Study IDs rare CFTR mutations that could respond to CFTR modulators

Research could help make treatment options available for more CF patients

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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In lab studies, researchers have identified rare mutations in the CFTR gene — which are the cause of cystic fibrosis (CF) — that are not currently eligible for CFTR modulator therapies but might be treatment responsive.

The researchers hope the findings will provide guidance to developer Vertex Pharmaceuticals when considering seeking label expansions that would make the treatments eligible for more types of mutations.

They also might inform doctors and patients about possibly seeking off-label trial periods of the medications where certain noneligible mutations exist.

The study, “In vitro modulator responsiveness of 655 CFTR variants found in people with cystic fibrosis,” was published in the Journal of Cystic Fibrosis.

CF is caused by mutations in the CFTR gene, leading to a lack of functional CFTR protein that regulates the movement of salt and water in and out of cells. In particular, CFTR regulates the movement of chloride, a negatively charged salt particle.

More than 4,000 different CFTR mutations have been reported in humans, but each has a different effect on the CFTR protein, and not all types of CFTR mutations cause the disease.

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850 CFTR mutations reported in study are rare, yet to be characterized

Among people with CF, more than 1,600 mutations have been reported to the Clinical and Functional Translation of CFTR (CFTR2) project. While the disease-causing effects have been confirmed for many, most of the remaining 850 are quite rare and have yet to be characterized, according to the authors.

The type of CFTR mutation has important implications for treatment. CFTR modulators like the triple combination therapy Trikafta (elexacaftor/tezacaftor/ivacaftor), developed by Vertex, work to boost CFTR functionality, substantially improving outcomes for CF patients. However, only people with certain types of mutations are eligible for them.

In 2017, the U.S. Food and Drug Administration (FDA) allowed the use of in vitro, or in-the-lab, studies for establishing whether a mutation might respond to treatment and can be added to CFTR modulator prescribing labels.

This can help make patients with rare mutations eligible for treatment, even if they were not represented in clinical trials. Based on these in vitro studies, the number of patients eligible for treatment has grown over the years. Currently, there are 178 mutations listed on Trikafta’s prescribing label in the U.S.

In their study, the scientists conducted additional in vitro experiments to characterize how rare CFTR variants might respond to CFTR modulators.

The researchers selected 655 mutations from the CFTR2 database that were known to be disease-causing, or were expected to be, 478 of which are not currently approved for any CFTR modulator therapy.

The CFTR gene containing each mutation was incorporated into rat cells then were exposed to the three CFTR modulators that make up Trikafta: elexacaftor, tezacaftor, and ivacaftor.

CFTR activity, reflected by the cells’ electrical activity associated with chloride movement, was measured before (baseline) and after treatment.

Around 83% of the variants exhibited an increase by 10% or more of what’s observed in cells with a normal CFTR gene (called wild-type) upon exposure to triple modulator treatment, which researchers said is the cut-off for estimating whether a variant might be amenable to CFTR modulator treatment.

376 variants not approved for Trikafta responded to treatment

Among variants already approved for Trikafta, 94% also were found to be responsive to CFTR modulators based on the cut-off in this current study. Moreover, 376 of the 478 variants that are not already approved for Trikafta demonstrated treatment responsiveness.

Among 342 variants with very low (less than 10%) CFTR function at baseline — generally a strong indicator they’re disease-causing — about two-thirds showed an improvement in CFTR functionality by at least 10% of wild-type. This included 152 variants not already approved for Trikafta treatment.

“This level of response is an indicator of probable clinical benefit for people harboring any of these variants,” the researchers wrote.

Another 224 variants that exhibited more than 10% of normal function at baseline also responded to treatment. Although such mutations are generally associated with milder disease, “there is no question that many people harboring these variants could still benefit from drug treatment,” the researchers wrote.

They cautioned, however, that the 10% cut-off should not be considered a rigid threshold for estimating a therapeutic effect.

For example, a relatively common mutation called N1303K barely missed this cut-off (a 9.4% improvement), and is not approved for any CFTR modulator. Yet, reports in multiple countries indicate a benefit of Trikafta for people with this mutation, according to the authors.

On the other hand, 10 mutations that are FDA-cleared for Trikafta failed to meet the threshold in this study.

Finally, the results also offer insight into variants that don’t respond to CFTR modulators and can inform the development of different treatment approaches for those patients, moving toward “the goal of developing a therapy for all [people with CF],” the researchers wrote.