ABSTRACT
Objectives: The aim of this ongoing longitudinal study is to examine the effects of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) on aspects of physical fitness (PF, strength endurance, explosive power, coordination under time pressure, coordination for the precision aspect, trunk flexibility, peak workload, habitual physical activity (HPA, steps/day, intensity), and zscores of FEV1 and BMI in children with cystic fibrosis (CF)). All children have been receiving ELX/TEZ/IVA for 19.2 ± 10.4 (11–33) months. Methods: Six children with CF agreed to participate (3f/3 m) mean age 13 ± 4yrs (9–17 yrs), FEV1 z-score − 1.017 ± 1.817 (-3.2–0.8). PFwas assessed using 5 test items at baseline and 4.51 ± 0.98 years later;strength endurance (PU push-ups, SU sit-ups), explosive power (SLJ standing long jump), coordination under time pressure (JSS jumping side to side), coordination for the precision aspect (BB balancing backward on beams), and trunk flexibility (FB, forward bend). Cycle-ergometry (Godfrey-protocol) was used to determine Wpeak. Lung function was measured by spirometry. Results: Significant improvements were seen in test items representing strength endurance (PU, SU) and coordination under time pressure (JSS) (p < .05). Although HPA expressed as steps/day remained the same, thetime of moderate to vigorous intensity of HPA decreases significantly (p < .05). A slight, not significant, improvement of BMI Z-score was observed (p > .05). No or small changes could be observed for the parameter FEV1 z-score, Wpeak, PF, SLJ, BB and FB (p > 0.05). Conclusion: ELX/TEZ/IVA therapy seems to be a facilitator to increase some aspects of PF. The decrease in intensity of HPA is possibly an effect of the COVID-19 Pandemic that has already been described in healthy and asthmatic children. In this ongoing study, we assume that clearer effects will be shown with a greater number of children included. However, ELX/ TEZ/IVA enhanced muscle strength endurance in children with CF.
ABSTRACT
Background: Epithelial sodium channels (ENaC) have been demonstrated to be hyperactive in patients with Cystic Fibrosis (CF) and to contribute to reduced airway surface liquid, mucus dehydration and airway mucus accumulation. An antisense oligonucleotide (ASO) which inhibits murine αENaC expression was demonstrated to be efficacious in two different mouse models of CF. ION-827359 is a chemically modified ASO, 16 nucleotides in length with a phosphorothioate backbone and constrained ethyl (cEt) modifications. In healthy volunteers the ASO was found to decrease ENaC mRNA expression in bronchial brushings by a mean of 56%.Methods: This ascending dose trial was conducted in three parts, the first two of which were in healthy volunteers. The third part of this trial was a randomized, double-blind, placebo-controlled multiple ascending dose (MAD) study in patients with CF. Patients were allowed to stay on their usual CF medications throughout the trial. The primary objective was the evaluation of safety and pharmacokinetics of ION-827359 delivered via a Pari eFlow © mesh nebulizer. A total of 33 subjects in 4 cohorts received doses of 10, 37.5, 75, or 100 mg once weekly for 4 doses, with an additional dose administered during the first week. Subjects were followed for 13 weeks after dosing. Results: ION-827359 was well-tolerated with an acceptable safety profile after multiple inhalations. The rate of adverse events was similar between ION-827359 and placebo treated groups. There were no clinically relevant changes in chemistry, hematology, urinalysis, ECG, or vital signs. There were no drug related serious adverse events or discontinuations due to adverse events although three subjects discontinued early due to concerns about COVID-19. Pharmacokinetics demonstrated low systemic exposure with a plasma half-life of approximately 2 weeks. Spirometry showed a numerical dose dependent increase in FEV1 at the end of the 4-week treatment period (4.5% difference for 100mg group from placebo). Conclusions: These results demonstrate strong evidence of tolerability and safety at the doses and regimens tested and supports further investigation of ENaC ASO ION-827359 in patients with cystic fibrosis.