Treatment with Orkambi significantly improves exercise tolerance in adult cystic fibrosis patients with severe disease as early as 4 weeks after treatment — as shown by results of the six-minute walk test (6MWT), a study found.
The findings support the use of exercise tolerance as an important clinical outcome for assessing treatments in CF patients with severe disease.
The study, “Lumacaftor/ Ivacaftor improves exercise tolerance in patients with Cystic Fibrosis and severe airflow obstruction,” was published in the journal BMC Pulmonary Medicine.
Orkambi, marketed by Vertex Pharmaceuticals, is an approved therapy for people with CF who have two copies of the F508del mutation — the most common disease-causing mutation — in the CFTR gene, which provides instructions for making a needed protein. The therapy is a combination of lumacaftor and ivacaftor.
Treatment with Orkambi for 24 weeks has been shown to result in 30 to 39% fewer pulmonary exacerbations — acute worsening of lung health and function — in CF patients ages 12 or older with two copies of the F508del mutation who had less severe disease. These patients still retained moderate lung function, as assessed by a percent predicted forced expiratory volume in one second (ppFEV1) of 40 to 80%.
However, whether Orkambi’s efficiency is maintained in adult CF patients carrying two copies of the F508del mutation with more severe disease — with ppFEV1 below 40% — is less clear.
The team therefore set out to investigate clinical parameters to find the most sensitive clinical measure capable of detecting change in people with severe CF following treatment with Orkambi. The trial (ACTRN12619000708156) took place in Australia.
Researchers assessed each patient’s response through spirometry tests, and compared the changes to those seen in exercise capacity tests, including the 6MWT, and other lung function tests. These included the nitrogen multi-breath washout test (MBW), the carbon monoxide gas transfer factor (DLCO), and lung volume changes assessed by plethysmography, a measurement of changes in the body’s volume.
The MBW measures the capacity and airflow of the lungs, while the DLCO measures the efficacy of the transfer of oxygen from the air to the blood in pulmonary blood vessels.
Spirometry, nitrogen MBW test, and 6MWT were performed on the day participants began Orkambi treatment (baseline), and again after four, 12, 24, and 52 weeks. Plethysmography and DLCO tests were performed at baseline, 24 weeks, and 52 weeks.
The trial included 10 adults with severe disease treated at the John Hunter Hospital CF centers, in Australia. The participants received Orkambi for 12 months through a compassionate access program provided by Vertex. Their results were compared to 10 matched historical controls from the same center, who had been observed over 12 months.
Results showed that treatment with Orkambi led to significant improvements in patient’s exercise tolerance as seen at 4 weeks. The distance walked in the 6MWT after 4 weeks increased by an average of 74 meters (243 feet), and continued to increase after one year to an average 118.1 meters (388 feet).
No significant improvement in FEV1 was observed until after week 24, though it was maintained at week 52. This represented a mean increase from baseline in FEV1 of 28.8% by 6 months, and 23.2% by 12 months. At 12 months, this represents a relatively small, though significantly different absolute mean increase in FEV1 — 0.398 L/min from baseline.
Forced vital capacity (FVC), another measure of lung function, also improved after 24 weeks of treatment, with this enhanced capacity being maintained at 52 weeks. The results represent a mean absolute increase in FVC of 0.492 L after 12 months.
No differences were detected in the MBW or DLCO.
After 12 months of treatment with Orkambi, the 6MWT increased by 118 meters, while it decreased by 61.3 meters in the control group. A decline in FEV1 also was seen in controls, while in the Orkambi group it improved.
Overall, the results show that treatment with Orkambi “results in a clinically significant improvement in 6MWT that was evident at 4 weeks and maintained at 52 weeks. Improvement in exercise tolerance is an important outcome to consider in those with more severe airways disease,” the researchers said.
The team also suggested that the 6MWT “provides a sensitive and early indicator of the functional impact of LUM/IVA [Orkambi] treatment in CF patients.”
It should “be considered more often in CF as an outcome measure in those with severe lung disease for both intervention trials, data registries, and regulatory authorities to assess response to treatments,” the researchers said.