Trikafta is a next-generation combination of three cystic fibrosis (CF) medications: elexacaftortezacaftor, and ivacaftor. Developed by Vertex Pharmaceuticals, the combination therapy was approved by the U.S. Food and Drug Administration (FDA) to treat CF patients 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, which provides instructions for cells to make the CFTR protein. CFTR is a transporter protein that controls the movement of charged ions across the membrane of cells. Mutations in CFTR mean that salts are not trafficked normally across cell membranes, which 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 a truncated or shorter-than-normal CFTR protein being made. Truncated CFTR cannot be shuttled to the surface of the cell as efficiently as normal CFTR where it normally exerts its activity, meaning that ion transport is impaired in cells.

How does Trikafta work?

Trikafta is a CFTR modulator therapy; 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 so that more of the protein can be shuttled to the cell membrane instead of being degraded. Ivacaftor (also marketed independently as Kalydeco) is a potentiator — it binds to the CFTR protein and holds the channel open so that more salt is trafficked through it.

In this combination of all three therapies, more CFTR protein reaches the cell membrane and the protein that reaches the membrane is more active and functional.

Trikafta in clinical trials

Two components of Trikafta have already been assessed in CF patients and approved either a monotherapy or as a dual combination therapy: Kalydeco (ivacaftor) was approved by the FDA in 2012, Orkambi (a combination of lumacaftor and ivacaftor) in 2015, and Symdeko (a combination of tezacaftor/ivacaftor) in 2018; it is known as Symkevi in the European Union.

Trikafta was approved based on the results of two Phase 3 clinical trials: AURORA F/MF (NCT03525444) in 403 CF patients with one F508del mutation and one minimal function mutation.  This trial tested Trikafta against placebo for 24 weeks.

AURORA F/F (NCT03525548) included 107 patients with two F508del mutations given 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 13.8 percentage points for this group in AURORA F/MF, and by 10 percentage points for those in AURORA F/F.

The treatment was generally well-tolerated by patients in these studies.


Last updated: Oct. 26, 2019


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