Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

17th Annual Congress of the European Respiratory Society

Stockholm, Sweden / September 15-19, 2007

As stated by Dr. Eric Bateman, Director of Respiratory Medicine, University of Cape Town, South Africa, and Global Initiative for Asthma (GINA) executive member, “Although the GINA guidelines for asthma management strategies shifted focus in 2006 from asthma severity to asthma control, inhaled corticosteroids [ICS] remain the cornerstone of treatment. There is good evidence that the clinical manifestations of asthma such as symptoms, sleep disturbances, limited daily activity, lung function impairment or need for rescue medication can be controlled with appropriate treatment.”

ICS Mechanism of Action in Asthma Control

The revised GINA guidelines classify asthma medications as controllers or relievers. Controllers are long-term agents taken daily to control the disease by means of anti-inflammatory effects. Relievers rapidly reverse bronchoconstriction on an as-needed basis. Dr. Bateman characterized inhaled glucocorticosteroids as the most effective controller medications currently available. “Since asthma control means the extent to which clinical manifestations are removed or reduced, the aim is to at least reduce those manifestations,” he indicated.

GINA executive member Dr. Paul O’Byrne, Director, Firestone Institute for Respiratory Health and Chair, Department of Medicine, McMaster University, Hamilton, Ontario, reported that clinical studies of the newer ICS agents ciclesonide and mometasone furoate demonstrated improved asthma control. “Ciclesonide is unique among the newer ICS in that it is inactive in the mouth, but is cleaved into the active metabolite desisobutyryl ciclesonide by airway-specific lung esterases in the lower airways to become clinically activated,” he explained. “This keeps local and systemic adverse effects to a minimum and provides for once-daily dosing. The potential advantages are that activation is targeted to the lung and should reduce topical side effects in the mouth as well as systemic side effects and oropharyngeal events, all of which help to improve compliance.”

Dr. O’Byrne noted that non-activated ciclesonide is characterized by a very low binding affinity for the intracellular glucocorticoid receptor compared to commonly used budesonide, fluticasone and mometasone furoate, which have very high receptor binding. Once activated, however, the ciclesonide metabolite has the same glucocorticoid receptor affinity as the commonly available inhaled glucocorticosteroids, thereby demonstrating inactivity before and high activity after cleavage occurs. He added that the activated compound is more highly protein-bound (about 99%) in the systemic circulation than the other steroids, indicating a limited ability to interact with glucocorticoid receptors outside the lung.

Study Findings

Noting that several clinical efficacy studies have now been reported in the literature, Dr. O’Byrne reported that the novel ICS at 80 or 320 µg q.d. in 360 patients previously treated with another ICS showed significantly improved peak expiratory flow (PEF) and forced expiratory volume in 1 second (FEV1) at both doses compared to placebo. Most of the benefit achieved by improving FEV1 was seen at the lower dose given once a day. “There was no significant effect on urinary cortisols with either dose, so for this period of time, no easily measurable systemic adverse effects were observed,” he remarked.

He concluded that relative to budesonide and fluticasone, agents known to be effective as monotherapy in asthma, ciclesonide demonstrated at least equivalent efficacy in pulmonary function and control of persistent moderate asthma.

In a 12-week study of 554 adult men and women randomized to once-daily ciclesonide at doses of either 80 µg or 320 µg, or budesonide 160 µg b.i.d., there was no significant difference between patients in the three treatment arms in the primary efficacy variable FEV1 (Hansel et al. Clin Ther 2006;28(6):906-20). FEV1 increased significantly from baseline in all three patient groups (P<0.0001), and there were no significant between-group differences. Mean FEV1 measured 267, 256 and 355 L, respectively. Ciclesonide was non-inferior to budesonide in the primary analysis. Morning PEF also increased significantly from baseline in all groups (P<0.01) with no significant between-group differences. Asthma symptom scores and rescue medication use significantly decreased for all groups compared to baseline (P<0.0001) with no significant between-group differences, although the use of rescue medication tended to favour patients receiving ciclesonide. It was also reported that suppression of urinary cortisol was observed with budesonide, but not with either dose of ciclesonide.

Tolerability

In another study, GINA colleague Prof. Daniel Dusser, Head of Respiratory Medicine, Hôpital Cochin, Paris, France, reported a significantly lower incidence of oropharyngeal candidiasis in patients treated with the novel ICS.

He randomized 259 individuals with well-controlled, moderate to severe persistent asthma to receive ciclesonide 320 µg b.i.d. and 244 others to fluticasone 500 µg b.i.d. Regular use of long-acting beta-agonists (LABAs) during the 24-week treatment period was permitted. “Ciclesonide and fluticasone comparably maintained lung function in this trial,” he told delegates. “Non-inferiority of ciclesonide was shown [P<0.0001] for FEV1, FVC and morning PEF. Median values for asthma symptom scores and rescue medication use were zero at baseline and remained stable in both groups during treatment. The mean number of days with asthma control [days without day or nighttime asthma symptoms, rescue medication or asthma exacerbations] was 100 in both groups.”

Prof. Dusser added, “The proportion of patients experiencing lack of efficacy [exacerbations requiring oral steroids] was low in both groups [ciclesonide 2.3%, fluticasone 2.9%].” He indicated that candidiasis of the oropharynx was considerably less frequent in the ciclesonide arm (nine cases in eight patients) than with fluticasone (22 cases in 19 patients). The between-treatment difference with regard to candidiasis was significantly in favour of the novel agent (P=0.0054). The number of patients with treatment-emergent events of dysphonia was comparable between the two groups at about 6%.

Prof. Dusser concluded that the two compounds maintain lung function and asthma control equally well in patients with well-controlled, moderate to severe asthma using a free addition of LABA.

Citing important clinical findings in other patient categories, GINA member Dr. Soren Pedersen, Head Clinician and Chief, Department of Pediatrics, Kolding Hospital, Denmark, told listeners that ciclesonide efficacy was found to be comparable to budesonide and fluticasone in adolescent patients with persistent asthma. Decreased 24-hour urine cortisol, indicating suppression of HPA-axis function, was observed with budesonide and fluticasone, but not with ciclesonide, which demonstrated placebo-like safety and tolerability at all doses. Ciclesonide and fluticasone were also comparable in improving lung function among prepubertal children, both reducing asthma symptom scores and rescue medication use to a similar degree.

Future Directions

Dr. O’Byrne described an innovative study in which maintenance steroid doses were gradually reduced until patients fulfilled criteria for exacerbation of asthma. At that time, 63 patients were randomized to a very high, unapproved dose of ciclesonide 640 µg b.i.d. while 67 patients received prednisone 40 mg/day for two weeks. The latter is considered a standard treatment for acute exacerbations.

“Both groups achieved a very substantial improvement in peak flow, which was identical in the two treatment arms,” he reported. “This higher inhaled dose of ciclesonide was about as good as a dose of prednisone 40 mg/day for exacerbations. Symptom scores and rescue medication use, if anything, tended toward a better effect of ciclesonide than with prednisone, but did not reach statistical significance.”