Cystic fibrosis is a genetic disease where patients produce too much thick, sticky mucus that damages many organs, particularly the lungs and digestive tract. The amount and thickness of the mucus are controlled by chloride channels, which are cell proteins that help move salts and water across cells membranes. Patients with cystic fibrosis have a mutation in the CFTR gene, causing them to have faulty chloride channel proteins.
How Orkambi works
Orkambi is a combination of two compounds — lumacaftor and ivacaftor (FDA-approved in 2012 for the treatment of cystic fibrosis and marketed as Kalydeco). These compounds target the defective chloride channel. Lumacaftor increases the amount of this channel on cell surfaces, while ivacaftor helps defective channels work better. Together, they maintain the balance between salt and water, keeping mucus from clogging the ducts of organs.
Everyone inherits two copies of the CFTR gene — one from each parent. There are over 1,700 mutations that have been found in the CFTR gene. Orkambi works for those with two copies of the F508del variant of the CFTR mutation, the most common mutation in patients with cystic fibrosis worldwide.
Orkambi in clinical trials
Orkambi was initially approved in 2015 for patients, ages 12 and above, based on the results of three Phase 3 clinical trials: TRAFFIC (NCT01807923), TRANSPORT (NCT01807949), and PROGRESS (NCT01931839). The TRAFFIC and TRANSPORT studies collectively looked at 1,108 cystic fibrosis patients with two copies of the F508del mutation and found that patients who took either 400 mg or 600 mg of lumacaftor plus 250 mg of ivacaftor every morning (combo tablet) and another 250 mg of ivacaftor at night for six months had much better lung function, fewer hospital admissions, and lower antibiotic usage.
Patients were then invited to the extension PROGRESS trial, continuing on the same dosages they were assigned to in TRAFFIC and TRANSPORT — with those in placebo groups moving to 600 mg of lumacaftor plus 250 mg of ivacaftor every morning plus ivacaftor at night — and evaluated for two years. The PROGRESS study confirmed that long-term Orkambi usage could also improve lung function, maintain patients’ body-mass index (a measure of body weight for height), and was safe and tolerable.
In 2016, FDA approval for Orkambi was expanded to include CF patients ages 6 to 11 with two copies of the F508del mutation, a decision that allows an estimated 2,400 more children in the U.S. to benefit from this treatment. Two Phase 3 clinical trials (NCT01897233 and NCT02514473) were carried out in patients in this age group. In both, treatment-group patients were given 200 mg lumacaftor and 250 mg ivacaftor every 12 hours for six months. Like in previous studies, children in these trials showed improvements in lung function, and Orkambi’s use was safe and tolerable.
Vertex is looking to expand access to patients ages 2 to 5. An open-label Phase 3 clinical trial (NCT02797132) that investigated lumacaftor (100 mg and 150 mg doses) and ivacaftor (125 mg and 188 mg doses) given to 60 children every 12 hours for six months was completed in September 2017.
Orkambi is available as single-pill tablets containing dosages of either lumacaftor 100 mg/ivacaftor 125 mg (patients ages 6 to 12) or lumacaftor 200 mg/ivacaftor 125mg (ages 12 and older). Orkambi should be taken every 12 hours with fat-containing foods, such dairy products, nuts, and avocados, as fat helps the body better absorb the medication.
The most common side effects associated with Orkambi use include breathing problems or chest tightness, nausea, diarrhea, stomach discomfort, cold symptoms (a sore throat and runny nose), fatigue, rash, or irregular menstrual periods. Children may experience headaches, stuffy noses, stomach pain, and an increase in the amount of phlegm.
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