Lumacaftor/ Ivacaftor improves exercise tolerance in patients with Cystic Fibrosis and severe airflow obstruction

Abstract

Background Treatment of patients with Cystic Fibrosis homozygous for the Phe508del gene, with Lumacaftor / Ivacaftor (LUM/IVA) improves outcomes in patients with FEV1 > 40% predicted. We set out to observe the most sensitive clinical measure that would change with treatment in terms of exercise capacity or lung function in adults with severe lung disease as defined by an FEV1 < 40% predicted when clinically stable. Methods 10 adults homozygous for the Phe508del received LUM/IVA. We assessed; six minute walk test (6MWT), spirometry, gas transfer (DLCO), plethysmography, and nitrogen multiple breath washout (MBW) at baseline, 4, 12, 24 and 52 weeks. Comparison was made with 10 matched historical controls that had been observed over 12 months. Results There was a significant improvement in 6MWT by 4 weeks of treatment; with a mean increase of 78 m (SD 62.3) and this increased to 118.1 m (SD 80.9) (ANOVA p = 0.006) by 52 weeks. Significant improvements were also seen in the resting heart rate and the oxygen saturation (SaO2) after 6 min walking. A significant improvement was not seen in FEV1 though until 24 weeks, though this was maintained at 52 weeks (ANOVA, p = 0.0004). There were no significant differences seen in the MBW or DLCO. After 12 months treatment with LUM/IVA, in comparison to historical controls; the 6MWT increased by 118 m (SD 80.9), but fell in the controls − 61.3 m (SD 31.1). FEV1; LUM/IVA led to an increase of 0.398 L/min, compared to a fall in the controls − 0.18 (SD 0.2). Conclusion In adults homozygous for Phe508del with severe disease, treatment with LUM/IVA results in a clinically significant improvement in 6MWT that was evident at 4 weeks and maintained at 52 weeks. Improvement in exercise tolerance is an important outcome to consider in those with more severe airways disease. Trial registration This was an observational trial conducted on individuals who became eligible to receive LUM/IVA. All investigations were carried out as part of routine clinical care. The trial was registered in retrospect on the 13/5/2019 on the Australian New Zealand Clinical Trials registry; ACTRN12619000708156 .

Real-World Safety of CFTR Modulators in the Treatment of Cystic Fibrosis: A Systematic Review

“…Characteristics of the full manuscripts and conference abstracts describing observational cohort studies are summarized in Table 1 and Table 2 , respectively. Two observational cohort studies included control subjects as comparison for non-safety outcomes related to LUM/IVA therapy [ 25 , 26 ], but only data regarding the participants on LUM/IVA was extracted and included in the descriptive analysis of this review. One case series was based on survey results presented in aggregate [ 27 ]; therefore, it was included in Table 1 .…”

“…In the observational studies, the number of subjects included ranged from 4 to 845 (median: 28). Fourteen (26%) of the observational studies focused on patients with severe airflow obstruction, defined as ppFEV 1 < 40%; in 11 of these studies, patients accessed the CFTR modulator via a compassionate access program (also referred to as a “managed access”, “early access’, “expanded access”, or “named patient” program) through the manufacturer [ 25 , 26 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ]. Twenty (65%) of the full manuscripts were deemed to have safety as a primary focus or outcome [ 27 , 28 , 29 , 30 , 32 , 33 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 ].…”

“…The majority of AEs reported with LUM/IVA were respiratory-related. Chest tightness, dyspnea, increased sputum, and declines in ppFEV 1 were among the most common respiratory AEs and tended to occur within the first few days after initiation, even as quickly as 3–4 h after the first dose [ 25 , 26 , 27 , 31 , 32 , 33 , 34 , 35 , 37 , 38 , 41 , 42 , 43 , 44 , 45 , 60 , 61 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 83 , 84 , 85 , 90 ]. Bronchodilators were beneficial in mitigating symptoms of chest tightness, wheeze, and increased work of breathing in some individuals [ 31 , 41 , 66 , 67 , 75 ].…”

Cystic fibrosis year in review 2019: Section 1 CFTR modulators

“…However, a high rate of chest tightness or dyspnea (55%) led to discontinuation of therapy (32%) 29 . Another study of 10 adults homozygous for the F508del mutation with severe lung disease (FEV1 < 40% predicted) examined exercise and pulmonary function parameters before and after initiation of lumacaftor/ivacaftor, compared changes with historical controls 30 . After 4 weeks of therapy, the six‐minute walk distance (6MWT) improved from a mean (SD) of 78 (62) to 118 (81) m. Historical controls had a reduction in 6MWT distance.…”

Exercise Physiology Across the Lifespan in Cystic Fibrosis

“…This therefore highlights the need to instill healthy behaviors at an early age. Recent case series reports regarding the influence of Orkambi ® , one of the CFTR modulator combination therapies, on daily physical activity and exercise tolerance over a 2 year period are highly encouraging (Savi et al, 2019), especially when considered in conjunction with reports of improvements in peak oxygen consumption (trueV˙O 2 peak ) and percent predicted forced expiratory volume in 1 s (ppFEV 1 ; Hatziagorou et al, 2018; Philipsen and Pressler, 2018). Thus, as these therapies become more common and are able to be initiated at younger ages, exercise capacity may be preserved and/or improved in individuals with CF across their lifespan.…”