Trikafta in Cystic Fibrosis Patients

iPS Cell Response to CFTR Modulators: Study of Trikafta in CF Patients Carrying Partial Function Mutations or N1303K CFTR

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 carry at least one copy of F508del, 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.

Participants with CF with evidence of partial function (sweat chloride < 80 milliequivalents per liter (mEq/L) or pancreatic sufficiency) will receive Trikafta for 28 days.

Participants will take Trikafta which is a combination tablet comprised of 100 milligrams (mg) of elexacaftor, 50 mg of tezacaftor and 75 mg of ivacaftor (2 tablets taken in the morning), and 150 mg of ivacaftor taken in the evening.

FEV1 provides a direct measurement of patient health among individuals with cystic fibrosis and declines in FEV1 are associated with poor outcomes among those with CF. FEV1 is measured by spirometry and is the maximum amount of air the participant can blow out in one second.

Cutaneous punch biopsy material will be collected from each participant so that iPS cells can be differentiated into airway epithelial monolayers and tested for response to the treatment, in vitro. By using iPS cells differentiated to exhibit a respiratory epithelial phenotype, this study will determine whether the cells can be used to predict clinical responsiveness to Trikafta.

Persons with CF have higher levels of chloride in their sweat. Sweat chloride concentrations of less than or equal to 29 mmol/L are considered normal, concentrations of 30-59 mmol/L are considered intermediate and indicate that the individual may have CF. Concentrations of 60 mmol/L and more mean that a diagnosis of CF is likely.

Participants will take the CFQ-R that corresponds to their age to assess quality of life. Responses to questions are coded as 1 = very true or always, 2 = mostly true or often, 3 = somewhat true or sometimes, and 4 = not at all true or never. Some items are reverse scored so that higher scores indicate increased ability and higher quality of life. For this study, a summary score will be calculated to provide a single quality of life value. The questionnaire for ages 12-13 includes 35 questions and total scores can range from 35 to 140. The questionnaire for ages 14 and older has 50 questions and total scores range from 50 to 200.

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