CF combination therapy offers 
new hope

New Drug

Cystic fibrosis (CF) is one of the most common life-limiting, autosomal-recessive genetic diseases, resulting in deficient or dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) protein. Dysfunctions of the CFTR protein result in excess secretions in the lungs, which lead to chronic airway infections, loss of lung function, and eventually respiratory failure. The F508del is the most common CFTR mutation, with approximately 45%–50% of patients with CF being homozygous for this allele. The median survival among patients who are homozygous for the F508del CFTR mutation is only 37 years.

Traditionally, therapies for CF have focused on the use of medications and physiotherapy to enhance mucociliary clearance and the use of antipseudomonal antibiotics for infection control. Newer therapies, however, are aimed at targeting the specific mutation abnormalities and restoring the function of the defective CFTR protein. 

One of these new therapies, lumacaftor/ivacaftor (Orkambi—Vertex), recently received FDA approval for the treatment of CF in patients aged 12 years and older who are homozygous for the F508del mutation in the CFTR gene. 

Both lumicaftor and ivacaftor work by correcting the misfolded CFTR protein, which is the root cause of the F508del mutation. Specifically, lumacaftor has been shown to correct F508del CFTR misprocessing and increase the amount of cell surface-localized protein, and ivacaftor has been shown to increase the probability of open CFTR channels. 

As monotherapy, these agents were not shown to provide meaningful benefit in patients who were homozygous for the F508del CFTR mutation; however, in combination, the activity of CFTR was increased enough to provide significant improvements in patients. 


The efficacy and safety of lumacaftor/ivacaftor were evaluated in two Phase III studies known as TRAFFIC and TRANSPORT. These two, randomized, double-blind, placebo-controlled trials enrolled 1,108 patients aged 12 years and older with CF and homozygous for the F508del CFTR mutation. Patients were randomized to lumacaftor 400 mg or 600 mg/ivacaftor 250 mg every 12 hours or placebo for 24 weeks.

After 24 weeks of treatment, results of the primary endpoint, which was absolute change from baseline in the percentage of predicted expiratory volume in 1 second (FEV1), showed that significant improvements occurred in both of the active treatment groups compared with placebo. The difference between active treatment (i.e., lumacaftor 400 mg/ivacaftor 250 mg) and placebo with respect to the primary endpoint was 2.6 percentage points in one trial and 3.0 percentage points in another. In addition, pooled analyses showed that the rate of pulmonary exacerbations was 30%–40% lower in the lumacaftor/ivacaftor groups than in the placebo groups.

According to the label, the most common adverse events with use of this new therapy were dyspnea, nasopharyngitis, nausea, diarrhea, upper respiratory tract infection, fatigue, abnormal respiration, increased blood creatine phosphokinase, rash, flatulence, rhinorrhea, and influenza.

Patient counseling

Educate patients on proper dosing, which includes taking the tablets twice daily with fat-containing foods. Give patients examples of the types of foods that should be eaten. Also educate patients on missed doses instructions. Inform patients about the potential for adverse events. Tell them that blood tests to monitor the liver are needed and that baseline and follow-up eye exams are recommended for younger patients initiating treatment.

Lumacaftor/Ivacaftor (Orkambi)

Manufacturer: Vertex

Drug class: Cystic fibrosis transmembrane conductance regulator (CFTR) potentiator

Indication: Treatment of cystic fibrosis in patients aged 12 years and older who are homozygous for the F508del mutation in the CFTR gene

Dosage: For adults and children aged 12 years and older, two tablets (each tablet contains lumacaftor 200 mg/ivacaftor 125 mg) taken orally every 12 hours with fat-containing foods (e.g., eggs, avocados, nuts). 

  • If missed doses are remembered within 6 hours, the dose should be taken. If more than 6 hours have passed, the dose should be skipped and the patient should resume the normal dosing schedule; no double doses should be taken.

  • For patients with moderate hepatic impairment (Child–Pugh Class B), two tablets in the morning and one tablet at night are recommended, and for patients with severe hepatic impairment (Child–Pugh Class C), one tablet in the morning and one tablet at night are recommended.

Of note: Warnings and precautions listed in the label include using the drug cautiously in patients with advanced liver disease; the potential for liver-related events such as elevations in liver transaminases; respiratory events (e.g., chest discomfort, dyspnea); drug interactions; and cataracts.

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