Abstract Introduction Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have transformed outcomes for many individuals with cystic fibrosis (CF); however, patients with minimal-function Class I CFTR mutations are generally considered unlikely to benefit due to absent or severely truncated protein production. As a result, these individuals often continue to experience progressive disease without targeted therapy options. We present a case of meaningful clinical and biochemical improvement in a patient with two such variants following initiation of vanzacaftor/tezacaftor/deutivacaftor (VTD). Case Description A 15-year-old male with cystic fibrosis and genotype c.825CG (p.Tyr275X) and c.273 + 3AC had a history of recurrent pulmonary exacerbations, frequent hospitalizations, progressive decline in lung function, cystic fibrosis-related diabetes (CFRD), and significant treatment adherence challenges. Neither of his mutations were approved for modulator therapy. Theratyping was attempted but did not yield results due to technical issues. He was hospitalized for a pulmonary exacerbation and initiated VTD several days into the admission. Sweat chloride values subsequently improved from 93.5 mmol/L pre-VTD to 76 mmol/L after approximately 11 weeks of therapy. Prior to VTD initiation, his percent-predicted forced expiratory volume in one second (ppFEV1) had declined from 42% to 22% over 10 months. After starting VTD, ppFEV1 stabilized within the 26-36% predicted range without further decline. Regarding his CFRD, he previously required multiple correction insulin doses per meal several times daily, along with basal insulin, to maintain target blood glucose. After starting VTD, he now requires only occasional 1-2 unit correction doses approximately every 4-5 days, no longer requires basal insulin, and his blood sugars remain within target, with liberalization of dietary restrictions. Substantial improvements in nutritional status were also observed. He has experienced no pulmonary exacerbations in the four months since starting VTD, compared with three hospitalizations for pulmonary exacerbations in the six months prior. Novelty and Importance Both CFTR mutations in this patient are Class I (one nonsense, one splice-site) and are traditionally categorized as minimal-function and non-responsive to modulators. Despite this, the patient demonstrated biochemical response, clinical stabilization, improved metabolic control, and reduced exacerbation frequency. This case challenges assumptions regarding modulator non-responsiveness in certain Class I mutations and supports consideration of therapeutic trials in similar patients. Based on this outcome, two siblings with the same genotype will now be offered VTD therapy. Reporting such cases may expand recognition of modulator benefit in rare, presumed non-responsive CFTR variants even in the absence of theratyping. This abstract is funded by: None
Baddourah et al. (Fri,) studied this question.