Tezacaftor may inhibit making of ceramide, key in brain development

Medication is active ingredient in CF therapies Symdeko and Trikafta

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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In this illustration of brain growth, a tree is seen growing from the top of a human brain.

Tezacaftor, a medication used to treat cystic fibrosis (CF), may unexpectedly trap certain fats in the lungs, diverting their use as chemical raw material that the body converts into ceramides, which are needed for the brain to develop and respond to stress, according to a new study.

While the “impact of our findings is likely negligible or inexistent” for adults with CF, these results raise concerns about the safe use of tezacaftor — one of the active ingredients in Symdeko and Trikafta, both CF treatments marketed by Vertex Pharmaceuticals — in early stages of fetal and newborn development, particularly during pregnancy and breastfeeding.

“We believe that further investigations on tezacaftor should be envisaged, particularly for [its] use … during pregnancy, breastfeeding and in the early stages of development,” the team wrote.

The study’s findings, from work in patient-derived lung cells, are detailed in “Tezacaftor is a direct inhibitor of sphingolipid delta-4 desaturase enzyme (DEGS),” published in the Journal of Cystic Fibrosis by a team of researchers in Italy.”

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Further study needed on tezacaftor use during pregnancy, breastfeeding

In CF, mutations result in a flawed CFTR protein that causes mucus to become thick and stick to the airways, leading to trouble breathing. Tezacaftor works by correcting flaws in the CFTR protein so that it can fold into the correct shape.

Researchers already knew that a two-day treatment with Trikafta (elexacaftor/tezacaftor/ivacaftor), marketed as Kaftrio in Europe, causes dihydroceramides to build up in lab-grown human bronchial epithelial cells, a type of tightly packed cells that line the airways.

Dihydroceramides are a type of fats that is converted into ceramides by the action of an enzyme called delta-4 sphingolipid desaturase, or DEGS. Aside from forming part of the myelin sheath — a protective layer that surrounds nerve fibers — ceramides are involved in signaling and in the brain’s response to stress.

To better understand this off-target effect, the researchers grew bronchial epithelial cells from three patients carrying the F508del mutation — the most common genetic cause of CF — and three healthy individuals. The cells were treated with Trikafta for as long as 14 days, or about two weeks.

Treatment resulted in a “steady accumulation” of dihydroceramides inside cells, regardless of whether they had come from patients or healthy individuals. While the levels of DEGS remained unchanged, the researchers found that Trikafta inhibited the enzyme, slowing its ability to convert dihydroceramides into ceramides. Testing each of the ingredients individually revealed that tezacaftor alone caused this inhibition in a “concentration-dependent manner,” with higher doses causing greater inhibition.

From the standpoint of safe use of [Trikafta], particularly during pregnancy and in the early developmental stages, we believe that our evidences on DEGS [enzyme] inhibition should be further investigated.

When researchers treated healthy mice with Trikafta or a vehicle twice a day for 4.5 days, they found a slight increase in the levels of dihydroceramides in the brains of those treated with Trikafta, suggesting that the effects of tezacaftor on DEGS may not be limited to the lungs.

While many patients do experience lasting brain fog and memory loss as side effects of Trikafta, the researchers found that the impact on these results for CF adults was likely nonexistent. Earlier work suggested that titrating down Trikafta, or slowly reducing its dose, could help ease such type of side effects.

However, because a shortage of ceramides may impair the integrity of the myelin sheath and hinder how well the brain responds to stress, more research is needed “to define the best therapeutic strategy for each CF individual,” the researchers wrote.

This is particularly important during more sensitive stages of brain development, for example during fetal development in pregnancy, and during breastfeeding and early infancy.

“From the standpoint of safe use of [Trikafta], particularly during pregnancy and in the early developmental stages, we believe that our evidences on DEGS inhibition should be further investigated,” the researchers wrote, noting that “tezacaftor can cross … the placental … and pass through the mother’s milk.”