This study is a single center study of clinical and laboratory outcomes in patients ≥ 12 who transition from use of Orkambi to tez/iva. Clinical and laboratory measurements will be measured at baseline, 1 month, 3 months, and 6 months after initiation of tez/iva. Change from baseline at 6 months pre-specified will be reported. The length of study participation will be approximately 6 months.

While cystic fibrosis (CF) therapeutic development previously targeted the signs and symptoms of the disease, in the last 5 years, two drugs that treat the basic defect in CF have been approved, ivacaftor (iva) and lumacaftor/ivacaftor (lum/iva). This class of drugs, deemed cystic fibrosis transmembrane conductance regulator (CFTR) modulators, variably improve CFTR function as measured by pilocarpine iontophoresis and sweat collection, and clinical outcomes including lung function, body mass index (BMI), rate of exacerbations and patient reported quality of life.

In patients with the G551D mutation who received iva, there was a marked decrease in sweat chloride and marked improvement in lung function as measured by absolute change from baseline of percent predicted expiratory volume in 1 second (ppFEV1). The clinical outcomes assessed in the phase III studies of lum/iva and tez/iva were similar, and included lung function, rate of pulmonary exacerbations, BMI, and CFQ-R scores. While the correlation between improvement in sweat chloride and lung function is poor, and a minimum threshold for change in sweat chloride that correlates with clinical outcomes has yet to be defined, it has also not been determined if an increase in sweat chloride caused by a transition from one drug to another would adversely impact clinical outcomes. Outcomes between the phase III studies of lum/iva and tez/iva were similar, tez/iva has three advantages that are likely to make it more appealing to patients and providers than lum/iva including positive clinical efficacy data, fewer drug-drug interactions, and an improved tolerance profile.

Following tez/iva approval, a rapid uptake of tez/iva for patients homozygous for F508del CFTR is expected; as a result of the transition from lum/iva to tez/iva, sweat chloride will increase possibly resulting in an adverse impact on clinical outcomes. This study aims to determine the rationale for patient transition from lum/iva to tez/iva, in addition to evaluate the impact of transition on CFTR function, pulmonary health, gastrointestinal health, and general health. While it is possible that there will be no change in sweat chloride or small changes that are without clinical significance, systematic collection of data as patients transition from lum/iva to tez/iva would permit rapid identification of any safety issues. Because the U.S. always leads the way with approval and reimbursement of new therapeutics, our experience with this transition will help guide its conduct for physicians and patients in the rest of the world.

Inclusion Criteria:

• Confirmed diagnosis of CF
• Male or female subjects greater than or equal to 12 years of age
• Ability to reproducibly perform spirometry testing
• Physician decision to treat with tezacaftor/ivacaftor (Smydeko)
• Ability to understand and sign a written informed consent or assent and comply with the requirements of the study
• Continuous use of orkambi for at least 1 month prior to visit 1

Exclusion Criteria:

• History of hypersensitivity to tezacaftor and/or ivacaftor
• Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data
• Any acute lower respiratory symptoms treated with oral, inhaled or intravenous antibiotics (IV) or systemic corticosteroids within the 2 weeks prior to Visit 1
• Major or traumatic surgery within 12 weeks prior to Visit 1
• For women of child-bearing potential: a positive pregnancy test at Visit 1
• Unable or unwilling to fast (including no enteric tube feedings) for at least 6 hours prior each visit
• Initiation of any new chronic therapy within 4 weeks prior to Visit 1
• Use of an investigational agent within 28 days prior to Visit 1
• Use of chronic oral corticosteroids within 28 days prior to Visit 1
• Treatment for nontuberculous mycobacterial (NTM) infection, consisting of greater than or equal to two antibiotics (oral, IV, and/or inhaled) within 28 days prior to Visit 1
• History of lung or liver transplantation, or listing for organ transplantation

Cystic fibrosis with 2 copies of F508del mutation.

6 months

The limitation is the small sample size. Less patients with cystic fibrosis transitioned from lumacaftor/ivacaftor to tezacaftor/ivacaftor than expected. The enrolled number of patients left the study underpowered to detect differences.