CF Therapy’s Effectiveness With Rare Mutations Can Be Determined in Lab

An ex vivo technique using nasal epithelial cells from a young girl carrying a rare mutation profile for cystic fibrosis (CF) was successful at predicting the efficacy of an approved CF therapy, a case report shows.

Researchers first tested the effectiveness of Orkambi (lumacaftor/ivacaftor) on the child’s own cells in the laboratory — a process referred to as ex vivo, meaning the cells were taken from a living organism and analyzed outside the body. As predicted by the results of this work, the girl’s health improved significantly in response to this treatment.

The report, “Ex vivo model predicted in vivo efficacy of CFTR modulator therapy in a child with rare genotype,” was published in the journal Molecular Genetics & Genomic Medicine.

CF is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which encodes a protein responsible for controlling the flow of chloride ions in and out of cells. Treatment options depend on the type of mutations the patient has. CFTR potentiators, such as Kalydeco (ivacaftor), help the defective CFTR protein to work better, restoring the flow of ions; other therapies such as lumacaftor are CFTR correctors that help to increase the amount of CFTR protein, avoiding its degradation and allowing it to reach the cell surface.

Previous studies showed that about 45% of CF patients carry a F508del mutation on one chromosome and another, less common mutation on the other (more than 1,700 CFTR mutations are known). Whether therapy will be effective in patients with rare mutations is difficult to determine, as those with rare genetic profiles are generally not included in clinical trials.

This failing led a team of researchers in Italy to create a new way of testing the responsiveness of CF therapies before giving them to a patient.

The team had previously isolated cells from the nasal mucosa, the mucous membrane lining nasal cavities, of a girl carrying an F508del mutation (p.Phe508del) plus a rare mutation called p.Gly970Asp. They then treated the cells with Orkambi (marketed by Vertex Pharmaceuticals). Despite a lack of evidence that p.Gly970Asp would be responsive to Orkambi, ex vivo experiments showed the therapy effective in restoring CFTR protein function.

Researchers now report on outcomes after the girl’s treatment with Orkambi.

Sweat chloride, lung clearance index (LCI), fecal elastase, and body mass index (BMI; a measure of weight) were evaluated in the 4-year-old girl before treatment with Orkambi. LCI and fecal elastase are markers of lung and pancreatic function, respectively. The same parameters were measured at different time points during follow-up. The girl received Orkambi (lumacaftor 200 mg/ivacaftor 250 mg, given every 12 hours) for nine months.

No adverse reactions or changes in liver function were reported during her treatment.

After nine months, almost all measures analyzed had improved. Sweat chloride values decreased from 114 millimoles per liter (mmol/L) to 38 mmol/L, LCI dropped by around 21.6%, and fecal elastase increased from 139 to 469 micrograms/gram. BMI remained unchanged during follow-up. No respiratory flares or other CF symptoms were reported.

“The child is very well, has not had any episode of respiratory exacerbation, nor CF related manifestations. She is continuing regular respiratory physiotherapy,” the researchers wrote.

Overall, “the present case demonstrates that drug response obtained on nasal epithelial cells correlates with changes in vivo [inside a living body] therapeutic endpoints, such as LCI and [sweat chloride] values, confirming the efficacy of ex vivo testing on nasal epithelial cells as a predictor of clinical efficacy of novel drugs,” the team wrote.

However, the researchers noted that special equipment is needed to carry out ex vivo testing, which may not be available in a clinic.

Thus, “it would be appropriate to create a network of ex vivo assay laboratories, with standardized analysis protocols, to provide fast and accurate results to CF clinical centers dealing with patients with rare mutations at the national and international levels,” the team suggested.