One drug added 40 years to a life expectancy

Investigators of the Trikafta trials showed that correcting the folding of one faulty protein raised lung function within weeks and moved projected life expectancy past 80.

Three missing base pairs

Cystic fibrosis is caused by mutations in a single gene on chromosome 7. In 1989, Riordan and colleagues reported its identification in Science. The gene, named the cystic fibrosis transmembrane conductance regulator, or CFTR, encodes a protein with two similar halves, each with a membrane-spanning domain and a domain that binds ATP. In patients, the authors found a deletion of three base pairs that removes a single phenylalanine from the middle of the first ATP-binding domain. That mutation is F508del. The protein it produces misfolds and is degraded before it reaches the cell surface, where it should move chloride across the membrane. According to the pivotal trial published thirty years later, nearly 90 percent of patients carry at least one copy.

What survival looked like before

Stephenson and colleagues, using the U.S. and Canadian registries, reported in Annals of Internal Medicine in 2017 that the median age of survival in the United States over 2009 to 2013 was 40.6 years, against 50.9 in Canada. The U.S. Cystic Fibrosis Foundation's 2018 registry report gave a median predicted survival of 47.4 years for a child born in 2018, with a 95 percent confidence interval of 44.2 to 50.3, and 44.4 years for those born 2014 through 2018. The same report records that half of the 410 people with cystic fibrosis who died in 2018 were younger than 30.8, and that 13.9 percent of deaths occurred before age 20. The Foundation noted that its prediction assumed no further improvement in mortality and did not account for the potential of CFTR modulators.

Correcting the fold

The first modulator, ivacaftor, was approved in 2012, but it worked for a small set of mutations in which the protein reaches the surface and merely fails to open. F508del required something else: a corrector that helps the misfolded protein assemble and reach the membrane, paired with a potentiator that opens the channel once it is there. Two-drug combinations had produced modest gains. Elexacaftor was the third component, a second corrector acting at a different site.

Two trials in 2019

Middleton and colleagues reported the first phase 3 trial in the New England Journal of Medicine in November 2019. A total of 403 patients aged 12 or older, each carrying one F508del allele and one minimal-function allele, a genotype for which no modulator had worked, were randomized to elexacaftor, tezacaftor and ivacaftor or placebo for 24 weeks. The primary endpoint was the change in percent of predicted forced expiratory volume in one second, FEV1, a standard measure of lung function. At four weeks, FEV1 was 13.8 percentage points higher than placebo; through 24 weeks it was 14.3 points higher. The rate of pulmonary exacerbations was 63 percent lower. Sweat chloride, a direct measure of CFTR function, fell by 41.8 millimoles per litre relative to placebo. Patients' own respiratory symptom scores were 20.2 points higher on a 100-point scale. One percent discontinued for adverse events.

Heijerman and colleagues published the second trial in The Lancet the same month. It enrolled 113 people homozygous for F508del at 44 sites in four countries between August and December 2018. After a four-week run-in on tezacaftor and ivacaftor, 107 were randomized to add elexacaftor or continue the two-drug regimen for four weeks. Adding elexacaftor raised FEV1 by 10.0 points, with a confidence interval of 7.4 to 12.6, lowered sweat chloride by a further 45.1 millimoles per litre and raised respiratory symptom scores by 17.4 points. No participant discontinued.

Approval

On October 21, 2019, the U.S. Food and Drug Administration approved the combination as Trikafta for patients 12 years and older with at least one F508del mutation, a population the agency estimated at 90 percent of people with cystic fibrosis, or roughly 27,000 in the United States. The application received Priority Review along with Fast Track, Breakthrough Therapy and orphan drug designations. The safety assessment rested on the 510 patients in the two trials. The label warns of elevated liver enzymes, interactions with drugs that act on the CYP3A enzyme, and a risk of cataracts.

Where the number 80 comes from

No trial has measured survival on the triple combination; the trials lasted 24 and four weeks. The figure in this story's title comes from a model. Lopez and colleagues, in the Journal of Cystic Fibrosis in 2023, built a person-level microsimulation for people homozygous for F508del aged 12 and older, drawing disease progression from the literature and treatment effects from the phase 3 trials and their extrapolation. The model projected a median survival of 71.6 years on the triple combination, an increase of 33.5 years over best supportive care alone and 23.2 years over tezacaftor and ivacaftor. In a scenario analysis in which treatment began between ages 12 and 17, the projected median was 82.5 years, 45.4 years more than supportive care. The authors wrote that early initiation might allow near-normal life expectancy.

Registry data have moved in the same direction but not as far. The Foundation's 2024 highlights report that, among people born 2020 to 2024, half are predicted to live to age 65 or beyond, with median survival lower, by possibly more than a decade, for those ineligible for modulators. Based on 2025 data, the Foundation's prediction for children born 2021 to 2025 is 66 years. Half of the deaths recorded in 2024 occurred before age 38.8, eight years later than the 2018 figure.

What the story does and does not show

The two pivotal trials enrolled 403 and 107 people and ran for 24 weeks and four weeks. They measured lung function, exacerbations, sweat chloride and symptoms. They did not and could not measure survival. The claim that life expectancy has moved past 80 rests on a simulation, funded by the manufacturer, for one genotype and one starting age; the registry's observed-data prediction for children born today is 65 to 66 years, itself a figure that assumes no further change in treatment.

The story's statement that median survival was under 40 before 2019 matches the median age at death in 2018, which was 30.8, and the 2009 to 2013 median age of survival of 40.6, but not the Foundation's 2018 predicted survival at birth of 47.4 years. Depending on which baseline is used, the model's gain is 35 to 45 years. The 90 percent figure describes who is eligible by genotype, not who responds, and roughly one in ten people with cystic fibrosis has no modulator available. The story's slide about children planning for retirement is a projection, not an observation. What the record shows is a drug that corrected the folding of a protein identified thirty years earlier, raised lung function within four weeks in two randomized trials, and shifted every subsequent survival estimate upward.

Forty years of predicted life, from one medicine.