New Cystic Fibrosis Medication May Be a Game Changer

Robust improvements in pulmonary function and quality of life seen in clinical trials

The U.S. Food and Drug Administration approved TRIKAFTA™ (elexacaftor/tezacaftor/ivacaftor and ivacaftor) in October 2019. TRIKAFTA — the first triple combination therapy for patients with cystic fibrosis (CF) — is groundbreaking, according to pediatric pulmonologist Nathan Kraynack, MD. Dr. Kraynack directs Cleveland Clinic Children’s Cystic Fibrosis Program.

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“This therapy is a game changer,” says Dr. Kraynack. “I don’t think it’s quite a cure, but it significantly improves patients’ lung function. It can reduce symptoms and dramatically improve quality of life, and it’s something that no one really could foresee 20 to 25 years ago.”

Reducing airway obstruction by acting directing on CFTR molecule

TRIKAFTA has been approved for use in CF patients ages 12 and up with a F508del mutation. “This is the most common mutation in CF,” Dr. Kraynack says. “The theory behind the medication is that you activate the cystic fibrosis transmembrane conductance regulator (CFTR) molecule, improving clearance of mucus within the airways. Within a relatively short period of time — say within a couple of weeks — you will see a reduction in airway obstruction.”

The FDA fast-tracked approval of TRIKAFTA for CF, which is considered an orphan disease. Many of the CF drugs have been similarly fast-tracked, particularly the newer, CFTR modulators, according to Dr. Kraynack. Ivacaftor was studied first, and initially was approved for patients with a single genotype. “It seemed to work well in patients with that particular CF gene, which is how it all started. Other drugs that have come since then have been studied in basically the same fashion. And, since they’ve all shown similar results with different levels of robustness, they’ve been approved relatively quickly, which is great from a patient care standpoint.”

Clinical trials demonstrated a very robust improvement in pulmonary function

In a double-blind, placebo-controlled, Phase 3 trial in patients heterozygous for F508del and a specific mutation, patients taking TRIKAFTA had a 13.8 percentage point improvement in lung function from baseline vs the placebo, as measured by percent predicted forced expiratory volume in 1 second (ppFEV1). At week 24, TRIKAFTA patients had seen a 14.3 percentage point improvement in ppFEV1 from baseline, compared to patients taking the placebo. Notably, in this time frame, patients taking TRIKAFTA saw reductions in pulmonary exacerbations (63%), hospitalization (71%) and IV antibiotic use (78%). Sweat chloride was reduced by 41.8 mmol/L and body mass index increased by 1.0 kg/m2, on average.

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In a double-blind, active-controlled, head-to-head Phase 3 trial in patients homozygous for F508del mutation, patients taking TRIKAFTA had an increase of 10 percentage points in ppFEV1 and a 45.1 mmol/L reduction in sweat chloride levels at week four, compared with those in the control group who took tezacaftor/ivacaftor and ivacaftor. Additionally, TRIKAFTA patients improved 17.4 points on the Cystic Fibrosis Questionnaire Revised (CFQ-R) compared with those taking the active comparator.

Early experience with TRIKAFTA

For the last 20 or 30 years, the usual care for patients with CF has involved combining a number of different medications targeted at symptoms, according to Dr. Kraynack. “In the past, every therapy we’ve had has been a reaction to a problem that is a downstream effect of the CFTR abnormality. We had patients on maybe five or six different medications on a routine basis to try to manage all of their symptoms. But TRIKAFTA changes everything for patients who can take it. Right now, we do think TRIKAFTA should be used in combination with currently available CF medications for optimum symptom management. What we don’t know yet is whether patients will need those other medications in the longer term.”

“I have just a couple of patients taking TRIKAFTA now, simply because I’ve been seeing younger patients for whom TRIKAFTA has not yet been approved,” Dr. Kraynack continues. “And so far so good. They haven’t really had any problems. It’s brand new…so I haven’t seen them back in clinic to look for those rather robust improvements in lung function.”

Frequent visits early in life lay groundwork for good somatic growth

Dr. Kraynack describes his approach to managing patients with CF as “very aggressive.”

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“I see patients very, very frequently,” Dr. Kraynack says. “Even with these new medicines, we know that the lung function in individuals with cystic fibrosis declines over time. Even with the best possible therapy, 10 years down the line, someone’s lungs are going to be much sicker than they are right now. And so my approach is to see individuals about every two months, which is a little bit more frequently than what is currently recommended, because you can pick up subtle findings, maybe a little bit of weight loss or loss of lung function. And if you react to that quickly, you can generally keep patients healthier.”

Dr. Kraynack sees younger patients even more frequently. “In the first year of life, we might see a baby once they’re diagnosed by newborn screening,” Dr. Kraynack explains. “We might see them weekly for the first couple of months of life, and then every couple of weeks, and then — by the end of that first year — we might see them every two months. It really depends on how they’re doing. I think it’s important to lay groundwork early on for good somatic growth. When kids gain weight well, and have good nutritional status, that pays dividends in the long run.

Reason for hope

Researchers have been looking for a cure for CF since CFTR was discovered in 1989, according to Dr. Kraynack. “We’ve been thinking about it, and hoping for it, but we’ve not really been able to find a cure. Therapies like TRIKAFTA are getting very close, which is encouraging. Now, when I sit down with a distraught family of a 2-week old child who was just diagnosed with CF by a newborn screening, I feel like I can offer hope in many cases. I can turn around and say: ‘There is reason for optimism.’ We’ve come so far in just the last 10 years that I foresee a cure during many of my patients’ lifetimes.”