CF patients using Kaftrio/Trikafta may enjoy ‘near normal’ lifespans

Simulation UK study also links greatest gains to starting therapy at younger ages

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Use of Kaftrio (elexacaftor/tezacaftor/ivacaftor) may help people with cystic fibrosis (CF) and the F508del mutation in both CFTR gene copies live to a median age of 71.6 and possibly longer if treatment is started in adolescence, a U.K.-based study reported.

In a scenario where treatment with Kaftrio — sold as Trikafta in the U.S. — is initiated between 12 and 17 years old, a patient’s median estimated lifespan is 82.5 years. That’s 45.4 years longer than estimates for CF patients on best supportive care alone.

That age also is close to life expectancy for the general U.K. population, which is about 83 years old. Early treatment with this triple-combination therapy can help people with CF “achieve near-normal life expectancy,” the researchers wrote.

The study, “Elexacaftor/tezacaftor/ivacaftor projected survival and long-term health outcomes in people with cystic fibrosis homozygous for F508del,” was published in the Journal of Cystic Fibrosis.

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Survival probability with Kaftrio (Trikafta) versus other treatment approaches

CF is caused by mutations in a gene that provides instructions for making the CFTR protein, which helps control the flow of salt and water in and out of cells. A faulty protein leads to a thick, sticky mucus that builds in various organs.

Vertex Pharmaceuticals’ Kaftrio, as the therapy is known in the European Union and U.K., is a combination of three different medications shown to improve lung function, enhance health-related quality of life, and lower the frequency of pulmonary exacerbations, or the acute worsening of the disease’s respiratory symptoms.

“The impact of this treatment on lifetime clinical outcomes and survival, however, has yet to be assessed,” the researchers wrote.

To determine estimates of such benefits with Kaftrio as opposed to other treatment options, scientists used computers to run a microsimulation, a model that mimics the effects of treatment on individual members of the CF population.

They drew on data of disease progression from articles published in scientific journals. Data on how well each treatment worked came from Phase 3 clinical trials and extrapolations of clinical information.

The microsimulation was conducted for CF patients, ages 12 and older, who carried two copies of F508del — the most common CF-causing mutation — and were on treatment with Kaftrio, Symkevi (tezacaftor/ivacaftor; available as Symdeko in the U.S.), Orkambi (lumacaftor/ivacaftor), or best supportive care alone.

The study was supported by Vertex, which also markets Symkevi/Symdeko and Okrambi, and four of its five researchers are Vertex employees.

An initial “survival probability was assigned to each simulated individual based on age-specific mortality derived from the 2008 UK Cystic Fibrosis Registry,” representing expected survival in the absence of a CFTR modulator treatment like Kaftrio, a disease-modifying therapy, the researchers wrote.

Median projected survival for those on Kaftrio was 71.6 years. This was an increase of 23.2 years relative to estimates for patients using Symkevi, 26.2 years versus Orkambi, and an increase of 33.5 years relative to patients on best supportive care alone.

In addition, it was estimated that people on Kaftrio would experience better lung function across greater spans of life than those on best supportive care (50.5% vs. 7% of life-years with mild disease) and, subsequently, less time with severe lung disease (0.8% vs. 46.8% of life-years). Life-years were defined as the estimated years of life assigned with a given treatment in these simulations.

While living longer, people on Kaftrio also were projected to have 13 fewer pulmonary exacerbations over a lifetime than those on best supportive care, the scientists reported.

Greater life benefits projected when treatment started in teenage years

Likewise, simulations pointed to Kaftrio’s use increasing by up to five times the proportion of life spent with mild lung disease compared with Symkevi or Orkambi treatment, and reducing the annual rate of pulmonary exacerbations by nearly 75%.

Taking Kaftrio also could lower the need for a lung transplant relative to best supportive care (0.1% vs. 9.6%), and roughly double the time to a transplant procedure among those needing it (24.5  vs. 12 years).

“Because lung function has been identified as a key predictor of long-term survival, the unprecedented and significant improvements demonstrated in the clinical trial program … suggest that [Kaftrio] treatment may provide a lifetime therapeutic benefit” for patients, the scientists wrote.

The greatest survival benefit relative to those on best supportive care was observed when patients started on Kaftrio at a mean age of 14.9, the study reported.

Relative to best supported care alone, the median projected survival was 82.5 years for those who started treatment at ages 12 to 17. Among simulation patients started with Kaftrio between 18 and 24 years old, their anticipated lifespan was  77.9 years; it was  62.2 years for those who beginning treatment at age 25 or older.

“These results contribute to accumulating evidence that early intervention in [people with CF] is associated with better outcomes later in life,” the researchers wrote, adding they “support the potential transformative effects on the health and well-being” of patients on this next-generation triple combination therapy.