Benefits of Triple-Combo Trikafta for CF Mostly Due to Elexacaftor

The therapeutic benefits of the triple-combination medication Trikafta are mostly due to the effects of elexacaftor, a next-generation corrector of CFTR, the faulty protein in cystic fibrosis (CF), a study has found.

These findings suggest that new combinations with elexacaftor may be even more effective than Trikafta.

Trikafta, marketed by Vertex Pharmaceuticals and approved in the U.S. in 2019, combines elexacaftor, tezacaftor, and ivacaftor, and was designed to treat 90% of CF patients.

Notably, the combined effect of Trikafta was found to be insufficient to completely rescue CFTR defects associated with the F508del mutation — the most common CF-causing mutation and the current indication for this therapy.

While this partial efficacy may be sufficient to cause significant therapeutic benefits in CF patients carrying F508del mutations, the findings suggest that more potent corrector combinations can be achieved and may be desired for patients with worse CFTR defects, the researchers noted.

“Our study indicates that it is still possible to further improve mutant CFTR rescue with the development of corrector combinations having maximal effects on mutant CFTR structural and functional properties,” the investigators wrote.

The study, “Partial Rescue of F508del-CFTR Stability and Trafficking Defects by Double Corrector Treatment,” was published in the International Journal of Molecular Sciences.

CF is caused by mutations in both copies of the CFTR gene, resulting in the production of a faulty CFTR protein channel. CFTR normally controls the flow of water and salts through the membranes of cells that produce mucus, sweat, saliva, tears, and digestive enzymes. Thus, these mutations lead to the production of excessive mucus and salty sweat.

Trikafta is a CFTR modulator approved for CF patients ages 12 and older with either two F508del mutations or one F508del mutation and another CFTR mutation. In addition to the U.S., the therapy has been approved in Australia, and in the EU.

In Europe, the therapy is sold under the brand name Kaftrio.

The common CF-causing CFTR mutation leads to the production of a misfolded CFTR protein that, instead of being transported to the cell membrane where it exerts its action, is mainly targeted for degradation.

In addition, even if the mutant protein does reach the cell membrane, it has functional deficits, meaning that it does not allow the appropriate passage of water and salts.

Trikafta combines two CFTR correctors with complementary mechanisms of action — specifically elexacaftor and tezacaftor — and ivacaftor, a CFTR potentiator. Notably, ivacaftor also is marketed separately as Kalydeco.

The CFTR correctors bind to the faulty protein to help it fold correctly, allowing more protein to shuttle to the cell membrane. Meanwhile, ivacaftor works by holding the CFTR channel open to facilitate water and salt passage.

This combination “appears to provide a significant clinical benefit with respect to previous treatments,” without the second CFTR corrector, elexacaftor, the researchers wrote.

Those treatments consist of a combination of ivacaftor with either tezacaftor (a combo therapy sold as Symdeko or Symkevi) or lumacaftor — a combination treatment sold as Orkambi.

A team of researchers in Italy have now assessed the rescue effects of combining elexacaftor with either tezacaftor or lumacaftor in lab-grown cells genetically modified to have the F508del mutation or derived from CF patients carrying that mutation.

Notably, either tezacaftor or lumacaftor is thought to improve CFTR folding through similar mechanisms, complementary to those of elexacaftor. A combination of CFTR correctors with complementary mechanisms is expected to promote even greater benefits.

The results showed that elexacaftor alone was superior to both tezacaftor and lumacaftor at correcting CFTR folding and preventing its degradation. While these beneficial effects were more pronounced when elexacaftor was combined with either one of the other CFTR correctors, a substantial amount of mutant CFTR was still degraded, the researchers found.

In addition, neither combination fully restored the mutant protein’s stability, trafficking to the cell membrane, and gating function, the results showed.

When added to the channel potentiator, ivacaftor, the elexacaftor-lumacaftor combination was generally more effective in restoring CFTR’s function than both the elexacaftor-tezacaftor combo and elexacaftor alone.

Notably, combining elexacaftor with lumacaftor restored the mutant CFTR’s function to 66% of normal levels.

This partial restoration may still be clinically relevant, since “a rescue of 50–70% … resembles, in theory, the condition of F508del carriers, who are notoriously devoid of symptoms,” the researchers wrote. F508del carriers refer to people carrying a F508del mutation in one CFTR gene copy.

In addition, in most of the team’s experiments, the effects of the elexacaftor-tezacaftor combination were generally similar to those of elexacaftor alone. Those findings highlight that the folding-associated benefits of Trikafta may be attributed to elexacaftor alone.

Interestingly, the team also found that combining elexacaftor with lumacaftor partially restored CFTR’s gating function, even in the absence of ivacaftor. Given that elexacaftor showed only 28% of potentiator activity relative to ivacaftor, the researchers hypothesized that the structural stabilization provided by the CFTR corrector may itself improve CFTR gating.

Together, these findings highlighted that, “despite a high level of functional rescue by the triple combination (two correctors plus a potentiator), F508del-CFTR protein is still characterized by a significant level of instability and degradation,” the researchers wrote.

“This may be due to a suboptimal efficacy of either [lumacaftor] or [tezacaftor],” they added.

Also, while the data suggest that the partial functional rescue may be sufficient to promote significant benefits in CF patients carrying F508del mutations, “the development of even more active corrector combinations … may be desirable in the future, for example, to treat patients bearing mutations with an even more severe trafficking defect than that caused by the F508del mutation,” the scientists concluded.