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.