In children with cystic fibrosis (CF) and homozygous for the F508 mutation, the combination of lumacaftor and ivacaftor appears generally safe, and biomarker data suggest its efficacy, according to results from a new open-label phase 3 trial.
In September, the Food and Drug Administration approved lumacaftor/ivacaftor for patients aged 1 years and above. Waiting in the wings is the triple combination of elexacaftor, tezacaftor, and ivacaftor (ETI), which is available for patients with at least one copy of the F508 mutation aged 6 and over. ETI is also being tested in younger patients.
One driving factor for early treatment is countering the malnutrition that can occur among CF patients because of poor pancreatic insufficiency and chronic inflammation. “We’ve known for many years that (being) at or above average body weight and height predict better lung function. And we’ve known for quite a while that the height-for-age percentile, in preschool years, actually predicts your lung function later, and how long you’re going to live, so nutrition is incredibly important,” said study author Susanna McColley, MD, in an interview. It’s also difficult to use lung function tests in young children, since even adults can find them challenging, she said.
“FEV1 [forced expiratory volume in 1 second] is the strongest predictor of survival, and then nutrition is the highest predictor of FEV1, so that’s kind of the construct. They had similar improvement in the functional measures of their pancreas and in the measures of inflammation in the gut. I think the story here is that starting a modulator early has a likelihood to have positive health effects that go forward. We can’t say that from the data in the paper. It’s a 24-week study, but looking at the pancreatic and intestinal functioning and also the fact that there was a decrease in sweat chloride is important,” said Dr. McColley, who is a professor of pediatrics in pulmonary and sleep medicine at Northwestern University, Chicago.
The study adds more evidence that earlier treatment in CF may lead to better outcomes, but the digestive improvements are an overlooked factor, according to Dr. McColley. “Even with early treatment, and even with pancreatic enzymes and supplements taken to digest food, it’s a huge burden. When they come in and say that digestion seems better, there is less bloating, things like that, these are the things that aren’t captured so much in the clinical trial data, but they’re meaningful to families,” she said.
Single-agent ivacaftor is available for children as young as 4 months, but is limited to patients with the G551D gating mutation. Most young children with CF can only be treated for symptoms.
The lack of new safety signals in the new study is reassuring, and the research presents some hope to young children who are not yet eligible to receive ETI, according to Carlos Milla, MD, who is a pediatric pulmonary physician at Stanford (Calif.) University. “We already know that the next version of this drug is much more efficacious, the triple-combination therapy. It’s a little bit like we’re falling behind when it comes to treating these young kids because we are offering right now what we know is a less effective drug as opposed to the ones that are available now down to age 6, and hopefully sometime soon down to age 2. It’s better [than] to have no treatment at all, so it’s a good start,” said Dr. Milla.
“I think this is a great bridge for babies while they’re waiting to grow up to be old enough to get [triple combination therapy] and will prevent some of the complications until they can get the even more highly effective therapy in the future,” said Jennifer Taylor-Cousar, MD, who was asked to comment on the study. Dr. Taylor-Cousar is codirector of the Adult CF Program at National Jewish Health, Denver.
She also noted that the therapy could rapidly become more important. Since the approval of elexacaftor/tezacaftor/ivacaftor in 2019, pregnancies in women with CF have increased markedly. There were 310 such pregnancies in 2019, and 675 in 2020 after the combination became generally available in November of 2019. Many of the resulting babies had false-negative CF diagnoses because the mother was taking the triple combination and the medication crossed the placenta and prevented disease progression. The drugs are present in breast milk, but when breastfeeding isn’t possible, newborns are left without a therapeutic option. “There was no approval for babies who had two copies of F508. This helps tremendously with that albeit small population, although I suspect it may grow larger over the upcoming years as we continue to see so many pregnancies in women with CF because they are so much healthier,” said Dr. Taylor-Cousar.
The study was a phase 3, open-label trial with a cohort aged 18-24 months (cohort 1, n = 14) and another aged 12-18 months (cohort 2, n = 46). Participants received a 15-day treatment with a dose based on weight at screening. Participants then underwent a 24-week treatment period with a dose determined by pharmacokinetic data collected during the initial treatment, the authors wrote in the American Journal of Respiratory and Critical Care Medicine.
A total of 95.7% of children experienced adverse events during the 24-week treatment period; 52.2% of events were mild, and 39.1% were moderate. The most frequent adverse events were cough (34.8%), infective exacerbation of CF (21.7%), pyrexia (21.7%), and vomiting (17.4%); 10.9% had elevations of alanine aminotransferase and/or aspartate aminotransferase higher than three times the upper limit of normal, and one (2.2%) had concentrations of both high enough that the study drug was discontinued.
There were significant reductions in sweat chloride concentration at week 24, suggesting strong efficacy (–29.1 mmol/L; 95% confidence interval, –34.8 to –23.4 mmol/L). Body mass, weight, and length remained normal during the 24-week treatment period, and there were trends towards improvement in biomarkers of pancreatic function and intestinal inflammation, including fecal elastase-1 (+73.1mcg/g; 95% CI, 29.40-116.80 mcg/g), serum immunoreactive trypsinogen (–295.50 mcg/g; 95% CI, –416.60 to –174.50 mcg/g), and fecal calprotectin (–106.63 mg/kg; 95% CI, –180.60 to –32.66 mg/kg)
Dr. McColley, Dr. Taylor-Cousar, and Dr. Milla have no relevant financial disclosures. The study was funded by Merck.