Dual cystic fibrosis modulator therapy shows efficacy in four-year study

The combination modulator therapy tezacaftor (TEZ) and ivacaftor (IVA) for cystic fibrosis (CF) has demonstrated long-term safety and clinical benefit in a four-year trial.

The two CF modulators were assessed in patients 12 years and older. The participants tolerated the combination regimen over the course of the 96-week extension study. These patients had previously participated in a 120-day trial of the same combination.

In the recent study, the improvements achieved in the earlier trial were maintained. Therefore, the recent findings show tezacaftor plus ivacaftor could work long-term.

How do IVA and TEZ work?

The protein, known as the cystic fibrosis transmembrane regulator, or CFTR, controls the movement of water in the lung tissues. This allows for thin, free-flowing mucus production.

IVA was the first small molecule that targeted the CFTR protein directly. It binds to the CFTR protein at the cell surface, holds the gate of the channel open and keeps the protein channel open longer to allow for the movement of water and decrease the thickness of mucus. However, this drug is appropriate only for those persons who have a mutation that produces protein at the cell surface, which does not occur in patients with F508del.

TEZ, referred to as a corrector, binds to the CFTR protein and helps the protein to maintain shape so that it can function better. This is important for those with F508del, as it can increase the quantity of protein at the cell surface, where it can now be acted upon by IVA.

Ivacaftor – a breakthrough treatment

The approval of IVA in 2012 marked a breakthrough in treating the disease. It spawned a new class of CF drugs called modulators that addressed the underlying problem in CF rather than merely treating the sequelae of CF. When patients were treated with a combination of CF modulators targeting the structure and function of the protein, the effects were even greater.

While this clinical trial was still being conducted, a three-part regimen composed of TEZ/IVA plus elexacaftor (Trikafta) was approved in 2019. It has since become standard of care.

“With TEZ/IVA, you see about a two percent to three percent increase in lung function in patients with CF, whereas with the triple, we see more like a 15 percent improvement in the lung function,” stated Medical University of South Carolina (MUSC) researcher and lead author of the article, Dr Patrick Flume.

Significantly, Flume highlighted: “before 2019, I would have anywhere from four to six people in the hospital on any given day. Now I have zero to one.” Flume added: “When I started in this business, the median survival was in the mid-20s, but now it’s in the mid-50s.” 

In conclusion, the study’s findings show that the combination modulator therapy is safe and well-tolerated over the long term, indicating that two of the three drugs in the standard-of-care therapy can be used safely over time.

The results were published in the Journal of Cystic Fibrosis.