New cystic fibrosis medications move closer to a cure

Genetic disorder worsens with time but intervening earlier could spare children from damaged lungs.

With every breath she takes, Chelsea Gagnon can feel how the lung-scarring damage of cystic fibrosis adds up over time.

The 28-year-old Montrealer says a bad cold or flu that might keep an otherwise healthy person home from work for a couple days can for her set off a cycle of debilitating lung infections that require potent antibiotics and multiple hospital visits.

“About six times a year, I need IV medication because the oral antibiotics don’t work,” said Gagnon, who was diagnosed at birth with the genetic disorder that often leaves her lungs clogged with thick mucus and vulnerable to bacterial infections.

“So then you go for the stronger stuff. They would tire me out, and then it would be kind of a cycle of me getting sick and being tired and getting the IV and being even more tired so that I never fully recover.”

That wasn’t the case when she was a kid. She says the respiratory infections back then were less frequent and less severe.

And that’s exactly how doctors and researchers would like to keep it for cystic fibrosis patients, particularly the young ones who have yet to suffer the kind of permanent damage that could leave sections of their lungs unusable and ultimately cut years off their life.

Results of a new drug trial published in The Lancet Respiratory Medicine journal suggest the next generation of medications, known as CFTR modulators, show potential to actually correct the genetic defect that causes cystic fibrosis and halt the disease’s destructive progression.

Intervene early

Cystic fibrosis is caused by having two copies of a mutated gene for the cystic fibrosis transmembrane conductance regulator protein (CFTR), which is active in cells lining certain organs, including the lungs. In people with the mutation, the protein is defective, and salt and water aren’t able to flow into cells properly. That’s one reason why a patient’s mucus gets so thick.

Currently, cystic fibrosis is managed mainly with antibiotics and mucolytics, which help patients to clear the mucus from their lungs before they become infected.

But CFTR modulators are designed to target the source of the problem rather than simply control the symptoms.

By intervening earlier with the new medications, researchers are hopeful children with the disease will be able to avoid the kind of accumulation of scarring and other damage experienced by people like Gagnon.

Dr. Felix Ratjen, head of respiratory medicine at Toronto’s Sick Kids Hospital, led the randomized children’s trial that featured a combination of two CFTR modulators — lumacaftor and ivacaftor — versus a placebo.

The cocktail, sold as Orkambi, is intended for those with the most common form of cystic fibrosis and who don’t produce enough CFTR protein. Doctors say that’s about 38 per cent of Canadian patients who could be candidates for the drug combination, alongside other treatments.

Ivacaftor, sold as Kalydeco, helps the protein made by the CFTR gene to function better, and lumacaftor is a CFTR corrector compound that helps bring more of the protein to the cell surface, where it can be activated.

The trial, which was funded by the drug combination’s manufacturer, Vertex Pharmaceuticals — from whom Ratjen received grants — included results from 102 children from Toronto, Montreal, Vancouver, the U.S., Europe and Australia who received at least one dose of the cocktail, and 101 others in the placebo group.

Ratjen said the trial showed the drug combination helps reduce the amount of lung-clogging mucus in children aged six to 11.

The impact of CFTR modulators means pediatricians can shift their goals, said Dr. Melinda Solomon, director of the cystic fibrosis clinic at Sick Kids, and one of the co-investigators for the research.

“Our goal is to keep them well,” Solomon said. “Treat the underlying disease before it creates deterioration and symptoms.”

Pharmaceutical companies are developing more CFTR modulators targeting various mutations, said Dr. Carla Colombo of the Cystic Fibrosis Centre at the University of Milan, who wrote a commentary published with the study.

Colombo said safety is a key concern for young patients, which is why doctors need to watch closely for liver damage in children taking the medications.

Prevent damage

For Cystic Fibrosis Canada, the immediate focus is to get the new drugs to patients as soon as possible, said John Wallenburg, chief scientific officer for the non-profit, charitable organization based in Toronto. He said that will require bringing governments and manufacturers together to negotiate an affordable price.

“At some point in the not too distant future, we will have drugs that will allow individuals living with cystic fibrosis to have close to, if not normal, levels of CFTR function, which would be effectively a cure,” he said.

Health Canada has approved Kalydeco and Orkambi for sale, but access remains a challenge.

The Canadian Agency for Drugs and Technologies in Health (CADTH), the independent organization set up by the provinces, territories and federal government to evaluate whether to fund certain drugs and procedures, recommended Orkambi not be reimbursed by government health plans for eligible individuals aged 12 and up.

In its cost-benefit analysis, CADTH’s expert panel called for further evidence to support the efficacy of the drug combination, which they estimated costs $682 per day or $248,988 a year. Patients could potentially have to take the drug for the rest of their life.

Wallenburg acknowledges that CFTR modulators won’t be an option for all cystic fibrosis patients, and that they don’t address other related conditions such as diabetes and liver disease.

“Long term, our goal is also to ensure that patients who have already accumulated a certain amount of damage, if you will … are not left behind,” he said.

When Gagnon tried to take lumacaftor and ivacaftor during previous clinical trials, it didn’t work out because of a conflict with one of her other medications. In July, she started taking the combination again and says, “So far, so good.”

She said the potential of CFTR modulators to help children is “amazing.”

“It would be so great if [for] kids today, there was no time for the infections to happen,” she said. “You’re just preventing all the damage.”

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Photo credit: Chelsea Gagnon

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