The Other Side of the "Miracle Drug": A Long-Term Study Reveals Real-World Challenges of the New Cystic Fibrosis Therapy ETI

Introduction: A Leap from Symptomatic to Causal Treatment

Cystic Fibrosis (CF) is a rare genetic disease. A mutation in the CFTR gene in patients leads to abnormally thick mucus secretions, severely affecting lung and digestive system function. For a long time, CF treatment primarily focused on alleviating symptoms, such as using mucolytics and antibiotics to control infections, which severely limited patients' quality of life and life expectancy. However, in recent years, the advent of a triple combination drug called Elexacaftor/Tezacaftor/Ivacaftor (ETI) has been hailed as a "game-changer" in CF treatment. It no longer merely "treats the symptoms" but "treats the root cause" by repairing defective CFTR proteins, bringing unprecedented hope to the vast majority of CF patients, with significant improvements in lung function and nutritional status. But like all new drugs, when "miracles" become reality, what challenges will long-term real-world use bring? A five-year observational study recently published in the Journal of Clinical Medicine reveals the other side of ETI in long-term use—the true picture of adverse events (AEs).

Key Findings: Not a Smooth Road, Nearly One-Fifth of Patients Experience Adverse Events

This study, conducted at the Verona Cystic Fibrosis Center in Italy, tracked 414 CF patients receiving ETI treatment for a median follow-up period of nearly 3 years. The study results painted a more detailed and realistic clinical picture:

• Adverse Event Incidence: During long-term observation, approximately 21% (85 patients) reported at least one adverse event. This indicates that while ETI is generally well-tolerated, a non-negligible proportion of patients will experience side effects.
• Most Common Adverse Events: The study found that the most common adverse events included elevated liver function indicators (16.2%), rash (11.3%), epigastric pain (7.8%), headache, and depression (both 4.2%). This suggests that doctors and patients need to pay attention to changes in liver, skin, digestive tract, and mental status.
• Differences Between Children and Adults: A particularly noteworthy finding is that the types of adverse events differed between pediatric and adult patients. In pediatric patients, psychiatric disorders (such as attention deficit) and gastrointestinal disorders were most common; in adults, in addition to psychiatric problems such as depression and anxiety, musculoskeletal and respiratory system-related adverse events were also observed.
• Management and Outcomes: Permanent discontinuation of the drug due to adverse events was very rare, accounting for only 1.9% of all patients. More often, adverse events were managed by temporary drug discontinuation, temporary or permanent dose adjustments. Approximately 32% of adverse events led to permanent dose reduction. This indicates that with personalized dose management, most patients can continue to benefit from treatment while controlling side effects.

Research Methods: Long-Term Observation from the Real World

This study was a prospective observational study. This means that researchers did not conduct it in a strictly controlled clinical trial environment, but rather tracked patients who started using ETI in real clinical practice over a long period. Doctors actively monitored and recorded adverse events during patients' routine outpatient and inpatient visits through inquiries and examinations. The advantage of this study design is that it can reflect the safety and tolerability of the drug in a broad population and under complex real-world conditions, providing valuable practical evidence for clinical drug use.

Limitations of the Study

The research team also candidly pointed out the limitations of the study. First, this was a single-center study, and its results may not fully represent the situation of patients in all regions. Second, the collection of adverse events relied on patient reports and doctor inquiries, and some minor events, or events that patients did not actively report due to fear of drug discontinuation, may have been missed, potentially underestimating the true incidence of adverse events.

Significance and Outlook: Seeking the Best Balance Between Efficacy and Safety

Despite its limitations, this study is still very significant. It emphasizes the necessity of long-term, systematic safety monitoring during ETI treatment. Particularly for changes in mental health, the study suggests that it should be part of routine screening, which is especially important for pediatric and adolescent patients. In addition, the study results reveal the feasibility of managing adverse events by adjusting drug dosage, which provides important reference for clinicians on how to find the best balance between ensuring efficacy and patient safety. As more and more patients use ETI long-term, future research needs to further explore the impact of dose adjustment on long-term efficacy and how to formulate optimal dosing regimens for different individuals (especially patients with liver dysfunction and low body weight).

Summary

ETI is undoubtedly a milestone in the history of cystic fibrosis treatment, greatly improving the lives of countless patients. However, this long-term real-world study reminds us that behind the "miracle" also lie real challenges. Understanding and properly managing these adverse events is key to ensuring that this revolutionary therapy can continue to safely benefit more patients. This study not only provides valuable data for doctors and patients but also points the way for future more refined and individualized CF treatment strategies.

References

• Lucca F, Meneghelli I, Tridello G, et al. Reported Adverse Events in Patients with CF Receiving Treatment with Elexacaftor/Tezacaftor/Ivacaftor: 5 Years Observational Study. J Clin Med. 2025;14(12):3456.