Trikafta in Cystic Fibrosis Patients

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.

Trikafta is currently approved for patients with CF carrying at least one copy of the common F508del variant and over 250 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. 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. This trial will 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 correlation will be established between in vitro Trikafta responsiveness of iPS cells and in vivo benefit (FEV1) in patients, and provide a tool for utilizing iPS cells to identify rare CF patient populations most suitable for cystic fibrosis modulator therapy.

• Trikafta (Drug), also known as ivacaftor, tezacaftor, elexacaftor: 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.

Primary outcomes

• Percent Predicted Forced Expiratory Volume in One Second (FEV1) Among Participants With Evidence of Partial Function [Baseline, Day 28]: 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.
• Sweat Chloride Among Participants Who Encode the N1303K Variant [Baseline, Day 28]: 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 greater mean that a diagnosis of CF is likely.
• Number of Participants With Induced Pluripotent Stem (iPS) Cells Predicting Response to Treatment Among Participants With Evidence of Partial Function [Baseline]: Response of iPS cells (iPSc) to treatment among participants with evidence of partial function was examined to determine whether iPS derived monolayers could predict "personalized" clinical benefit. Cutaneous punch biopsy material was collected from each participant so that iPS cells could be differentiated into airway epithelial monolayers and tested for response to treatment in vitro - as a potential way to predict improvement from Trikafta in vivo.

Secondary outcomes

• Percent Predicted Forced Expiratory Volume in One Second (FEV1) Among Participants Who Encode the N1303K Variant [Baseline, Day 28]: 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.
• Sweat Chloride Among Participants With Evidence of Partial Function [Baseline, Day 28]: 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 greater mean that a diagnosis of CF is likely.
• Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Domain Score [Baseline, Day 28]: Participants take the CFQ-R corresponding to their age for assessing 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. Scores for items in the respiratory domain are summed and standardized and the standardized score ranges from 1 to 100. A minimum clinically important difference (MCID) of 4 or more points represents improved respiratory-related quality of life.
• Weight [Baseline, Day 28]: Weight is measured in kilograms.
• Body Mass Index (BMI) [Baseline, Day 28]: Body mass index is calculated as weight in kilograms divided by height in meters squared.
• Number of Participants Where the Assay Successfully Predicted Treatment Response Using iPS Cells Among Participants Encoding N1303K [Baseline]: Cutaneous punch biopsy material was collected from each participant so that iPS cells could be differentiated into airway epithelial monolayers and tested for response to treatment in vitro - i.e., as a potential way to predict benefit from Trikafta in vivo. By using iPS cells differentiated to exhibit a respiratory epithelial phenotype, the study aims to determine whether iPScs can be used to predict clinical improvement due to Trikafta.

Sex: All, ages: 12 Years to any

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

Participant flow

Outcome results

• Percent Predicted Forced Expiratory Volume in One Second (FEV1) Among Participants With Evidence of Partial Function (Primary), Least squares mean, percent of predicted FEV1: Participants With Evidence of Partial Function (Sweat Chloride < 80 mEq/L or Pancreatic Sufficiency) 74.8 (72.4 to 77.2)
• Sweat Chloride Among Participants Who Encode the N1303K Variant (Primary), Least squares mean, mmol/liter: Participants Who Encode the N1303K Variant 109 (105.6 to 112.4)
• Number of Participants With Induced Pluripotent Stem (iPS) Cells Predicting Response to Treatment Among Participants With Evidence of Partial Function (Primary), Count of participants, Participants: Participants With Evidence of Partial Function (Sweat Chloride < 80 mEq/L or Pancreatic Sufficiency) 0
• Percent Predicted Forced Expiratory Volume in One Second (FEV1) Among Participants Who Encode the N1303K Variant (Secondary), Least squares mean, percent predicted FEV1: Participants Who Encode the N1303K Variant 75.8 (73.3 to 78.3)
• Sweat Chloride Among Participants With Evidence of Partial Function (Secondary), Least squares mean, mmol/liter: Participants With Evidence of Partial Function (Sweat Chloride < 80 mEq/L or Pancreatic Sufficiency) 66.9 (63.8 to 70.1)
• Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Domain Score (Secondary), Least squares mean, score on a scale: Participants With Evidence of Partial Function (Sweat Chloride < 80 mEq/L or Pancreatic Sufficiency) 66.4 (59.8 to 73.1); Participants Who Encode the N1303K Variant 60.6 (54.6 to 66.5)
• Weight (Secondary), Least squares mean, kilograms: Participants With Evidence of Partial Function (Sweat Chloride < 80 mEq/L or Pancreatic Sufficiency) 75 (74.5 to 75.6); Participants Who Encode the N1303K Variant 57.5 (57.0 to 58.0)
• Body Mass Index (BMI) (Secondary), Least squares mean, kg/m^2: Participants With Evidence of Partial Function (Sweat Chloride < 80 mEq/L or Pancreatic Sufficiency) 25.4 (25.3 to 25.6); Participants Who Encode the N1303K Variant 22.1 (21.9 to 22.3)
• Number of Participants Where the Assay Successfully Predicted Treatment Response Using iPS Cells Among Participants Encoding N1303K (Secondary), Count of participants, Participants: Participants Who Encode the N1303K Variant 0

Adverse events

Time frame: Information about adverse events was collected from the time of consent through Day 56.

Serious adverse events by term

Other adverse events by term

Limitations and caveats: Analysis of using iPS cells to predict individual response to Trikafta was limited due to technical difficulties when optimizing the new iPS cell-derived epithelial cell model. Challenges and delays with processing iPS cell samples to mature airway epithelial monolayers were also encountered. The study team spent an additional 16 months further refining the novel assay developed for examining iPS cell response for this study but the assay is not functioning for the intended purpose.

• Results publication: Solomon GM, Linnemann RW, Rich R, Streby A, Buehler B, Hunter E, Vijaykumar K, Hunt WR, Brewington JJ, Rab A, Bai SP, Westbrook AL, McNicholas-Bevensee C, Hong J, Manfredi C, Barilla C, Suzuki S, Davis BR, Sorscher EJ. Evaluation of elexacaftor-tezacaftor-ivacaftor treatment in individuals with cystic fibrosis and CFTRN1303K in the USA: a prospective, multicentre, open-label, single-arm trial. Lancet Respir Med. 2024 Dec;12(12):947-957. doi: 10.1016/S2213-2600(24)00205-4. Epub 2024 Aug 26. PMID 39208836
• Results publication: Linnemann RW, Solomon GM, Westbrook AL, Rich R, Streby A, Hunter E, Rab A, Bai S, Mcnicholas CM, Hong JS, Manfredi C, Hunt WR, Stecenko AA, Barilla C, Suzuki S, Davis BR, Sorscher EJ. Elexacaftor-Tezacaftor-Ivacaftor for Individuals with Residual CFTR Activity: An Open-Label, Nonrandomized Clinical Trial. Ann Am Thorac Soc. 2026 Jun 10:aaoag136. doi: 10.1093/annalsats/aaoag136. Online ahead of print. No abstract available. PMID 42271629

• Study Protocol and Statistical Analysis Plan (PDF, 2022-05-10)
• Informed Consent Form (PDF, 2022-09-07)

• Eric Sorscher, MD, Principal investigator, Emory University

NIH grants: R01HL139876