Lumacaftor/Ivacaftor
Lumacaftor/IVA (LUM/IVA) has also had some extended long-term data published in the past year. Two studies examined open label extension beyond the initial 24 weeks of LUM/IVA, extending to 96-120 weeks in both 2–5 7 and 6–11 year-old participants8. Both studies found no changes in safety signals and sustained improvements in clinical outcomes. It is notable that only 9% of the 2–5-year-old participants had respiratory adverse event, especially in light of 2-5 year olds being a common age for early transient wheeze and older participants (≥ 12 years) in the LUM/IVA studies having respiratory adverse events as a common cause of discontinuation in prior studies7. Especially in the 2–5-year-old age group, where no other CFTR modulator is available for PwCF homozygous for F508del, it is reassuring to see that extend use continued to be safe and have improved clinical outcomes.
Two countries, the US9 and France10, examined effects in a more real world setting for 12 and 24 months respectively. The US study, PROSPECT, evaluated 196 participants, over age 6 years9, while the French looked at 40 participants between ages 12 and 18 years10. As with other real-world studies, no changes in safety signals, SC decreased, and BMI increased. Of note, however the French participants had an increase in FEV1pp10, while the US study did not, mentioning that US participants had a higher starting FEV1 compared to the phase 3 clinical trial9. Exacerbations were not improved in either study, while the US found no differences in hospitalizations, or PA infection9 and the French analysis found no changes in oral or IV antibiotic usage or CT scan evaluations10. Improvement in FEV1pp was noted to have an inverse correlation with age at LUM/IVA initiation10. Neither study found a correlation between changes in SC and FEV1pp, BMI percentile or BMI9,10. This lack of correlation with SC was also seen in a single center study of 160 participants over six months. Of interest, there was a larger decrease in SC in females (-28.6 mmol/L) compared to males (-18 mmol/L)11. A sub study of PROSPECT examined mucociliary clearance and found no significant change, except in cough assisted clearance12. Both evaluations support LUM/IVA as a beneficial medication, thus, in countries where LUM/IVA is the only available CFTR modulator, clinical use is valuable, however, LUM/IVA is less effective and thus if other highly effective modulators are available, their use may be of more benefit to PwCF.
LUM/IVA has also seen expanded eligibility. In vitro, the mutation A455E has shown to be responsive to LUM/IVA, thus clinical outcomes were evaluated in a randomized, double blind, placebo controlled, multicenter, phase 2 study, in an 8-week crossover design in 20 participants13. The medication was safe and well tolerated, however, the primary endpoint was not met, with only a mean absolute change in FEV1pp of 0.1%, decrease in SC of -7.8 8mol/L and a mean absolute change from baseline change in CFQ-R of 3.5 points. Participant derived organoids showed concentration dependent swelling to LUM/IVA, however, in this small group of participants, there was no correlation with clinical response13. Similar to the study of organoids in IVA alone, this study adds to the use of organoids as a marker of modulator responsiveness, although in this instance, not correlated with clinical outcomes.
Continuing to work to understand the effect of LUM/IVA in populations that were not included in the original clinical trials were reported this year. One study evaluated adults over one year who had advanced lung disease ((ALD) defined as FEV1pp <40%)14. Of the 24 who reached the one-year time frame, a decrease in pulmonary exacerbations requiring hospitalization, days of hospitalization, IV antibiotic days, improvements in FEV1pp, and BMI were seen. No apparent clustering of improvement was seen, such that those with the greatest reduction in health care utilization were not the ones with the greatest stabilization of FEV1pp or greatest improvement in weight. Again, the importance of this study extends to PwCF and ALD in countries where no other CFTR modulator is available allowing them to benefit.
Another population not studied in the clinical trial, PwCF and CF related liver disease (CFLD), LUM/IVA was examined in 28 PwCF over age 12 (4 with multinodular liver disease and portal hypertension, 19 with CFLD and 5 without CFLD)15. Biomarkers of liver disease were all decreased after 12 months of treatment, while ultrasound findings varied (19 unchanged, 3 with resolution, and one with increased echogenicity). No correlation was seen between biomarkers and ultrasound findings.
Beyond new populations, additional effects on clinical outcomes have come to light. For example, changes in fat soluble vitamins. In 45 patients, over age 2 years who had treatment with LUM/IVA for one year, the following was seen, no changes in Vitamin D levels or Retinol, an increase in international normalized ratio (INR), and a decrease in Vitamin E16. By two years of treatment, there were no additional changes in Vitamin D or INR, yet retinol increased, and Vitamin E decreased16.
The clinical outcome of pancreatitis has also been associated with modulator use. A case series of 5 PwCF with pancreatic insufficiency, demonstrated increased risk of acute pancreatitis after use of modulator (IVA or LUM/IVA)17. In contrast, using MarketScan, a database of inpatient and outpatient health care covering over 200 million individuals, an overall reduction in acute pancreatitis in both pancreatic sufficient and insufficient patients was seen after introduction of CFTR modulators18. Although these reports conflict, clinicians should be aware of possible pancreatitis in PwCF.