(257) Rapid Health Decline in Young CFTR^G551D Ferrets After Discontinuation of CFTR Modulator

Background: In the highly effective modulator therapy (HEMT) era more CF women are having children. Prior ferret studies demonstrated CFTR modulator crossed the placental barrier and reached effective doses in breastmilk to improve the postnatal health of CFTR^G551D kits. This raises the clinically important questions of outcomes for continued HEMT dosing for nursing mothers, versus current clinical practice to discontinue HEMT.

Methods: We studied the consequences of sustained or discontinued HEMT on young CFTR^G551D ferrets. Pregnant ferrets initiated VX-770 dosing at Day 28 of gestation (2^nd trimester). Kits either remained on VX-770 or were discontinued at one month of age. CF ferrets removed from VX-770 were supplied with pancreatic enzymes. Liver and kidney function were evaluated by VetScan® Mammalian Liver and Kidney Profile and exocrine pancreatic functions was evaluated by elastase-1 levels in feces. Lung and pancreatic histopathology were scored on animals that required euthanasia due to poor health (here classified as mortality).

Results: Discontinuation of VX-770 in 1-month-old ferrets dramatically increased mortality in two phases. Phase I had 20% mortality and occurred at ~7 weeks of age, 3 weeks after stopping VX-770. Phase II had 35% mortality and occurred at ~12 weeks of age, 8 weeks after stopping VX-770. Phase I mortality had a rapid onset and occurred prior to weaning at Week 8. Phase II mortality was preceded by a transient loss in body weight post-weaning not observed in ferrets with continuous HEMT. No obvious histopathology was observed in the lungs of ferrets sacrificed following discontinued HEMT. Phase II mortality was associated with a significant elevation in plasma alanine aminotransferase (ALT) levels, suggestive of hepatic damage. Mortality was also associated with hypocalcemia and hypokalemia. By contrast, surviving CF animals that discontinued HEMT had normal plasma ALT, calcium, and potassium levels. After withdrawing of HEMT, fecal elastase-1 levels rapidly dropped to zero in all CF animals regardless of survival status. The pancreas presented with typical CF features, either macroscopically or histopathologically—fibrosis, cystic dilation of ducts, and extensive loss of exocrine parenchyma. For CF ferrets on HEMT the pancreas was largely histologically normal except for focal lobules with CF pancreatic features. CF ferrets withdrawn from HEMT present with higher histopathological scores of inflammation, cellular damage, fibro-adipose accumulation, and ductal obstruction than ferrets with continuous treatment and controls; ferrets with continuous HEMT treatment had score closer to wild-type controls.

Conclusions: These findings suggest beneficial effects of in utero and sustained postnatal HEMT on CF exocrine pancreatic function. Withdrawal of HEMT early in life led to a rapid decline in pancreatic and hepatic function, with the later being associated with increased mortality. Therefore, hepatic (liver) function tests may be useful in monitoring the health of CF infants born on, but removed from, HEMT after birth.

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