Safety and Efficacy Established in Two Phase 3 Studies in Patients Age 12 Years and Older^1,2 

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 Outcomes^1,2

• 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

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

Discontinuation 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^1,2

• 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

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

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

ALT, alanine aminotransaminase; AST, aspartate aminotransaminase; BMI, body mass index; CFQ-R, cystic fibrosis questionnaire-revised; CI, confidence interval; IV, intravenous; LS, least squares; q12h, every 12 hours; ppFEV₁, percent predicted forced expiratory volume in 1 second; ULN, upper limit of normal.