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12

Safety and Efficacy Established in Two Phase 3 Studies in Patients Age 12 Years and Older1,2

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.

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Download the Clinical Brochure

Trials 1 and 2 | Phase 3, Randomized, Double-Blind, Placebo-Controlled
Efficacy and Safety Studies

Trials 1 and 2 were 24-week, Phase 3, randomized, double-blind, placebo-controlled studies of patients age 12 years and older with CF who were homozygous for the F508del-CFTR mutation, were clinically stable, and had a percent predicted FEV1 (ppFEV1) of 40-90 at screening. Patients received either ORKAMBI tablets (lumacaftor 400 mg/ivacaftor 250 mg q12h) or placebo with fat-containing food and continued to take their prescribed CF therapies. The primary endpoint in both trials was an absolute change in ppFEV1 from baseline at Week 24 assessed as the average of the treatment effects at Week 16 and at Week 24.1,2

Download the Short- and Long-term Clinical Data Brochure for ages 12 years and older.


ORKAMBI Improved and Sustained Lung Function and Other Key Clinical Outcomes1,2

  • In each trial, a hierarchical testing procedure was performed within each active treatment arm for primary and secondary endpoints vs placebo. For an endpoint to be significant, both it and all previous tests had to achieve P≤0.02502
    • Statistically significant endpoints are indicated by the shaded boxes in the table below
  • The safety of ORKAMBI was evaluated based on a pre-specified pooled analysis
  • A separate pooled analysis for efficacy was not pre-specified and did not correct for multiple comparisons.1,2 Secondary analyses of Trials 1 and 2 were conducted to evaluate efficacy


TRIAL 11,5 TRIAL 21,5 POOLED5
ORKAMBI (n=182) Placebo (n=184) ORKAMBI (n=187) Placebo (n=187) ORKAMBI (n=369) Placebo (n=371)
PRIMARY ENDPOINTS
Absolute change in percent predicted FEV1 at Week 24 (percentage points)a Treatment difference (95% CI) 2.6
(1.2, 4.0) (P=0.0003)		 — 3.0
(1.6, 4.4) (P <0.0001)		 — 2.8
(1.8, 3.8)		 —
KEY SECONDARY ENDPOINTS
Relative change in percent predicted FEV1 at Week 24 (percentage)a Treatment difference (95% CI) 4.3
(1.9, 6.8) (P=0.0006)		 — 5.3
(2.7, 7.8) (P <0.0001)		 — 4.8
(3.0, 6.6)		 —
Absolute change in BMI at Week 24 (kg/m2) Treatment difference (95% CI) 0.1
(-0.1, 0.3)		 — 0.4
(0.2, 0.5) (P=0.0001)		 — 0.2
(0.1, 0.4)		 —
Absolute change in CFQ-R Respiratory Domain score at Week 24 (points) Treatment difference (95% CI) 1.5
(-1.7, 4.7)		 — 2.9
(-0.3, 6.0)		 — 2.2
(0.0, 4.5)		 —
Proportion of patients with ≥5% relative change in percent predicted FEV1 at Week 24a % 37% 22% 41% 23% 39% 22%
Odds ratio (95% CI) 2.1
(1.3, 3.3)		 — 2.4
(1.5, 3.7)		 — 2.2
(1.6, 3.1)		 —
Number of pulmonary exacerbations through Week 24b No. of events (rate per 48 weeks) 73
(0.7)		 112
(1.1)		 79
(0.7)		 139
(1.2)		 152
(0.7)		 251
(1.1)
Rate ratio (95% CI) 0.7
(0.5, 0.9)		 — 0.6
(0.4, 0.8)		 — 0.6
(0.5, 0.8)		 —

aAssessed as the average of the treatment effects at the Week 16 and Week 24 time points.1
bA pulmonary exacerbation was defined as a new or change in antibiotic therapy (IV, inhaled, or oral) associated with 4 or more of the following 12 pre-specified sinopulmonary signs/symptoms: change in sputum; new or increased hemoptysis; increased cough; increased dyspnea; malaise, fatigue, or lethargy; temperature >38°C (100.4°F); anorexia or weight loss; sinus pain or tenderness; change in sinus discharge; change in physical chest exam; decrease in pulmonary function by 10%; radiographic changes indicative of pulmonary infection.2

IV, intravenous.

Please click below to download an overview of ORKAMBI clinical data.

This includes Trials 1 and 2, as well as results from the long-term extension study and Rate of Change analyses.

Download the Short- and Long-term Clinical Data Brochure.

The Overall Safety Profile of ORKAMBI Is Based on
Pooled Data From Trials 1 and 21

Discontinuations Due to Adverse Events1

ORKAMBI 5%; placebo 2%

Serious Adverse Reactions1

  • Whether considered by investigators to be drug-related or not, serious adverse reactions that occurred more frequently in patients treated with ORKAMBI included the following (these occurred in ≤1% of patients):
    • Pneumonia
    • Hemoptysis
    • Increased blood creatine phosphokinase
    • Cough
    • Transaminase elevations

Liver-Related Adverse Reactions1

  • In Trials 1 and 2, the incidence of maximum transaminase (ALT or AST) levels >8, >5, and >3 x ULN was similar between patients who received ORKAMBI vs placebo
  • 3 patients who received ORKAMBI had liver-related serious adverse reactions, including 2 reported as transaminase elevations and 1 as hepatic encephalopathy vs none in the placebo group
    • 1 of the 3 had elevated transaminases (>3 x ULN) associated with bilirubin elevation (>2 x ULN). Following discontinuation or interruption of ORKAMBI, transaminases decreased to <3 x ULN
  • 1 of the 6 patients with pre-existing cirrhosis and/or portal hypertension who received ORKAMBI experienced worsening liver function with increased ALT, AST, bilirubin, and hepatic encephalopathy
    • The event occurred within 5 days of the start of dosing and resolved following discontinuation of ORKAMBI

Respiratory Symptom-Related Adverse Reactions

  • In Trials 1 and 2, the incidence of respiratory symptom-related adverse reactions (eg, chest discomfort, dyspnea, and respiration abnormal) was more common in patients treated with ORKAMBI (22%) compared to patients who received placebo (14%)1
    • Respiration abnormal (chest tightness): ORKAMBI (9%) vs placebo (6%)
    • Dyspnea: ORKAMBI (13%) vs placebo (8%)
    • The incidence of these adverse reactions was more common in patients treated with ORKAMBI with lower pretreatment FEV1
  • Most respiratory symptom-related adverse events occurred within the first week of treatment and resolved within 2 weeks2
  • During a 24-week, open-label, Phase 3b clinical trial in 46 patients age 12 years and older (Trial 5) with advanced lung disease (ppFEV1 <40) [mean ppFEV1 29.1 at baseline (range: 18.3 to 42.0)], the incidence of respiratory symptom-related adverse reactions was 65%1

Menstrual Abnormalities1

  • In Trials 1 and 2, the incidence of combined menstrual abnormality adverse reactions (eg, amenorrhea, dysmenorrhea, menorrhagia, menstrual irregular) was more common in female patients treated with ORKAMBI (10%) compared to placebo (2%)
  • These events occurred more frequently in the subset of female patients treated with ORKAMBI who were using hormonal contraceptives (27%) compared to those not using hormonal contraceptives (3%)

Increased Blood Pressure1

  • In Trials 1 and 2, adverse reactions related to increases in blood pressure (eg, hypertension, blood pressure increased) were reported in 1.1% (4/369) of patients treated with ORKAMBI and in no patients who received placebo
  • The proportion of patients who experienced a systolic blood pressure value >140 mm Hg or a diastolic blood pressure >90 mm Hg on at least two occasions was 3.6% and 2.2%, respectively, in patients treated with ORKAMBI compared with 1.6% and 0.5% in patients who received placebo

Trials 1 and 2 in Patients Age 12 Years and Older:
Common Adverse Reactions

Adverse Reactions in ≥ 5% of Patients Treated With ORKAMBI and at a Higher Rate Than Placebo1

Adverse Reaction
(Preferred Term)		 ORKAMBI
n=369 (%)		 Placebo
n=370 (%)
Dyspnea 48 (13) 29 (8)
Nasopharyngitis 48 (13) 40 (11)
Nausea 46 (13) 28 (8)
Diarrhea 45 (12) 31 (8)
Upper respiratory tract infection 37 (10) 20 (5)
Fatigue 34 (9) 29 (8)
Respiration abnormala 32 (9) 22 (6)
Blood creatine phosphokinase increased 27 (7) 20 (5)
Rash 25 (7) 7 (2)
Flatulence 24 (7) 11 (3)
Rhinorrhea 21 (6) 15 (4)
Influenza 19 (5) 8 (2)

aReported as chest tightness.5


Please click below to download an overview of ORKAMBI clinical data.

This includes Trials 1 and 2, as well as results from the long-term extension study and Rate of Change analyses.

Download the Short- and Long-term Clinical Data Brochure.

Professional Resources

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. Konstan MW, McKone EF, Moss RB, et al. Assessment of safety and efficacy of long-term treatment with combination lumacaftor and ivacaftor therapy in patients with cystic fibrosis homozygous for the F508del-CFTR mutation (PROGRESS): a phase 3, extension study. Lancet Respir Med. 2017;5(2)(suppl1-28):107-118. 3. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. VXR-US-20-01588(2); 2016. 4. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. VXR-HQ-20-00238; 2016. 5. Wainwright CE, Elborn JS, Ramsey BW, et al. TRAFFIC and TRANSPORT Study Groups. Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N Engl J Med. 2015;373(3):220-231.