iPS Cell Response to CFTR Modulators

Cystic Fibrosis (CF) is a life threatening genetic disorder resulting from mutations found in
the gene known as the cystic fibrosis transmembrane conductance regulator (CFTR). Defects in
this gene prevent correct chloride absorption in and out of the cells. The current trial is
intended to show for the first time that primary induced pluripotent stem (iPS) cells
differentiated to an airway epithelial phenotype can be used to predict in vivo clinical
response for a rare CF patient population, with the long-term goal of facilitating drug
access for individuals with other rare CF variants.

This study addresses gaps in knowledge, and limitations to therapeutic drug access, as these
features relate to CF precision medicine. Specifically this study highlights the situation
for individuals carrying P67L, an orphan allele noted in approximately 240 CF patients and
emblematic of hundreds of other rare CFTR mutations. Individuals with the P67L variant
exhibit recurrent pseudomonas pneumonia, reduced FEV1, and early death. This study is an
open-label, two-center study of orally administered lumacaftor and ivacaftor (Orkambi) that
will enroll 22 patients (11 at each site) with the P67L/F508del genotype. The researchers
will monitor clinical endpoints that include FEV1, sweat chloride, and nasal potential
difference. The researchers will also obtain cutaneous punch biopsy material from each
subject so that iPS cells can be differentiated into airway epithelial monolayers and tested
for response to Orkambi.

Inclusion Criteria:

- Provision of signed and dated informed consent form

- Stated willingness to comply with all study procedures and availability for the
duration of the study

- Male or Female age ≥12

- A clinical diagnosis of CF as defined by current guidelines and the P67L/F508del
genotype

- FEV1% predicted ≥ 40 and ≤ 90 Post Bronchodilator

- Clinically stable in the past 4 weeks with no evidence of CF exacerbation

- BMI > 18 kg/m2

- Willingness to use at least one form of acceptable birth control including abstinence
or condom with spermicide. (Hormonal contraceptives may be ineffective in the setting
of Orkambi treatment.) This will include birth control for at least one month prior to
screening and agreement to use such a method during study participation for an
additional four weeks after the last administration of study drug

- Ability to take Orkambi and be willing to adhere to the study regimen

- Agreement to adhere to all current medical therapies as designated by the CF care
center physician

Exclusion Criteria:

- Documented history of drug abuse within the last year

- Subjects should not have a pulmonary exacerbation or changes in therapy for pulmonary
disease in the 4 weeks prior to screening

- Cirrhosis or elevated liver transaminases > 3 times the upper limit of normal (ULN)

- Pregnant or breastfeeding

- Inhibitors or inducers of CYP3A4, including certain herbal medications and
grapefruit/grapefruit juice, or other medicines known to negatively influence Orkambi
administration

- History of solid organ transplant

- History of non-tuberculous mycobacterial infection (any positive culture in the past
18 months) or active therapy for these infections.

- Known allergy to Kalydeco

- Any other condition that in the opinion of the lead investigators might confound
results of the study or pose an additional risk from administering study drug

- Treatment with another investigational drug or other intervention within one month
prior to enrollment, throughout the duration of study participation, and for an
additional four weeks following final drug administration