General Information

Orkambi is a combination of lumacaftor and ivacaftor, both of which are oral cystic fibrosis transmembrane conductance regulator (CFTR) modulators. Lumacaftor is a CFTR corrector and aims to increase CFTR function by increasing the trafficking, or movement, of CFTR to the cell surface. Ivacaftor is a CFTR potentiator and aims to increase the function of defective CFTR proteins by increasing the gating activity, or ability to transport ions across the cell membrane, of CFTR at the cell surface. 

Orkambi is specifically indicated for the treatment of cystic fibrosis (CF) in patients 12 months of age 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. 

Dosing/Administration

Orkambi is supplied as a tablet (lumacaftor 200 mg and ivacaftor 125 mg) for oral administration. The recommended dose is as follows:

• Pediatric patients age 2 through 5 years and weighing less than 14 kg: one packet of granules (each containing lumacaftor 100 mg/ivacaftor 125 mg) mixed with 1 teaspoon (5 mL) of soft food or liquid and administered orally every 12 hours with fat-containing food.  

• Pediatric patients age 2 through 5 years and weighing 14 kg or greater: one packet of granules (each containing lumacaftor 150 mg/ivacaftor 188 mg) mixed with 1 teaspoon (5 mL) of soft food or liquid and administered orally every 12 hours with fat-containing food.  

• Pediatric patients age 6 through 11 years: two tablets (each containing lumacaftor 100 mg/ivacaftor 125 mg) taken orally every 12 hours with fat-containing food.

• Adults and pediatric patients age 12 years and older: two tablets taken orally every 12 hours. Reduce the dose in patients with moderate or severe hepatic impairment. When initiating Orkambi in patients taking strong CYP3A inhibitors, the reduce Orkambi dose for the first week of treatment.

For specific dose reductions, please see the drug label.

Mechanism of Action

Orkambi is a combination of lumacaftor and ivacaftor, both of which are oral cystic fibrosis transmembrane conductance regulator (CFTR) modulators. The CFTR protein is a chloride channel present at the surface of epithelial cells in multiple organs. The F508del mutation results in protein misfolding, causing a defect in cellular processing and trafficking that targets the protein for degradation and therefore reduces the quantity of CFTR at the cell surface. The small amount of F508del-CFTR that reaches the cell surface is less stable and has low channel-open probability (defective gating activity) compared to wild-type CFTR protein. Lumacaftor improves the conformational stability of F508del-CFTR, resulting in increased processing and trafficking of mature protein to the cell surface. Ivacaftor is a CFTR potentiator that facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR protein at the cell surface. In vitro studies have demonstrated that both lumacaftor and ivacaftor act directly on the CFTR protein in primary human bronchial epithelial cultures and other cell lines harboring the F508del-CFTR mutation to increase the quantity, stability, and function of F508del-CFTR at the cell surface, resulting in increased chloride ion transport. In vitro responses do not necessarily correspond to in vivo pharmacodynamic response or clinical benefit.

Side Effects

Adverse effects associated with the use of Orkambi may include, but are not limited to, the following: 

• Dyspnea
• Nasopharyngitis
• Nausea
• Diarrhea
• Upper respiratory tract infection
• Fatigue
• Respiration abnormal
• Blood creatine phosphokinase increased
• Rash
• Flatulence
• Rhinorrhea
• Influenza

Clinical Trial Results

The FDA approval of Orkambi was based on a dose ranging trial and two confirmatory trials.

Dose Ranging:

One double-blind, placebo-controlled, multiple-cohort trial enrolled 97 Caucasian patients with CF (homozygous for the F508del mutation) 18 years of age and older with a screening ppFEV1 ≥40. In the trial, 76 patients (homozygous for the F508del mutation) were randomized to receive lumacaftor alone at once-daily doses of 200 mg, 400 mg, or 600 mg or 400 mg q12h for 28 days followed by the addition of ivacaftor 250 mg q12h and 27 patients (homozygous or heterozygous for the F508del mutation) received placebo. During the initial 28-day lumacaftor monotherapy period, treatment with lumacaftor demonstrated a dose-dependent decrease in ppFEV1 compared to placebo. Changes from Day 1 at Day 28 in ppFEV1 compared to placebo were 0.24, -1.4, -2.7, and -4.6 for the 200-mg once daily, 400-mg once daily, 600-mg once daily and 400 mg q12h lumacaftor doses, respectively. Following the addition of ivacaftor 250 mg q12h, the changes from Day 1 at Day 56 in ppFEV1 compared to placebo were 3.8, 2.7, 5.6 and 4.2, respectively. Sweat chloride was also assessed in this trial. Following the initial 28 days of lumacaftor monotherapy, the changes from Day 1 at Day 28 in sweat chloride compared to placebo were -4.9, -8.3, -6.1 and -8.2 mmol/L for the 200 mg once daily, 400 mg once daily, 600 mg once daily and 400 mg q12h lumacaftor doses, respectively. Following the addition of ivacaftor 250 mg q12h, the changes from Day 1 at Day 56 in sweat chloride compared to placebo were -5.0, -9.8, -9.5 and -11 mmol/L, respectively. These data supported the evaluation of lumacaftor 400 mg/ivacaftor 250 mg q12h (Orkambi formulation) and lumacaftor 600 mg once daily/ivacaftor 250 mg q12h in the confirmatory trials.

Confirmatory Trials:

The efficacy of Orkambi in patients with CF who are homozygous for the F508del mutation in the CFTR gene was evaluated in two randomized, double-blind, placebo-controlled, 24-week clinical trials (Trials 1 and 2) in 1,108 clinically stable patients with CF of whom 369 patients received Orkambi twice daily. Trial 1 evaluated 549 patients with CF who were aged 12 years and older with ppFEV1 at screening between 40 and 90. Trial 2 evaluated 559 patients aged 12 years and older (mean age 25.0 years) with ppFEV1 at screening between 40 and 90. Patients in both trials were randomized 1:1:1 to receive either Orkambi (lumacaftor 400 mg q12h/ivacaftor 250 mg q12h; or lumacaftor 600 mg once daily/ivacaftor 250 mg q12h) or placebo. Patients took the study drug with fat-containing food for 24 weeks in addition to their prescribed CF therapies. The primary efficacy endpoint in both trials was change in lung function as determined by absolute change from baseline in ppFEV1 at Week 24, assessed as the average of the treatment effects at Week 16 and at Week 24. In both trials, treatment with Orkambi resulted in a statistically significant improvement in ppFEV1. The treatment difference between Orkambi and placebo for the mean absolute change in ppFEV1 from baseline at Week 24 (assessed as the average of the treatment effects at Week 16 and at Week 24) was 2.6 percentage points in Trial 1 (P=0.0003) and 3.0 percentage points in Trial 2 (P<0.0001). These changes persisted throughout the 24-week treatment period. Improvements in ppFEV1 were observed regardless of age, disease severity, sex and geographic region.

The FDA approval of Orkambi in children ages 2 through 5 years was based on a Phase 3 open-label safety study in 60 patients that showed treatment with Orkambi was generally safe and well tolerated for 24 weeks, with a safety profile similar to that in patients ages 6 years and older. Improvements in sweat chloride were observed at week 24 (mean decrease in sweat chloride from baseline of 31.7 mmol/L; n=49).