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Trikafta as a New Treatment for Cystic Fibrosis

by Adit Patel  

Imagine waking up one morning and taking a deep breath in. You start coughing uncontrollably as thick, sticky mucus blocks your airways. You suffer from pain not only in your chest but also in your abdomen, as this mucus envelops your organs. Cystic Fibrosis (CF) is a genetic disease affecting roughly 35,000 people in the United States. It is caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that implicates the regulation of salt and water across cell membranes. The result is a mucus that damages organs, which creates a fatal threat, calling urgently for new treatments. In 2019, the FDA approved Trikafta, which is a triple-combination therapy that corrects the protein defect in CF patients. Trikafta is seen as a breakthrough in CF treatment and medicine as a whole, but there are still some concerns surrounding the drug. 

The mutation to the CFTR gene’s protein function can be grouped into six classes. The most relevant is the F508del mutation, as it is the most common (affecting 90% of CF patients) and causes incorrect protein folding and degradation. The consequences are widespread: impaired chloride and bicarbonate transport leads to thick mucus, chronic bacterial and fungal infections, poor digestion, and systemic inflammation. Past treatments have targeted airway clearance, antibiotics, and pancreatic enzymes, but have fallen short of stopping disease progression. However, when the CFTR gene was discovered in 1989, new therapy options became available, targeting the cause of CF. 

CF research experienced a turning point with the development of CFTR modulators. Some of these early examples included ivacaftor that improved gating mutations, while lumacaftor/ivacaftor (Orkambi) targeted F508del homozygotes with limited success. Trikafta combines three active ingredients: elexacaftor (ELX), tezacaftor (TEZ), and ivacaftor (IVA). Trikafta uses two correctors (TEZ and ELX) and a potentiator (IVA) to improve folding and gating of the CFTR protein. After successful preliminary results, FDA approval came in 2019. 

Trikafta’s clinical trials resulted in unprecedented improvements in patient health. In Phase 3 trials, patients with one F508del mutation and one minimal-function mutation (those in the CFTR gene that cause an absence of the CFTR protein) experienced a 13.8% increase in ppFEV1 (measurement of lung function) after just 24 weeks. Sweat chloride concentrations decreased by more than 40 mmol/L (it is above 60 mmol/L in those diagnosed with CF and under 40 mmol/L for the average person), confirming restoration of CFTR function. Pulmonary exacerbations dropped dramatically, with treatment groups experiencing less than half as many compared to placebo. Even patients homozygous for F508del saw sustained improvements when switched from tezacaftor/ivacaftor to Trikafta. Patients reported better quality of life, weight gain, and reduced hospitalizations. 

Recent studies also point to benefits beyond CFTR correction. Research on Aspergillus fumigatus—a fungus that commonly colonizes CF lungs—shows that Trikafta reduces fungal biofilm formation. In vitro experiments demonstrated that cultures exposed to Trikafta had reduced adherence and biofilm mass, especially when combined with antifungal drugs. This suggests that Trikafta may indirectly strengthen host defenses by altering the environment in which pathogens grow. Since fungal infections can accelerate lung decline, these findings highlight an additional way Trikafta could improve long-term outcomes. 

Despite its promise, Trikafta has several challenges. Side effects include rash, gastrointestinal problems, elevated liver enzymes, and in some cases mood changes. The most pressing concern is cost: at over $311,000 per year in the U.S., Trikafta is inaccessible to many patients without strong insurance coverage. Globally, access is even more limited, with many low- and middle-income countries unable to afford it. Furthermore, questions remain about long-term safety and effectiveness. Since Trikafta has only been in use since 2019, researchers do not yet know whether the benefits will persist over decades or whether complications may emerge. Some skepticism also remains about whether Trikafta is equally effective across all patient populations. 

The future of Trikafta is promising but uncertain. Clinical trials are extending its approval to younger children, with the hope that early intervention will prevent irreversible lung damage. Research continues into its effects on microbial infections like Aspergillus fumigatus, which could expand its value beyond CFTR modulation. At the same time, advocacy groups are pushing for improved insurance coverage, price negotiations, and global access to ensure that life-changing therapies do not remain limited to wealthy nations. Beyond Trikafta, advances in gene editing and stem cell therapies may one day provide a permanent cure, but until then, Trikafta represents the most effective therapy available. 

Trikafta represents a major milestone in the history of cystic fibrosis treatment, ast is the first widely accessible drug to significantly restore CFTR function, improving lung function, quality of life, and survival. However, side effects till occur and some evidence also suggests that its impact may go beyond CFTR correction, altering microbial infections that contribute to lung decline. Moreover, it raises difficult questions about cost, side effects, and equitable access.. While advocates celebrate Trikafta as revolutionary, skeptics caution that the story is still unfolding. Ultimately, Trikafta symbolizes both the power and the limitations of precision medicine: a remarkable breakthrough that must be paired with policies ensuring affordability, safety, and accessibility for all patients.