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Reversing the irreversible: Another potential benefit of CFTR modulators

To the Editor, Cystic fibrosis (CF) is a genetic condition resulting from a fundamental defect in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. This defect leads to a reduction or absence of chloride transport across the cell surface of many‐body systems. In 2012, the US Food and Drug Administration, approved a novel therapy that targeted this specific CFTR defect, ivacaftor (Kalydeco). Although it was deemed safe and effective for only a small portion of patients with the disease, ivacaftor opened the door for future therapies. Starting in 2015, the next generation of CFTR modulators were released as combination tablets with components lumacaftor/ ivacaftor (Orkambi), tezacaftor/ivacaftor (Symdeko), and tezacaftor/ ivacaftor/elexacaftor (Trikafta). These medications have been shown to improve lung function, decrease requirements for antibiotics and hospitalizations, and increase the quality of life. Additional data regarding the extrapulmonary effects of modulators is expanding with the wider use of these medications. A review by Sergeev et al suggests potential benefits across eight additional organ systems. One highly impacted organ, the pancreas, is often damaged in utero causing pancreatic insufficiency in at least 85% of patients. This damage was considered to be permanent and irreversible; however, recent publications have shown that this may not be the case.3‐5 While this response has been previously documented with ivacaftor monotherapy, we present this case of a pediatric CF patient who regained pancreatic function after initiation and use of lumacaftor/ivacaftor. Our patient is a 9‐year‐old female, homozygous for F508del mutations (initially identified as part of the Iowa Newborn Metabolic Screening Program, later confirmed by Ambry Genetics and sweat chloride values of 118 and 110mmol/L). Her initial fecal elastase in October 2010, at 3 weeks of age, was 65 μg/g, indicating severe exocrine pancreatic insufficiency. She was started on pancreatic enzyme replacement at that time and was maintained on standard‐of‐ care therapies including pancreatic enzyme replacement therapy, high‐calorie diet, and fat‐soluble vitamin supplementation. She exhibited appropriate, stable weight gain and height growth over the next several years. From ages 2 to 6 years, her height‐for‐age, weight‐ for‐age, and body mass index (BMI)‐for‐age percentiles remained between the 25th and 50th percentiles. Lumacaftor/ivacaftor was initiated in November 2016 at 6 years of age. After lumacaftor/ivacaftor was started, she remained on standard therapies, but began to have dramatic increases in growth rates. Values are documented in Table 1. Over time, the patient's BMI‐for‐age percentile increased above the 85th percentile into the overweight category. The patient and her family were educated on these growth trends and given age‐ appropriate nutrition education on general healthy eating practices for weight maintenance and recommendations for servings of major food groups and nutrients. Our patient's lung function has consistently remained above 100% percent predicted forced expiratory volume in 1 second. Her CF‐related comorbidities include impaired glucose tolerance, intermittent Pseudomonas aeruginosa infection, methicillin‐ resistant Staphylococcus aureus colonization, and nasal sinus polyps. In September 2018, at 8 years of age, she experienced an episode of abdominal pain and diarrhea. Labs done at a local clinic revealed an elevated blood lipase level of 104 U/L (normal, 16‐63 U/L). Fecal elastase was rechecked in May 2019 and June 2019 and was within the normal range at 366 and 348 μg/g. Pancreatic enzyme replacement was stopped in June 2019. Even after pancreatic enzyme supplementation was stopped, the patient maintained adequate growth and fat‐soluble vitamin levels within normal limits with the continuation of lumacaftor/ivacaftor. Increased growth rates and fecal elastase levels indicate this patient had adequate nutrient absorption and likely restored pancreatic function. The authors of this paper acknowledge that many variables were present in this specific patient including diet. She also was on CFTR modulator therapy for less time than other reported cases of pancreatic function restoration. Despite the varying timeline and lack of current literature supporting pancreatic improvement