Persistent Recovery of Pancreatic Function in Patients with Cystic Fibrosis after Ivacaftor

Danielle Munce MD1, Meerana Lim MD1,2, Kathryn Akong MD PhD1,2

Abstract

Exocrine pancreatic insufficiency (EPI), which leads to malabsorption and poor weight gain, is seen in 85% of patients with Cystic Fibrosis (CF). EPI is treated with pancreatic enzyme replacement therapy (PERT) taken with each meal. The highly effective CFTR modulator Ivacaftor restores CFTR function in patients with responsive mutations. It is a widely held view that EPI in CF is irreversible due to complete destruction of pancreatic ducts and acinar cells. We describe three pediatric CF patients with EPI who were started on Ivacaftor, and subsequently showed evidence of restored exocrine pancreatic function with clinical and biochemical parameters.

Keywords:
Pancreatic enzyme replacement therapy, fecal elastase, pancreatitis
Conflict of Interest: None
Exocrine Pancreatic Function with Ivacaftor in CF

Background

Cystic Fibrosis (CF) is caused by deleterious mutations in the gene encoding the Cystic Fibrosis transmembrane conductance regulator (CFTR), which is responsible for regulating salt and fluid homeostasis in multiple organ systems. While pulmonary disease due to mucus plugging and airway inflammation is typically the focus in patients with CF, the majority of CF patients alsodevelop exocrine pancreatic insufficiency (EPI) within the first year of life (1). Impaired bicarbonate transportdue to CFTRdysfunction leads to viscous pancreatic secretions, pancreatic duct obstructionand ultimately duct degradation and parenchymal fibrosis. This destruction of the pancreas starts in utero and is progressive throughout the first years of life resulting in EPI (2). EPI presents with a spectrum of gastrointestinal symptoms due to malabsorption, often with detrimental effects on nutritional status and weight gain, thus early testing for EPI is standard of care. Diagnosing EPI is typically done using a fecal elastase test, with a value of <200 mcg/g being consistent with EPI (3). Once a CF patient is diagnosed with EPI, pancreatic enzyme replacement therapy (PERT) is initiated. Given the progressive nature of this pancreatic injury and destruction, repeat testing is not indicated once the diagnosis of EPI has been established. It has been a widely accepted dogma that EPI in CF is irreversible due to the permanent destruction of pancreatic ducts and acini.
The advent of highly effective CFTR modulators has beena major advance in the treatment of patients with CF. Small molecule CFTR modulators such as Ivacaftor function to correct the protein defects that result from specific genetic mutations, and lead to at least partialrestoration of CFTR function throughout the entire body. Ivacaftor, an oral CFTR potentiator, improves chloride transport by increasing the open probability of the CFTR channel at the cell surface. The first phase 3, randomized, placebo-controlled trial of Ivacaftor in CF patients with the G551D gating mutation who were 12 years and older demonstrated clinically and statistically significant improvement in lung function, rate of pulmonary exacerbations and weight gain (4). The mechanism of improved weight gain was not addressed in this study, though later studies of Ivacaftorin children explored the possibility of an effect on pancreatic function. Subsequent clinical trials of ivacaftor in children, including the KIWI and KLIMB study, investigating the pharmacokinetics, safety, and efficacy of ivacaftor revealed not only an improvement in lung function but also an increase in BMI and fecal elastase values during the study period. The observed weight gain with increased fecal elastase values suggest restoration ofexocrine pancreatic function with ivacaftor (5,6). More recently, specific case reports have been published describing cases of CF patients previously diagnosed with EPI, who had clinical restoration of pancreatic function after initiation of Ivacaftor(7,8). These data suggest that exocrine pancreatic function may be modifiable with highly effective CFTR modulator therapy, in contrast to previously accepted models of pancreatic dysfunction in CF. The patients reported heredemonstrate long-term sustained restoration ofexocrine pancreatic function on Ivacaftor, providing more evidence of modifiable exocrine pancreatic function after EPI diagnosis in CF.

Patient Data

Patient 1 is an 8-year-old female with CF (F508del and G551D), a genotype associated with exocrine pancreatic insufficiency (EPI) in 96% of patients (cftr2.org). She was diagnosed with EPI with a fecal pancreatic elastase of 40 mcg/g at 2 weeks old, and was started on PERT. She has mild pulmonary disease, with no history of hospitalizations for pulmonary exacerbations. In infancy, she had intermittent episodes of abdominal pain which improved with titration of PERT and laxatives. She enrolled in an Ivacaftor trial at 4 years of age, and continued Ivacaftor after the trial ended. As per request of patient’s mother, she underwent repeat fecal pancreatic elastase testing two years after initiation of Ivacaftor. Her fecal pancreatic elastase level returned at a normal level, >500 mcg/g. She was subsequently taken off PERT and repeat testing 7 months later revealed persistent fecal elastase levels >500 mcg/g. She continues to gain weight appropriately with stabilized BMI at the 50th percentile off PERT for 2 years.
Patient 2 is a 10-year-old female with CF (F508del and G551D), a genotype associated with EPI in 96% of patients (cftr2.org). She was diagnosed with pancreatic insufficiency with a fecal elastase level of <50 mcg/g at 1 months of age. Her diagnosis of EPI was further supported by a low vitamin E level 4.9 mg/L and a consistently low vitamin D level of less than 30 ng/mL even while on PERT. She was started on PERT as an infant with stabilization of BMI >50th percentile, however her clinical course was complicated by multiple episodes of acute pancreatitis. Her first episode of acute pancreatitis was at 14 months of age, presenting with abdominal pain, emesis and an elevated lipase level of 1076 U/L. While acute pancreatitis is rare in CF patients with EPI, it has been described in published literature (5). Unfortunately, repeat fecal elastase testing was not done at that time to re-evaluate her exocrine pancreatic status. Ivacaftor was started at 6 years of age. She was initially continued on PERT and a high calorie diet. Repeat fecal elastase testing 2 years after initiation of Ivacaftor was 371 mcg/g and PERT was discontinued. Repeat vitamin D and vitamin E levels remained within normal limits for her age after initiation of Ivacaftor. She had an additional two episodes of pancreatitis 7 months apart, at age 10 years requiring hospitalization. MRCP during both admissions were normal, without evidence of biliary duct obstruction. Despite recurrent pancreatitis, she was able to maintain a BMI >50th percentile, with normal weight gain and stooling in between episodes. Fecal elastase remained normal, >500 mcg/g, after pancreatitis episodes. Her nutritional status has remained stable with BMI >50th percentile for 3 years off PERT.
Patient 3 is a 9-year-old male with CF (F508del and 3272-26A>G), a genotype associated with EPI in 30% of patients (cftr2.org). He was diagnosed with pancreatic insufficiency at three months of age with a fecal elastase value of 61 mcg/g. He was started on PERT, however continued to have intermittent periods of poor weight gain. His CF was characterized by mild pulmonary disease with infrequent oral antibiotic courses and no hospital admissions for pulmonary exacerbations. He was started on Ivacaftor at 7 years of age. Repeat fecal elastase testing 4 months after Ivacaftor initiation revealed a normalized fecal elastase value of 342 mcg/g. He was subsequently taken off PERT. Unfortunately, on subsequent follow up, his weight was stagnant with decline in BMI percentile for age. Other factors such as food insecurity and changes in diet were suspected to be the cause, though malabsorption due to PERT cessation could not be absolutely discounted as a possibility. After careful consideration of risks and benefits with the patient and his family, PERT was re-started. Repeat testing at the time of PERT re-initiation revealed fecal elastase of >500 mcg/g. His weight gain trend improved coincident with improved access to food and other resources. His BMI remained stable in the target range for one year, and at that time, another fecal elastase was again normal at >500 mcg/g. PERT was discontinued again at this time. He has continued to gain weight without malabsorption symptoms off PERT for 4 months, now with BMI >98th percentile, consistent with pancreatic sufficiency.

Discussion

Due to the critical importance of CFTR function in the pancreas, 85% of CF patients are diagnosed with EPI.Once EPI is diagnosed, PERT is initiated. While PERT is crucial for growth and alleviation of gastrointestinal symptoms associated withmalabsorption, the requirement for daily frequent administration adds to an already significant treatment burden for CF patients and families. Excessive doses have also been associated with a very rare complication of fibrosing colonopathy.
CFTR modulators, such as Ivacaftor, have drastically changed the symptom burden and improved prognoses for patients who have responsive mutations. The KIWI trial, a pharmacokinetic, safety and efficacy study of Ivacaftor in CF patients ages 2-5 years, demonstrated that Ivacaftor not only leads toin near-normalized sweat chloride levels, improved weight and BMI, but also revealed an overall increase in fecal elastase values within 24 weeks. At the beginning of the study, 26 of 27 patients enrolled had fecal elastase values <200 mcg/g. By 24 weeks, 25% of these patients had fecal elastase values consistent with clinical pancreatic sufficiency, with an overall average increase of 99.8 mcg/g (4). This improvement in pancreatic function was maintained during the 84week open label extension of the KIWI study, KLIMB (5,6). Similar results were found with younger infants, aged 12-24 months, as soon as 2 weeks after initiation of Ivacaftor. In the ARRIVAL study, six of nine infants previously diagnosed with pancreatic insufficiency underwent repeat fecal elastase testing at 24 weeks with values >200 mcg/g, consistent with pancreatic sufficiency. Along with increase in fecal elastase values, the ARRIVAL study also found an overall decrease in immunoreactive trypsinogen values, suggesting not only an improvement with pancreatic function but also a decrease in pancreatic inflammation with ivacaftor (9).
A case report has been published discussing two children with CF complicated by EPI who converted to pancreatic sufficiency after Ivacaftor initiation. In both patients, an episode of acute pancreatitis prompted repeat fecal elastase testing which indicated recovery of exocrine pancreatic function (8). While pancreatitis is an overall rare complication for CF patients and typically associated with patients with pancreatic sufficiency, it may also be seen with CF patients with EPI. A large cohort study examining CF patients from 29 countries found that pancreatitis was seen in 0.5% of patients with EPI, like patient 2 (10). We surmised that the initial episode of pancreatitis in Patient 2 at 14 months of age was a rare, but known, occurrence in the context of EPI. Her increased frequency of pancreatitisat 10 years of age, 4 years after Ivacaftor initiation,was likely due to improvement in pancreatic enzyme production and secretion, as seen inthe previously published case report.
Similar to previous studies and case reports, our three cases reveal improvement in laboratory testing consistent with complete recovery of pancreatic function after initiation of Ivacaftor. However, more importantly, our cases also reveal more sustained clinical features of pancreatic sufficiency after PERT has been stopped for months to years.
While pancreatic acinar destruction starts in utero and progresses throughout life, these cases suggest that restoration of exocrine pancreatic function is possible with highly effective modulator therapy. We presume that this is more likely to occur in younger patients, where the destruction of the pancreatic acinar units is not yet complete, or there is some capacity for regeneration. We also speculate that this effect on pancreatic function may also be seen with other highly effective modulators, such as Trikafta, which will be available to many more patients. Based on our experience with these patients, we advocate for repeat fecal elastase testing after initiation of highly effective modulator therapy to evaluate pancreatic status. If pancreatic sufficiency is suggested by normal fecal elastase levels, then discontinuation of PERT may be considered with close monitoring for VX-770 clinical changes in digestion and growth, which can significantly reduce cost and treatment burden on patients and families.

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