Symdeko in Cystic Fibrosis Patients

Brief Summary:
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). This clinical study will enroll 22 participants without the F508del mutation, carrying partial function mutations not approved for Symdeko, and who are not expected to be approved for CFTR modulator treatment in the immediate future. Each participant will be given Symdeko for approximately four weeks. The study researchers will monitor clinical endpoints that include forced expiratory volume (FEV1), sweat chloride, and nasal potential difference. Additionally, the researchers will obtain skin biopsy material from each subject so that induced pluripotent stem (iPS) cells can be modified into airway cell monolayers and tested for response to Symdeko. 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 Symdeko 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.

Detailed Description:
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 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. Symdeko is currently approved for patients with CF carrying two copies of the common F508del variant, as well as individuals who have a single copy of one of 26 other specified mutations. This clinical trial will study 22 participants without the F508del mutation, carrying partial function mutations not approved for Symdeko, and who are not expected to be approved for CFTR modulator treatment in the immediate future (ie not included in ongoing trials of triple drug therapy). Each participant will have clinical and/or preclinical evidence that Symdeko should offer benefit, and each will be given Symdeko for approximately four weeks. The researchers will monitor clinical endpoints that include FEV1, sweat chloride, and nasal potential difference. The study will differentiate iPS cells from each subject to generate airway epithelial monolayers that can be tested for response to Symdeko. 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 Symdeko 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.


Study Type: Interventional  (Clinical Trial)
Estimated Enrollment: 22 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: iPS Cell Response to CFTR Modulators: Study of Symdeko in CF Patients Carrying Partial Function Mutations
Estimated Study Start Date: August 2019
Estimated Primary Completion Date: May 2023
Estimated Study Completion Date: May 2023

Arms:
- Experimental: Symdeko