Kaftrio Opens to All CF Patients, 12 and Up, in EU With F508del Mutation

The European Commission (EC) agreed to expand use of Vertex’s Kaftrio (ivacaftor/tezacaftor/elexacaftor), in combination with Kalydeco (ivacaftor), to include cystic fibrosis (CF) patients 12 and older who have at least one copy of the CFTR gene with an F508del mutation.

The EC approved this combination therapy last year to treat people 12 and older whose CF is due to either two F508del mutations or one F508del mutation and one minimal function mutation in the CFTR gene. But that approval did not include those with one F508del mutation and one of several other types of mutations, who now will be covered under this label extension.

“This indication extension is important as CF patients in Europe with gating and residual function mutations will have access to KAFTRIO for the first time,” Reshma Kewalramani, MD, president and CEO of Vertex Pharmaceuticals, said in a press release.

“It is welcome news for the CF community that the European regulatory authority has extended the licensed indications for this therapy based on the latest trial results which means that additional patients will gain access to this medication,” added Peter Barry, MD, with The University of Manchester.

Due to long-term reimbursement agreements with the Republic of Ireland, Northern Ireland, Denmark, and Luxembourg, as well as provisions for access in Germany and elsewhere, eligible patients in these countries will soon have access to the therapy.

Every person inherits two copies of the gene CFTR (cystic fibrosis transmembrane conductance regulator), one from each biological parent. But mutations leave the gene unable to produce a functional CFTR protein. Normally, this protein functions like a “gate” on the surface of cells, helping to regulate the flow of ions and water in and out of cells. The exact effects of a mutation on the CFTR protein depend on the specific type of mutation.

F508del is the most common disease-causing CFTR mutation, with at least one such mutation estimated to be found in nine of every 10 CF patients.

Kaftrio, marketed as Trikafta in the U.S. and elsewhere, contains a combination of three CFTR modulators, which are medications that help the CFTR protein to work more effectively. Kaftrio is given in the EU in combination with Kalydeco, another CFTR modulator developed and marketed by Vertex.

The EC’s decision to approve the therapy’s label expansion follows a positive opinion from the Committee for Medicinal Products for Human Use, a part of the European Medicines Agency.

The extension is supported by data from a global Phase 3 clinical trial (NCT04058353) sponsored by Vertex, which enrolled 271 patients ages 12 and older. All had one F508del mutation, and one other mutation: either a gating mutation (mutations that cause the CFTR “gate” to become “stuck closed”), or a residual function mutation — meaning not enough of working CFTR protein makes it to a cell’s surface.

Trial results demonstrated that treatment with Kaftrio led to statistically significant improvements in lung function, as well as significantly lower sweat chloride levels.

“In clinical trials [Kaftrio plus Kalydeco] showed positive significant results in people with cystic fibrosis ages 12 years and older who have at least one copy of the most common gene mutation (F508del) with the latest results showing clinical benefits in individuals who have an additional ‘gating’ (F/G) or ‘residual function’ (F/RF) gene mutation,” Barry said.

Added Kewalramani: “We look forward to working with health authorities and governments to ensure that all eligible patients who can benefit from this medicine have access as soon as possible.”

As Trikafta, this triple combination therapy is approved in the U.S. and Australia for CF patients ages 12 and older who have at least one copy of the F508del mutation in the CFTR gene, regardless of the other mutation type.