Clinical Trial Data Support Efficacy of Trikafta in People with One F508del Mutation and One Other Mutation

Trikafta (elexacaftor/tezacaftor/ivacaftor combo) improves lung function in cystic fibrosis (CF) patients who have one F508del mutation and either one gating mutation (F/G) or one residual function mutation (F/RF) in the CFTR gene, new clinical trial data show.

That finding was announced by Vertex Pharmaceuticals, which markets Trikafta.

“The results of this study demonstrate that the triple combination provides significant additional benefit compared to existing CFTR modulator therapy for F/G and F/RF patients and adds to the robust body of evidence supporting the benefit of this medicine for patients with at least one F508del mutation,” Carmen Bozic, MD, said in a press release. Bozic is executive vice president, global medicines development and medical affairs, and chief medical officer at Vertex.

CF is caused by mutations in the gene CFTR, which provides instructions to make a protein of the same name. Normally, the CFTR protein acts like a gated tunnel at the cell’s surface, regulating the passage of ions — most notably chloride — in and out of the cells.

CF-causing mutations lead to a lack of functional CFTR protein through different mechanisms that depend on the exact type of mutation. Some mutations lead to less CFTR protein being produced; others lead to the production of a misshapen protein that cannot function properly.

Trikafta is a combination of three CFTR modulators, which are therapies that broadly work by increasing the functionality of the CFTR protein. Trikafta was approved in 2019 by the U.S. Food and Drug Administration (FDA) for the treatment of CF in people 12 and older who have at least one F508del mutation. (Each person has two copies of the CFTR gene, one inherited from each biological parent.)

The F508del mutation is the most common CF-causing mutation, being present in about 90% of all people with CF. This mutation results in a misfolded CFTR protein.

The new data come from a global Phase 3 clinical trial (NCT04058353) with CF patients, age 12 and older, who had one F508del mutation and either one gating mutation (meaning the “gate” of the CFTR protein gets “stuck closed”) or one residual function mutation (meaning not enough functional CFTR protein gets to the cell’s surface). Both of these groups are covered by the current FDA approval.

All participants in the trial had a four-week run-in period of treatment with either ivacaftor or tezacaftor/ivacaftor, some of the CFTR modulators present in Trikafta. Following this run-in, 126 participants were randomized to continue on this same treatment for eight weeks (controls); the remaining 132 participants were treated with Trikafta.

The trial’s primary goal — its main measurement of effectiveness — was the change in percent predicted forced expiratory volume in one second (ppFEV₁) from the start of the trial through eight weeks of treatment. ppFEV₁ is a common assessment of lung function that essentially measures how much air a person can exhale in a second.

In participants treated with Trikafta, the average ppFEV₁ increased by 3.7 percentage points after eight weeks of treatment. This change was statistically significant.

A secondary effectiveness measurement was the change in sweat chloride levels. In Trikafta-treated participants, average sweat chloride levels decreased by 22.3 millimoles per liter (mmol/L) after eight weeks — a statistically significant change.

The safety profile of Trikafta in this trial was similar to that seen in previous clinical studies testing the therapy. The treatment was generally well-tolerated, with most reported adverse events (side effects) being mild or moderate in intensity. The most common adverse effect, in both Trikafta-treated and control participants, was headache.

Serious adverse events were reported in five (3.8%) Trikafta-treated participants and in 11 (8.7%) of controls.

According to Vertex, the results from this trial will be submitted to the FDA as part of a Trikafta post-marketing commitment.

The European Medicines Agency (EMA)’s Committee for Medicinal Products for Human Use (CHMP) recently issued a positive opinion for Trikafta (to be branded as Kaftrio in Europe in combination with Kalydeco) in people with CF, age 12 and older, who have either two F508del mutations or one F508del mutation and one minimal function mutation in the CFTR gene.

The CHMP opinion will be sent to the European Commission for a final decision on marketing authorization across the EU.

Vertex also will submit the new data from this trial to the EMA to support a potential expansion of the EU label.

“We look forward to submitting these data to the EMA in support of a potential indication expansion of the EU label following initial approval,” Bozic said.