Long-term treatment with Trikafta leads to sustained improvements in lung function, easing of respiratory symptoms, and better nutritional status for people with cystic fibrosis (CF) who have at least one copy of the F508del mutation.
That’s according to new data presented by the therapy’s developer Vertex Pharmaceuticals at the European Cystic Fibrosis Society’s (ECFS) 46th European Cystic Fibrosis Conference, held this month in Vienna, Austria.
Trikafta (elexacaftor/tezacaftor/ivacaftor) is a triple-combination therapy of three CFTR modulators, molecules that can boost the functionality of the mutated CFTR protein in people with CF caused by specific mutations. It’s approved in the U.S. for patients as young as age 2 who have at least one copy of F508del, the most common CF-causing mutation, or another mutation that responds to the medicine based on experimental data.
The initial approval of Trikafta was supported by data from two Phase 3 clinical trials — AURORA F/F (NCT03525548) and AURORA F/MF (NCT03525444) — that tested it against a placebo in patients 12 and older. The former enrolled patients with two copies of the F508del mutation; the latter included patients with one F508del mutation and another minimal function mutation.
After the placebo-controlled part of these studies was over, the participants could enter an open-label extension study (NCT03525574) where all were given Trikafta and monitored for 192 weeks (just over 3.5 years). Of 506 people who entered the extension, 356 completed it.
Full findings from the extension were shared at the ECFS conference in a presentation titled, “Long-term Safety and Efficacy of Elexacaftor/Tezacaftor/Ivacaftor (ELX/TEZ/IVA) in People With Cystic Fibrosis (CF) and At Least One F508del Allele: An Open-Label, 192-Week Extension Study.”
Lung function was measured using percent predicted forced expiratory volume in one second (ppFEV1), a common measure of how much air a person can blow out in a forceful breath. Soon after patients started taking Trikafta (either in the original trials, or in the extension for those who got a placebo in the original trial), ppFEV1 values shot up, by more than 10 points on average.
Gains for CF patients with Trikafta
Results from the extension showed this increase was maintained over 192 weeks of treatment. With more than three years of Trikafta, the mean yearly rate of change in ppFEV1 was less than 0.05. In other words, average scores barely changed after the initial increase in lung function when patients started treatment.
The severity of respiratory symptoms, as measured by average scores on the CFQ-R Respiratory Domain Score, also sharply improved soon after Trikafta was started and they remained largely stable over more than three years of treatment. Sweat chloride levels, which are usually elevated in CF due to decreased CFTR protein function, decreased after Trikafta was started and remained so throughout the extension.
“Clinically meaningful improvements in lung function, respiratory symptoms, and CFTR function observed in the pivotal trials of [Trikafta] were maintained through this 192-week extension study,” the researchers said.
Body mass index (BMI), a ratio of weight to height, tended to increase sharply over the first six months or so of treatment. Over the extension’s remainder, mean BMI tended to increase more gradually, appearing to reach a steady state after about two or three years. People with CF usually have a lower than normal BMI due to digestive symptoms that make it hard to get nutrients from food.
All these findings were comparable in patients with one or two copies of the F508del mutation. Safety data from the extension study were generally in line with the known safety profile of Trikafta and few patients discontinued treatment due to side effects.
Real-world outcomes with Trikafta
In a separate Vertex-led presentation at the conference, researchers shared data from registry studies that are tracking real-world outcomes for people prescribed Trikafta. The presentation was titled, “Registry-Based Study of People With CF Treated With Elexacaftor/Tezacaftor/Ivacaftor (ELX/TEZ/IVA): Up to 2 Years of Real-World Outcome Data.”
An analysis of 9,381 people in a U.S. registry showed the mean ppFEV1 increased by 8.9 points two years after starting Trikafta. A similar mean increase of 10.5 points was seen among 1,107 patients in a German registry. In both registries, mean ppFEV1 scores had been gradually decreasing in the years before starting Trikafta, which is consistent with the typical CF progression where lung function worsens as damage accumulates.
Data from both registries indicated rates of hospitalizations and pulmonary exacerbations (sudden worsening of lung function, usually due to infection) decreased markedly after starting Trikafta. Rates of death or lung transplant also were markedly lower.
The number of patients testing positive for infectious agents that commonly cause problems in CF, such as Pseudomonas aeruginosa, also decreased.
“These data confirm the clinical benefits associated with [Trikafta] previously reported in clinical trials … and demonstrate improvement in key clinical outcomes among people treated with [Trikafta] under real-world conditions of use,” the researchers said.
“The data on Trikafta … demonstrate that this medicine improves lung function sustainably and in a real-world setting. It also reduces the risks of pulmonary exacerbation, death and lung transplant, and it is generally well tolerated,” Isabelle Fajac, MD, PhD, a professor at Université Paris Cité in France, said in a press release from Vertex.