Trikafta in Cystic Fibrosis Patients

This clinical study will enroll 42 participants without the F508del mutation, carrying partial function or N1303K mutations not approved for Trikafta, and who are not expected to be approved for CFTR modulator treatment in the immediate future. Each participant will be given Trikafta for approximately four weeks. The study researchers will monitor clinical endpoints that include forced expiratory volume (FEV1) and sweat chloride. Additionally, the researchers will obtain skin biopsy material and/or blood sample from each subject so that induced pluripotent stem (iPS) cells can be modified into airway cell monolayers and tested for response to Trikafta. In this way, the study will evaluate an emerging and readily accessible in vitro endpoint as a predictor of clinical response. This study will serve as a pilot/test case for other clinical protocols relevant to patients with rare CFTR variants who do not currently receive modulator therapies. It is hypothesized that a robust correlation will be established between in vitro Trikafta responsiveness of iPS cells and in vivo benefit (FEV1) to patients, and will provide a new tool for utilizing iPS to identify patient populations most suitable for cystic fibrosis modulator therapy.

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 and bicarbonate transport in and out of cells. It has become increasingly important to develop new in vitro model systems capable of predicting in vivo clinical effectiveness of modulator therapy among patients with CF. This objective represents a significant and unmet need for advancing personalized therapeutics in the disease. The current trial is intended to show for the first time that primary iPS cells differentiated to an airway epithelial phenotype can be used to predict in vivo clinical response for rare CF patient populations, with the long-term goal of facilitating drug access for individuals with unusual (or even private) CF variants.

Trikafta is currently approved for patients with CF carrying at least one copy of the common F508del variant and over 170 other CFTR abnormalities. Because approximately 90% of CF patients in the United States meet these criteria, pharmacotherapies (Trikafta in particular) are now available to a sizable majority of those with the disease. However, thousands of patients harboring relatively common variants will remain without effective drug therapy. Others with ultra-rare or private CFTR mutations have forms of the disease that are very likely to benefit from available drugs, but do not have access to these therapies. It has been estimated that over 1,000 CFTR mutations are represented by less than 5 patients each. Establishing processes so that individuals with very rare and/or poorly characterized alleles can gain access to effective modulator treatment remains one of the predominant challenges in the field.

This clinical study will enroll 42 participants without the F508del mutation, carrying partial function or N1303K mutations not approved for Trikafta, and who are not expected to be approved for CFTR modulator treatment in the immediate future. Substudy 1 will comprise an open-label, two center trial of orally administered elexacaftor, tezacaftor and ivacaftor (Trikafta) that will enroll 22 patients with rare/orphan genotypes. Substudy 2 will enroll 20 participants who encode the N1303K variant as emblematic of a mutation not approved for Trikafta, but are likely to respond to the treatment.

Each participant will have clinical and/or preclinical evidence that Trikafta should offer benefit, and each will be given Trikafta for approximately four weeks. The researchers will monitor clinical endpoints that include FEV1, sweat chloride, quality of life, and weight. The study will differentiate iPS cells from each subject to generate airway epithelial monolayers that can be tested for response to Trikafta. In this way, this study will evaluate an emerging and readily accessible in vitro surrogate endpoint as a predictor of clinical response. This trial will also serve as a pilot/test case for other clinical protocols relevant to patients with rare CFTR variants and evidence of residual function who do not have an approved modulator therapy, due to rarity of their mutation. It is hypothesized that a robust correlation will be established between in vitro Trikafta responsiveness of iPS cells and in vivo benefit (FEV1) in patients, and provide a powerful tool for utilizing iPS cells to identify rare CF patient populations most suitable for cystic fibrosis modulator therapy.

Eligibility Criteria:
Inclusion Criteria:

* Provision of signed and dated informed consent form or assent 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 or CFTR-related disease and either: 1) evidence for a partial function mutation not currently covered or likely to be covered for treatment with a CFTR modulator (Substudy 1), or 2) N1303K CFTR and a minimal function mutation (Substudy 2)
* Sweat Chloride \< 80 mmol/L and/or pancreatic sufficiency (no exogenous pancreatic enzyme supplement therapy) or carrying the N1303K CFTR variant
* Able to perform spirometry meeting American Thoracic Society (ATS) criteria for acceptability and repeatability
* Clinically stable in the past 4 weeks with no evidence of CF exacerbation (prior to screening and study Day 1)
* Willingness to use at least one form of acceptable birth control including abstinence or condom with spermicide. 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 Trikafta
* Agreement to adhere to all current medical therapies as designated by the CF care center physician

Exclusion Criteria:

* Documented history of drug or alcohol 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
* Listed for lung or liver transplant at the time of screening
* Cirrhosis or elevated liver transaminases \> 3 times the upper limit of normal
* Pregnant or breastfeeding
* Inhibitors or inducers of CYP3A4, including certain herbal medications and grapefruit/grapefruit juice, or other medicines known to negatively influence Trikafta administration
* History of solid organ transplant
* Active therapy for non-tuberculosis mycobacterial infection or any plan to initiate non-tuberculosis mycobacterial therapies during the study period
* Known allergy to Trikafta
* Treatment in the last 6 months with an approved CFTR modulator
* 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
* Evidence of cataract/lens opacity determined to be clinically significant by an ophthalmologist at or within 3 months prior to the Screening Visit