Adults using Kalydeco, Trikafta show lung function, nutrition gains

Real-world study at Australian CF center finds Orkambi lacking reported benefits

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Adults using Kalydeco (ivacaftor) or Trikafta (ivacaftor/tezacaftor/elexacaftor) to treat their cystic fibrosis (CF) showed gains in lung function and nutritional status, according to a real-world, observational study in Australia.

In contrast, no significant improvements in lung function were seen in adults or children with CF using Orkambi (ivacaftor/lumacaftor) and Symdeko (ivacaftor/tezacaftor). The rate of adverse side effects also was higher among patients on Orkambi.

This study “adds weight to the existing CFTR modulator literature,” the researchers wrote, adding that the results of Orkambi and Symdeko “are less encouraging than those seen in clinical trials.”

The study, “Real world outcomes of CFTR modulator therapy in Australian adults and children,” was published in the journal Pulmonary Pharmacology and Therapeutics.

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3D MRI of lungs seen to help measure Trikafta response in study

Changes reported in 163 CF patients starting on various CFTR modulators

CF is caused by inherited defects in the production or function of the CFTR protein that lead to the buildup of thick and sticky mucus, particularly in the lungs, damaging tissue.

CFTR modulators are a class of therapies that work to improve the functionality of the CFTR protein in people with specific disease-causing mutations. Trikafta, Symdeko, Orkambi and Kalydeco, all marketed by Vertex Pharmaceuticals, belong to this group.

To better understand patient response to CFTR modulators and treatment side effects, researchers largely at Monash Children’s Hospital examined the records of 252 patients, 119 children and 133 adults, being followed at its CF center from May 2012, when modulator use began, until September 2020.

Main study goals were to assess the real-world impact of CFTR modulators on lung function and nutritional status, as well as changes in the number of hospital days.

Their analyses covered 163 CF patients (103 adults and 60 children) with clinical data collected at the start of treatment (baseline measures) and again every six months for up to two years.

A total of 129 patients — 74 adults and 55 children — were treated with at least one CFTR modulator during those years. Three people received three different CFTR modulators, and 31 at least two.

Most of the 60 children were treated with Orkambi (49 children), followed by Symdeko (six children), and Kalydeco (five children). No child was treated with Trikafta, a triple combination CFTR modulator that was not commercially available in Australia at the time of this study.

Among adults, 36 at some point received Orkambi, 32 Symdeko, and 26 were using Kalydeco. Seven adults with severe lung disease were treated with Trikafta through compassionate access programs.

Lung function significantly improved in adults using Kalydeco or Trikafta. An increase in percentage predicted forced expiratory volume in 1 second (ppFEV1) — the amount of air forcibly exhaled in one second — was found in 4.73% of those on Kalydeco and 10.07% of those using Trikafta.

Further analysis found that Kalydeco’s significant lung function benefits in adults were evident only within six months of this treatment’s start. “It is possible that adherence reduces with time, as well as the natural history of decline in lung function in CF,” the researchers wrote, adding “our results are in keeping with the initial improvement noted in previous studies.”

Among children, a 5.7% increase in ppFEV1 accompanied Kalydeco’s use, but “this group included only 5 patients and [the finding] was not statistically significant,” the researchers wrote.

No significant gains in lung function for adults or children were seen with either Orkambi or Symdeko, “although lung function was maintained over time,” the team noted.

Nutritional status was measured in adults via mean body mass index (BMI), a measure of body fat. In children, the BMI centile was used to compare BMI values to those of other children of the same age and sex.

BMI increased significantly in adults treated with Kalydeco, Orkambi, and Trikafta. Children treated with Orkambi also experienced significant improvements in their nutritional status, as evidence by a 5.84% increase in mean BMI centile. Improvements in this BMI measure were not evident among children on Symdeko.

No significant decreases were seen in days spent in the hospital.

Side effects led 25 patients to stop Orkambi, most switched to Symdeko

Over one-third of the patients using Orkambi (31 of 85, 36.5%) stopped the treatment, with 25 (81%) citing side effects as the reason. Orkambi had the highest rate of reported adverse events in this study, mostly in respiratory symptoms, including chest tightness, poorer lung function, wheezing, and cough.

Many of these side effects were mild, the researchers noted.

Of the 25 patients who stopped Orkambi, 23 (92%) changed to Symdeko and most (78.3%) tolerated this CFTR modulator.

“Whilst it is encouraging that lung function was maintained and nutritional parameters improved” with Orkambi’s use, “we did not demonstrate significant benefits as those seen in the initial trials,” the scientists wrote. “It is important to balance this small benefit with the potential adverse effects and added burden of treatment of these very expensive medications.”

No significant side effects were reported with Kalydeco’s use. Among the three patients who stopped this treatment, one did so due to pregnancy and two switched to Symdeko as it became available. None of the seven adults using Trikafta reported adverse effects, and all were continuing on the treatment when the study concluded.

All seven adults with severe lung disease and given  Trikafta showed “improvements in all parameters, and none had significant adverse effects,” the scientists wrote. “This is in line with the optimistic results seen in trials and around the world” for this triple-combination CFTR modulator.

Study findings, they added, “support ongoing use of [Kalydeco] for individuals with gating mutations, and transition to [Trikafta] once available.”

As Trikafta comes into wider use, real-world studies are needed to “determine if benefit and adverse events are consistent with those in clinical trials,” the researchers concluded.