Adherence
CFTR modulator use patterns, as seen above, are not always uniform. It
is relevant to study adherence in the case of modulators to assure
efficacy and to evaluate side effects. In the above real-world study in
France of lum/iva, out of 845 subjects, 154 (18.2%) discontinued the
medication at a median of 90 days (interquartile range 25-179
days)53. Of those who took full dose, 17.3% (129/745)
discontinued, while 25% (25/100) at reduced dose
discontinued53, compared to 4.2% of patients who took
lum/iva in the phase 3 safety/ efficacy trial55. The
primary reason (48.1%) for discontinuation was respiratory events
(chest tightness, dyspnea, bronchospasm, increased cough/sputum,
hemoptysis, and pneumothorax). Non- respiratory reasons such as
diarrhea, abdominal pain, myalgia, fatigue, headache, depression,
metrorrhagia, elevated LFTs, tachycardia, and rash were the next most
frequent at 27.9%. Subjects were more likely to discontinue lum/iva if
they were adults, their FEV1pp was ≤40%, or they had a greater number
of IV antibiotic courses the previous year. The Australian study
mentioned above of F508del homozygotes with FEV1pp ≤ 40% demonstrated
that despite benefits of reduced PEx and rates of lung function decline,
55% of 105 subjects had chest tightness or dyspnea and 32%
discontinued treatment56.
In contrast, a retrospective pharmacy refill history study in France of
96 patients showed very high adherence to therapy, with the mean
proportion of days covered (PDC) 96% at 6 months, and 91% at 12
months57. However, the PDC measure is calculated by
the total number of medication days divided by the number of days in the
given period, and high rates may reflect only filling or over-filling
the medication, not actually taking it. The proportion of adherent
patients, defined as PDC ≥0.80, was 89% (n = 86) and 83% (n = 80) at 6
and 12 months, respectively. Of those who were non-adherent, the
majority were in the 18–25-year-old group (56%) compared to patients
26–35-year-old (6.3%), >35 years old (6.3%), and the
12–17-year-old (31%). The generalizability of this study is limited by
the overestimation of adherence using the PDC measure, as well as by the
small sample size.
Adherence to lum/iva was difficult for some due to respiratory side
effects, and one study was performed to assure this population would not
have similar respiratory side effects with tez/iva. A phase 3b,
randomized, double blind, placebo-controlled, parallel group,
multicenter trial of placebo versus tez/iva enrolled subjects who had
discontinued lum/iva due to ≥1 respiratory sign or symptom considered
related to treatment58. Subjects were pwCF ≥12 years
old, homozygous for the F508del-CFTR mutation with FEV1pp of ≥25% and
≤90% and followed for 56 days of treatment and 28 days safety follow
up. Out of 97 participants, 50 received tez/iva and 47 received placebo.
The mean difference in FEV1pp with tez/iva versus placebo was 2.7%
(95% CI: 1-4.4). The incidence of respiratory related adverse events
was 7 (14%) in the tez/iva group versus 10 (21.3%) in the placebo
group. Only 1 (2%) respiratory event in the tez/iva group versus 4
(8.5%) respiratory events in the placebo group were thought to be
related to treatment. Two patients in each group (4%) discontinued
study drug. Overall, tez/iva was well tolerated without respiratory
related treatment adverse events or discontinuation in patients with
previous respiratory related symptoms due to lum/iva, many of whom had
FEV1pp ≤40%. This suggests tez/iva is safe, and due to absence of
significant respiratory related symptoms, may be better tolerated than
lum/iva in those with initial respiratory symptoms and thus result in
better adherence to therapy.