Trikafta is a next-generation combination of three cystic fibrosis (CF) medications: elexacaftortezacaftor, and ivacaftor. Vertex Pharmaceuticals developed the combination therapy, which was approved by the U.S. Food and Drug Administration (FDA) in October 2019 to treat CF patients, 12 and older, with at least one F508del mutation, the most common CF-causing genetic defect seen in about 90% of all CF patients.

What is CF?

CF is a rare genetic disease caused by mutations in the CFTR gene. This gene provides instructions for cells to make the CFTR protein, which is a transporter protein that controls the movement of charged ions across cell membranes. Mutations in CFTR mean that salts cannot cross cell membranes normally. This leads to the build-up of thick, sticky mucus in different tissues and organs, especially the lungs and the digestive tract. In the lungs, this mucus can interfere with breathing and make patients more susceptible to respiratory infections.

The F508del mutation is the most common CF-causing mutation. It results in a premature stop signal in the genetic code, causing cells to make a truncated or shorter-than-normal CFTR protein that they cannot shuttle to the surface as efficiently as normal CFTR. The result is abnormal ion transport.

How does Trikafta work?

Trikafta is a CFTR modulator. It helps defective CFTR proteins work more effectively. Elexacaftor and tezacaftor work as correctors. They bind to the faulty CFTR protein and help it fold correctly. This way, cells can shuttle more of it to the membrane instead of degrading it. Ivacaftor (also marketed independently as Kalydeco) is a potentiator. It binds to the CFTR protein and holds the channel open so that more salt can pass through it.

In this combination of all three therapies, more CFTR protein reaches the cell membrane and these proteins are more active and functional.

Trikafta in clinical trials

Before Trikafta’s FDA approval, researchers had already assessed two components of the therapy in CF patients. The two components had been approved either as a monotherapy or as a dual combination therapy. The FDA approved Kalydeco in 2012, Orkambi (a combination of lumacaftor and ivacaftor) in 2015, and Symdeko (a combination of tezacaftor and ivacaftor, and called Symkevi in the European Union) in 2018.

The FDA approved Trikafta based on the results of two Phase 3 clinical trials: AURORA F/MF (NCT03525444) and AURORA F/F (NCT03525548). The first trial recruited 403 CF patients with one F508del mutation and one minimal function mutation. It tested the effect of Trikafta against a placebo for 24 weeks.

The second trial included 107 patients with two F508del mutations who received either Trikafta or Symdeko for four weeks. The primary outcome measure was the change in percent predicted forced expiratory volume in one second (ppFEV1, a measure of lung function). The secondary measure was the number of pulmonary exacerbations (periods of worsening respiratory symptoms).

Data from both studies showed significant improvements in lung function in Trikafta-treated patients, with ppFEV1 improving by an average of 14.3 percentage points for this group in AURORA F/MF, and by 10 percentage points for those in AURORA F/F. Patients generally tolerated the treatment well.

Other information

In Europe, the Committee for Medicinal Products for Human Use issued a positive opinion in June 2020 for Vertex’s Kaftrio — a similar triple combo of elexacaftor, tezacaftor, and ivacaftor — to be used in combination with Kalydeco as a treatment for CF patients 12 and older who have either two F508del mutations or one F508del mutation and one minimal function mutation in the CFTR gene.

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

Last updated: July 2, 2020


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