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.