Addressing Tolerability Issues Associated With CFTR Modulators

• This program will cover what we have learned about tolerability related to cystic fibrosis transmembrane conductance regulator (CFTR) modulators, how to initiate the drugs, when it is appropriate to make dosage adjustments, and how to work with patients when a problem arises

Ivacaftor (Potentiator) Plus Lumacaftor (Corrector) in F508del CFTR: TRAFFIC and TRANSPORT Studies^[1]

• Ivacaftor is a potentiator that activates defective CFTR protein on the cell surface
• Lumacaftor is a corrector that moves mutant CFTR through the cell to the cell surface, where it can be activated

Lumacaftor/Ivacaftor Dosage Adjustments^[2]

Adverse Effects That Should Be Monitored/Followed and May Necessitate Stopping/Discontinuation of Lumacaftor/Ivacaftor

• It is important to distinguish between adverse events that require stopping the drug vs events that are transient and manageable
• Elevated liver enzymes that require drug discontinuation have not been observed at Johns Hopkins Cystic Fibrosis Center
• Severe bronchospasm and chest tightness, as well as severe cough and, occasionally, a decrease in lung function, have been observed in patients at Johns Hopkins
• Respiratory effects, as well as loose stools and diarrhea, have also been observed at the University of Washington Cystic Fibrosis Clinic
• Patients with more severe disease (ppFEV₁ of less than 40%) have more adverse events when initiating the drug -- typically bronchospasm and dyspnea -- than patients with mild or moderate disease

Before Initiating Lumacaftor/ivacaftor Therapy

• At University of Washington, patients who have a ppFEV₁ of less than 30% are typically hospitalized for initiation of lumacaftor/ivacaftor therapy, and started at a low dosage (eg, 1 tablet daily, increasing to 1 tablet twice a day, and then to full dosage of 2 tablets twice a day)
• Johns Hopkins does not typically hospitalize patients with severe disease for initiation of lumacaftor/ivacaftor therapy, but may initiate therapy after a patient has finished intravenous (IV) antibiotic therapy, or has been admitted to the hospital for other reasons
• Ensure that the patient is taking a long-acting bronchodilator
• Ensure that the patient's airway clearance is maximized with the patient's routine therapies; this may include rhDNase, hypertonic saline, inhaled antibiotics, and augmented airway clearance with manual chest physiotherapy or other devices perceived by the patient to be effective

Adverse Events Common in CF Also Reported in TRAFFIC and TRANSPORT^[1]

• Hemoptysis was reported in 13.6% to 14.1% of patients, an adverse event that Dr Goss and Dr West agree is most likely secondary to underlying cystic fibrosis (CF), and not drug-induced
• Although some events observed during the trials may have been caused by CF and were not necessarily drug-induced, the cough and chest tightness observed on initiation of lumacaftor/ivacaftor therapy is likely drug-induced

Managing Initiation of Lumacaftor/Ivacaftor Therapy

Drug-Drug Interactions With CFTR Modulators

Johns Hopkins University Observational Data^[3]

• If restarting lumacaftor/ivacaftor after discontinuing it because of drug-related adverse events, consider doing so after a round of IV antibiotics
• Optimize lung function
  • Ensure patient is taking all appropriate medications
• Consider pretreatment with prednisone

Thank you for participating in this activity

• How we react to the real-world experience of initiating lumacaftor/ivacaftor therapy has evolved

This content has been condensed for improved clarity.