CFTR modulators improve pancreatic function, study finds
Pancreatic insufficiency is a common symptom in cystic fibrosis
CFTR modulator therapy was associated with increases in fecal levels of the pancreatic elastase-1 enzyme (FE-1), reflecting improved pancreatic function, among young cystic fibrosis (CF) patients in a recent study.
A small subset of patients achieved FE-1 levels high enough that they were no longer considered to have pancreatic insufficiency (PI), a common CF symptom in which the pancreas does not release enough of certain enzymes needed for digestion.
Patients who started CFTR modulators at an earlier age tended to see the greatest benefits on pancreatic function.
“This study supports FE-1 testing among children on any CFTR modulator therapy,” the researchers wrote. “However, additional prospective data is needed to further identify characteristics of whom should be tested and at what time interval after initiation of therapy.”
In CF, PI is associated with gastrointestinal symptoms and nutritional deficiencies. The FE-1 test is used to evaluate patients for PI in the clinic; if values are low it is an indicator of the condition.
Patients with PI are treated with pancreatic enzyme replacement therapy (PERT) prior to eating to help with digestion and nutrient absorption.
CFTR modulators connected to FE-1 increases
The use of CFTR modulator therapies, which broadly aim to increase function of the CFTR protein, has been associated with increases in FE-1 in clinical trials, indicating these therapies also could help improve pancreatic function.
To learn more about the real-world effects of CFTR modulators on pancreatic function, the scientists evaluated FE-1 levels in young CF patients receiving CFTR modulator therapy and PERT across three CF care centers in the U.S.
The analysis included 70 CF patients, who ranged from 1-20 years old at the time of FE-1 testing. Most were male (54%), white (94%), and had two copies of F508del, the most common CF-causing mutation in the CFTR gene (57%).
Among them, Trikafta (elexacaftor/tezacaftor/ivacaftor) was the most recently used modulator (78.6%), followed by Orkambi (lumacaftor/ivacaftor; 11.4%), Kalydeco (ivacaftor; 7%), and Symdeko (tezacaftor/ivacaftor; 2.9%).
Patients had been using any CFTR modulator for a mean of 40.3 months (more than three years) and their current modulator for 18.64 months (about 1.5 years), at the time of FE-1 testing.
Most participants had pancreatic insufficiency
Among 53 patients with FE-1 values obtained prior to starting CFTR modulator therapy, 52 had a value below 200 micrograms per gram (mcg/g), indicating PI.
For these 53 people, there was a significant increase in FE-1 from a median of 25 mcg/g before starting on modulator therapy (baseline), to 57 mcg/g at their most recent measurement post-therapy. Age was correlated negatively with the change in FE-1, with younger patients seeing a greater increase in FE-1 values on modulator therapy.
Although most of these 53 people experienced a FE-1 rise, the category of pancreatic function (severe PI, moderate PI, pancreatic sufficiency) did not change for 64%. Still, only two patients demonstrated a worsening of category, declining from moderate to severe PI.
Among all 70 patients who had post-modulator FE-1 testing, 15 (21%) achieved FE-1 values of 200 mcg/g or greater, indicating pancreatic sufficiency.
Participants who achieved PS were significantly younger when starting modulator therapy and had higher baseline FE-1 values than those who did not.
Among the 15 patients who achieved pancreatic sufficiency, 13 stopped PERT and one had a dose reduction. Ten people who stopped PERT also stopped their CF-specific vitamin supplements.
For 10 patients with multiple post-modulator tests, values tended to be consistent across measurements in most cases.
Overall, improvements in FE-1 were consistent with previous reports of Kalydeco and Orkambi, but greater than in reports of Trikafta, the researchers noted.
Because the time to post-modulator FE-1 measurements were not standardized, it is not known how soon after starting treatment those improvements might be observed with real-world use.
Moreover, it isn’t known how soon it’s appropriate to stop PERT once pancreatic sufficiency is achieved.
“Monitoring growth trends and fat-soluble vitamin levels for patients who discontinue PERT can also ensure that they are continuing to experience nutritional benefits,” the scientists noted.
The researchers also suggested that multiple FE-1 measurements over time are likely beneficial for monitoring patients, particularly for patients with values at or near the cut-off for pancreatic sufficiency.