (3.0) 11/103 (11) 9/101 (9)
Dyspnea 1/58 (1.7) 5/103 (5) 5/101 (5)
Respiration abnormal 1/58 (1.7) 6/103 (6) 4/101 (4)
Chest discomfort 0/58 (0) 0/103 (0) 1/101 (1)

aNumber of subjects with at least one measurement during the period from initiation of study drug to 28 days following last dose.2

  • These trials were conducted in different patient populations and are not meant to be comparative

Common Adverse Reactions in Trial 38

Most Frequently Observed Treatment-Emergent Adverse Events in ≥10% of Patients8

TRIAL 3a
24 Weeks
ORKAMBI
n=58
Any TEAEs, n (%)55 (94.8)
Cough29 (50.0)
Infective pulmonary exacerbation12 (20.7)
Nasal congestion12 (20.7)
Headache12 (20.7)
Abdominal pain upper8 (13.8)
Sputum increased8 (13.8)
ALT increased7 (12.1)
Pyrexia6 (10.3)
Vomiting6 (10.3)
Abdominal pain6 (10.3)
Fatigue6 (10.3)
Nausea6 (10.3)

aTrial 3 Safety Set.
TEAE, treatment-emergent adverse event.

Common Adverse Reactions in Trial 46

Most Frequently Observed Treatment-Emergent Adverse Events in ≥5% of Patients in the ORKAMBI Arm and ≥3% Higher than Placebo6

TRIAL 4b
24 Weeks
ORKAMBI
n=103
Placebo
n=101
Any TEAEs, n (%)98 (95.1)98 (97.0)
Productive cough18 (17.5)6 (5.9)
Nasal congestion17 (16.5)8 (7.9)
Oropharyngeal pain15 (14.6)10 (9.9)
Headache13 (12.6)9 (8.9)
Abdominal pain upper13 (12.6)7 (6.9)
Sputum increased11 (10.7)2 (2.0)
Rhinorrhea10 (9.7)5 (5.0)
Rash6 (5.8)1 (1.0)

bTrial 4 Safety Set.

Lung Function Through 24 Weeks

Trial 3 | Percent Predicted FEV1 at Week 24 (Part of the Safety Assessment)

  • +2.5% point LS mean within-group improvement2,9
  • -3.2% point LS mean within-group decrease from Week 24 at Week 26 (washout)2

Trial 4 | Statistically Significant Improvement Through Week 24 vs Placebo4

Statistically Significant Improvement Through Week 24 Vs Placebo 4

Adapted from Ratjen F et al. Lancet Respir Med. 2017;5(7):557-567, with permission from Elsevier.
Improvements in lung function are represented by a negative change in LCI.

  • Within-group LS mean absolute change in LCI2.5 from baseline through Week 24 was 0.1
    (95% CI -0.2 to 0.3) for placebo vs -1.0 (95% CI -1.3 to -0.8) for ORKAMBI4
  • LCI is still considered an exploratory endpoint in clinical trials10

Trial 3: Sweat Chloride Was Reduced at Week 242

Sweat Chloride was Reduced at Week
  • -24.8 mmol/L LS mean within-group improvement at Week 242
  • Washout: +21.3 mmol/L LS mean within-group absolute change from Week 24 at Week 262
  • There was no direct correlation between decrease in sweat chloride levels and improvement in lung function (percent predicted FEV1)1

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

Indication

ORKAMBI® (lumacaftor/ivacaftor) is a combination of lumacaftor and ivacaftor indicated for the treatment of cystic fibrosis (CF) in patients age 2 years and older who are homozygous for the F508del mutation in the CFTR gene. If the patient's genotype in 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.

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. The safety profile in patients age 2 through 5 years from an open-label Phase 3 trial (Trial 6; N=60) was similar to that in patients aged 6 years and older

Click here to access full Prescribing Information.

References:

1. ORKAMBI [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; August 2018. 2. Milla CE, Ratjen F, Marigowda G, Liu F, Waltz D, Rosenfeld M; On behalf of the VX13-809-011 Part B Investigator Group. Lumacaftor/ivacaftor in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR. Am J Respir Crit Care Med. 2017;195(7):912-920. 3. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. VXR-HQ-88-00008(2); 2017. 4. Ratjen F, Hug C, Marigowda G, et al. Efficacy and safety of lumacaftor and ivacaftor in patients aged 6–11 years with cystic fibrosis homozygous for F508del-CFTR: a randomised, placebo-controlled phase 3 trial. Lancet Respir Med. 2017;5(7):557-567. 5. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. VXR-US-20-01795(2); 2017. 6. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. VXR-US-20-01794; 2017. 7. Chilvers M, Owen CA, Marigowda G, et al. Safety and efficacy of lumacaftor/ivacaftor (LUMA/IVA) in patients aged ≥6 years with CF homozygous for F508del–a phase 3 extension study. Poster and abstract presented at: 31st Annual North American Cystic Fibrosis Conference; Indianapolis, Indiana; November 2-4, 2017. 8. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. VXR-HQ-20-00333; 2018. 9. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. VXR-US-20-01799; 2017. 10. Kent L, Reix P, Innes JA, et al. Lung clearance index: evidence for use in clinical trials in cystic fibrosis. J Cyst Fibros. 2014;13(2):123-138.