Orkambi of Definite Benefit But Risk Evident in Patients Who Can’t Tolerate It, French Study Finds

Treatment with Orkambi (lumacaftor/ivacaftor) can effectively improve overall health in adolescents and adults with cystic fibrosis, but its use can be risky for those who do not tolerate the therapy, a study of its use in almost 850 CF patients across France found.

More than 18% of these patients discontinued Orkambi due to respiratory and other side effects, compared to about 5% in clinical trials that led to its approval.

The study, “Real-Life Safety and Effectiveness of Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis,” was published in the American Journal of Respiratory and Critical Care Medicine.

Orkambi was developed by Vertex Pharmaceuticals to address the underlying cause of CF, and restore the activity of the CFTR protein.

Its effectiveness was demonstrated in several clinical trials in patients 12 and older who carried two copies (one inherited from each parent) of the F508del CFTR mutation – the most common cause of CF.

Supported by these results, both the U.S. Food and Drug Administration and the European Medicines Agency approved the use of Orkambi in 2015. Since then, its use has been expanded to include younger groups of children affected by CF.

Recent data collected in real-world assessments of Orkambi’s use, which found higher-than-expected treatment discontinuations, have raised some doubts about its benefits across CF patients.

“[T]he magnitude of effect on percent predicted forced expiratory volume in 1 sec (ppFEV1), the small improvement in nutritional status and the limited use of concomitant treatment for reducing exacerbations have cast doubt on the clinical benefits associated with lumacaftor-ivacaftor,” the study notes.

Researchers in France reviewed health outcomes in 845 CF patients — 292 teenagers and 553 adults — treated with Orkambi and followed for one year at 47 CF centers across that country. All started with the treatment between Jan. 1 and Dec. 31, 2016, and were examined at initiation and again one, three, six and 12 months later. Their weight and ppFEV1 — the amount of air forcibly exhaled in one second — were among changes recorded.

Over that year, 641 patients (75.6%) continued with Orkambi, while 39 (4.6%) stopped then restarted with it (intermittent treatment), and 154 (18.2%) stopped it completely (discontinued treatment).

More adults discontinued using Orkambi (23.5%) than did adolescents (8.2%). The two main reasons for fully or temporarily stopping were respiratory difficulties and non-respiratory issues like digestive problems, fatigue and headache.

Analysis found better lung function, as measured by ppFEV1, with an “absolute change” of 2.7% in ppFEV1 recorded, among patients who continued to use Orkambi

Better lung health was noted in both continuous-use patients (a 3.67% improvement in ppFEV1), and those stopped but returned to the therapy (a 2.36% improvement). But in patients who discontinued Orkambi’s use because of adverse reactions a decline in lung function was seen, with a worsening in ppFEV1 values — a mean decreased of 1.36% — at 12 months.

Weight gain was found to be steady and regular in continuous-use patients, and more slow in those who stopped and restarted, reaching a mean gain of 2.1 kg (4.6 lbs) after one year overall. No weight gain was seen in adults who completely stopped taking Orkambi, but a limited gain was seen in adolescents who discontinued its use.

Orkambi was also found to limit the need for additional therapies, as seen by reductions in the number of intravenous antibiotic treatments — a 35% reduction overall — that patients were taking after starting on Orkambi compared to before its use. This reduction was particularly notable in those on continuous treatment, and not really evident in those who stopped permanently.

Repeat disease flares requiring antibiotic treatment in the year before Orkambi use, and “severe respiratory disease” as seen in a starting ppFEV1 of less than 40%, were “independent” indicators of likely treatment discontinuation, the study noted.

“For patients who are able to continue lumacaftor-ivacaftor [Orkambi], there is clinically meaningful improvement in respiratory disease and nutritional status,” Pierre-Régis Burgel, MD, PhD, lead author of the study, said in a press release.

However, the team emphasized, “adults who discontinued lumacaftor-ivacaftor, often due to adverse events, were found at high risk of clinical deterioration.”

Nearly 1 in 5 patients (18.2%) could not tolerate Orkambi because of side effects experienced. This rate, the researchers said, is higher than that found in Orkambi clinical trials, in which less than 5% of patients discontinued treatment. They attributed this finding to people in this study having poorer lung function (a ppFEV1 of 40% or less) and overall health (as seen in antibiotic use) at its start than is seen in CF patients considered eligible for a clinical trial.

“Our findings provide a useful complement to randomized clinical trials in which participants were selected based on very strict criteria,” Burgel said.

These data “highlighted the importance of large real-life studies to assess the safety and effectiveness profile of novel therapies because patients treated in post-marketing studies often show reduced lung function and less stable disease characterized by higher rates of exacerbations than those included in clinical trials,” the researchers wrote.

They suggested that eligible CF patients with severe disease and unable to tolerate Orkambi “be granted faster access to [Symdeko] tezacaftor-ivacaftor (which is unavailable in France at this time) or to triple combination therapy (once it becomes available).”

Additional studies in real-world settings are needed to further explore the efficacy and safety of Orkambi and other CFTR modulators, they concluded.