(606) Focused Clinical Trials of Modulator Response for Rare Cystic Fibrosis Genotypes

Background: Substantial progress has been made regarding personalized strategies for treatment of cystic fibrosis (CF). While highly effective modulators are available to a sizable majority of individuals with the disease, significant challenges to CF precision medicine remain. These include improving health of patients encoding variants not responsive to available compounds, drug cost and patient access to modulator treatment, molecular complexity involving refractory CFTR mutations, and addressing ultrarare or private CFTR abnormalities not suitable for conventional, double-blind, placebo-controlled trials. Our research team is establishing study protocols, statistical methods, and novel in vitro (iPSC-derived) models for determining theratype using small and scientifically meaningful patient cohorts.

Methods: An initial, open label clinical trial is in progress to evaluate subjects age 12 and older diagnosed with CF pulmonary disease and evidence of partial CFTR function (sweat chloride < 80 mEq/L, pancreatic sufficiency) but without access to FDA-approved CFTR corrector or potentiator compounds. The study will incorporate iPSC-derived airway epithelial monolayers to test an in vitro surrogate for patient benefit that accounts for complex CFTR alleles and may be less influenced by epigenetic factors such as chronic infection or inflammation. Clinical phenotype – rather than CF genotype – is being used to identify a group of patients in “the last 10%” that may be modulator responsive. Genotype-specific subgroups with strong scientific rationale are also being considered for similarly designed trials.

Results: Six of the first eight study subjects in the partial function trial demonstrated improvement in sweat chloride during a four-week treatment period with elexacaftor/tezacaftor/ivacaftor (ETI), and exhibited return towards baseline values during 28-day washout. Several patients also experienced modest weight gain and improved quality-of-life metrics. Three subjects who showed FEV1 improvement >5 - 20% predicted were able to apply their study results to gain insurance reimbursement for chronic modulator treatment. Based on favorable results from the sentinel trial, additional patient cohorts will be evaluated. For example, N1303K CFTR was profiled by our laboratory in vitro for potential responsiveness to ETI. N1303K is a class II variant present in >2% of patients with CF throughout North America. ETI treatment was shown to improve N1303K CFTR function in FRT cells (26.3% wild-type levels), human iPSC-derived epithelial monolayers (24.5% wild-type values), and primary airway epithelial monolayers ( >10% wild-type activity) in a subset of N1303K patient samples.

Conclusions: Small but highly focused ETI clinical trials based on strong scientific rationale can help identify individuals with CF likely to benefit from CFTR modulation – and guide future patient-oriented studies. Our approach to date supports testing of this type among individuals exhibiting a partial function CFTR phenotype. A clinical trial to evaluate N1303K CFTR has recent IRB approval and is scheduled to begin mid-2022. Data from both clinical studies, and a discussion with regard to protocol design, statistical analysis, and correlative iPSC-derived monolayer measurements will be presented.

Acknowledgements: People with CF study participants. Funding provided by NIH and CF Foundation.

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