Minorities in US Ineligible for CFTR Modulators Due to Poorly Studied Mutations

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by Forest Ray PhD |

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Individuals with cystic fibrosis (CF) from racial and ethnic minority groups in the U.S. are twice as likely to be ineligible for disease-modifying therapies than white patients, because their mutations are not known to be suited to approved treatments, a study reports.

The resulting lack of treatment access exacerbates these groups’ already severe disease course and earlier mortality, its researchers wrote.

The study, “Cystic Fibrosis Patients of Minority Race and Ethnicity Less Likely Eligible for CFTR Modulators Based on CFTR Genotype,” was published in the journal Pediatric Pulmonology.

CF is caused by various mutations in the CFTR gene that result in defects in the CFTR protein, preventing it from allowing ions and water to flow through the cell. This causes a thick mucus to build up in the lungs and other organs.

CFTR modulators are compounds that help to restore healthy CFTR function by targeting specific mutations. The specificity of these mutations, however, means that each modulator only works for patients with those specified mutations.

“Overall, approximately 90% of patients with CF have CFTR mutations that are currently FDA-approved for CFTR modulators, although this may not be true for all groups within the CF population,” the researchers wrote.

CFTR mutation frequency varies by ancestry, which is different from but related to demographic racial and ethnic group,” they added, noting that “eligibility for CFTR modulator therapy has not been previously reported by race and ethnicity.”

To address this gap, Megan McGarry, MD, with the University of California at San Francisco, and Susanna McColley, MD, with Northwestern University examined records from the 2018 CF Foundation Patient Registry to cross-reference patients’ CFTR mutations with U.S. Census-defined racial and ethnic groups.

The team analyzed records for 25,918 (84.2%) non-Hispanic white CF patients, 2,763 (9%) Hispanic patients, 1,351 (4.4%) Black patients, and 743 (2.4%) patients of other races. Because of the small number of people in the last group, they were combined and analyzed together.

Overall, 92.4% of non‐Hispanic white patients, 75.6% of Hispanic patients, 69.7% of Black patients, and 80.5% of other race patients were deemed eligible for at least one CFTR modulator.

The approved CFTR modulators considered in the analysis were: Kalydeco (ivacaftor), lumacaftor (VX-809), tezacaftor (VX-661), and elexacaftor (VX-445). Several of these treatments, all by Vertex Pharmaceuticals, are prescribed in combination.

In general, Black patients based on their CFTR mutations were least likely to be eligible for any of these medications. In contrast, for each CFTR modulator, non‐Hispanic white patients were most likely to be eligible.

Black (19.2%), Hispanic (24%), and other race (31.6%) groups showed the lowest percentage of patients with a CFTR genotype eligible for ivacaftor/lumacaftor (sold as Orkambi) compared with non-Hispanic white patients (47.9%).

The same was true for ivacaftor/tezacaftor (sold as Symdeko), for which 21.5% of Black patients were eligible, along with 29.8% of Hispanics, and 35.96% of other races, compared with 53.9% of non-Hispanic white patients.

The smallest disparity existed in eligibility for Kalydeco. Here, 11.4% of Black patients were eligible, and between 16.3% and 17.2% among all other groups.

Kalydeco, the study also noted, “is the only modulator approved for multiple rare mutations in the United States; approval for many of these mutations was granted based on in-vitro [lab dish study] evaluation alone.”

For the triple combination sold as Trikafta (elexacaftor/tezacaftor/ivacaftor), a total of 62.5% of Black patients showed eligibility, along with 67.3% of Hispanics, and 71.9% of other races. About 88% of non-Hispanic white patients did as well.

The most common CFTR mutation causing CF is known as delF508. People with two copies — called the delF508/delF508 genotype — qualify for three of the Vertex combinations: Orkambi, Symdeko, and Trikafta.

Registry data showed that more non-Hispanic white CF patients (47.9%) had this delF508 genotype than did Black people (19.2%), Hispanics (24%), or patients of the other racial groups (31.6%).

“Patients of a minority group were over twice as likely to have CFTR mutations that were not classified compared to non-Hispanic white patients,” the researchers concluded. “Patients without two known CFTR mutations cannot qualify for CFTR modulators.”

Eligibility for CFTR modulators also affected lung function, as measured by forced expiratory volume in one second (FEV1). Patients across groups who were ineligible for these CFTR modulators had the lowest FEV1 measures, meaning worse lung function.

“The lowest pulmonary function in the cohort was seen in non‐Hispanic white, Black/African‐American, and Hispanic patients not eligible for CFTR modulators,” the researchers wrote.

“These findings are alarming,” the team added, “as patients of a minority group already suffer a greater burden from CF compared to non-Hispanic white patients. This disparity in eligibility for CFTR modulators will widen disparities in morbidity and mortality.”

The researchers went on to note that besides being less eligible for CFTR modulator therapy, minorities tend to be under-represented in pharmaceutical trials. This issue, they said, will grow as the CF community’s demographics continue to change.

“CFTR modulator therapy for CF is a landmark example of the benefits of precision medicine,” the team wrote, but “until CFTR modulators can benefit patients equally, continued focus on developing genotype-neutral treatments for CF are essential.”


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