Summary Basis of Decision for Alvesco ®

3.3.1 Pharmacodynamics

Ciclesonide is converted by esterases to an active metabolite (M1) which is a potent glucocorticoid. As ciclesonide is targeted to the lung upon inhalation, the conversion to active metabolite and subsequent binding to glucocorticoid receptors occurs predominantly in the lung, resulting in local anti-inflammatory activity.

Phase II studies evaluated the effects of ciclesonide treatment on the hypothalamic-pituitary adrenal (HPA) axis. In one study, patients treated with ciclesonide received either 400 μg/day or 800 μg/day for a total of 12 weeks. HPA-axis function was assessed before treatment as well as at week 6 and week 12, visits 6 and 9, respectively. Visit 3 was day 1 of treatment. Pharmacodynamic evaluations of the HPA axis were based upon the following data: a) serum cortisol concentrations both before and after low- and high-dose cosyntropin-stimulation testing at visits 2, 6, 9 or early termination, b) urine cortisol measurements (corrected for creatinine) over a 24-hour period collected at visits 2, 6, 9 or early termination.

Mean low-dose peak cortisol levels at baseline were similar across treatment groups. Changes from baseline were minimal in the two ciclesonide treatment groups and placebo. Serum and urine cortisol levels were not significantly different between the placebo treatment group and either ciclesonide treatment group. No dose response was observed with the groups receiving ciclesonide 400 μg/day and ciclesonide 800 μg/day.

3.3.2 Pharmacokinetics

Alvesco^® is a metered dose inhaler which contains a new glucocorticosteroid, ciclesonide, dissolved in ethanol and propelled by HFA-134a. C iclesonide is an ester prodrug and is converted to its active metabolite M1 by esterases. As ciclesonide is targeted to the lung upon inhalation, the conversion to active metabolite and subsequent binding to glucocorticoid receptors occur predominantly in the lung. The pharmacokinetic characterization of ciclesonide includes the assessment of M1 as it is the active moiety.

Absorption

Studies with oral administration of radiolabelled ciclesonide have shown low oral absorption (25%). Based on gamma scintigraphy, approximately 50% of the dose that emerged from the actuator was deposited in the lungs. When inhaled, the oral bioavailability of ciclesonide and the active metabolite, M1, was negligible. The swallowed portion of the inhaled drug effectively does not contribute to the systemic absorption as a result of the extensive first-pass metabolism.

Distribution

Both ciclesonide and M1 are highly protein bound (99% and 98%, respectively) to human plasma proteins. The systemic exposure to unbound drug is very low (approximately 1-2% of the pulmonary absorbed dose).

Metabolism

Ciclesonide is rapidly and extensively de-esterified (hydrolyzed) to the active metabolite, M1. This metabolite is further metabolized to inactive products, predominantly by CYP3A4 enzymes.

Excretion

Following IV administration, ciclesonide had a half-life of 0.4 hours and its active metabolite had a half-life of 3.5 hours. The half-life estimated from the terminal elimination phase after inhaled administration of ciclesonide was approximately 6 hours. After IV and oral administration, radiolabelled ciclesonide was primarily excreted via bile into the faeces.

Special Populations

Data from different population groups showed that systemic drug exposure was doubled in the elderly and increased by factors of up to 2.8 in subjects with hepatic impairment. Dosing need not be altered in the elderly or in patients with hepatic insufficiency due to the pharmacokinetic (PK) profile of ciclesonide and its mode of delivery.

The PK data of healthy subjects and asthma patients were shown to be similar.

Drug Interactions

Ketoconazole, a potent CYP3A4 inhibitor, affected the PK parameters of the active metabolite of ciclesonide in healthy subjects. Exposure to the active metabolite was increased approximately 3.5-fold. The peak plasma concentration (C_max) and time to reach the maximum concentration (t_max) were also increased. Therefore, concomitant use of Alvesco^® with ketoconazole should be considered with caution.

The PK parameters of the parent compound ciclesonide were not affected by concomitant administration of ketoconazole with ciclesonide

3.3.3 Clinical Efficacy

Numerous clinical studies were used to assess the efficacy of Alvesco^®. Approximately 4600 patients were treated with the medicinal ingredient, ciclesonide, in studies of up to 12 weeks duration and approximately 1700 patients were treated in studies up to one year. Most studies were double-blind, some were placebo-controlled, while others used beclomethasone dipropionate, budesonide or fluticasone propionate as an active control. The efficacy was evaluated primarily on the basis of the following lung function variables: the Forced Expiratory Volume in one second (FEV₁), and Peak Expiratory Flow (PEF).

The dosing recommendations for Alvesco^® were mainly based on the placebo-controlled dose-range finding studies. The results of the active comparator studies are considered supportive.

Placebo-controlled Studies

Superiority to placebo was shown for 100, 200, 400, and 800 µg/day ciclesonide in patients with mild to severe asthma in regard to the lung function variables FEV₁ and morning PEF.

Superiority of ciclesonide to placebo was demonstrated in a study investigating oral corticosteroid sparing in severe asthmatics. Both 800 and 1600 µg/day ciclesonide were superior to placebo in reducing the required prednisone dose in patients with severe asthma on oral steroids.

Differences in the lung function variables between ciclesonide dose groups were mostly not statistically significant. Improvements with increased doses are known to be small for all inhaled corticosteroids. In most studies, the lack of efficacy was dose-dependent. For patients with mild to moderate asthma, a greater benefit was demonstrated with 400 µg/day ciclesonide compared to lower doses. Data on higher doses of 800 to 1600 µg/day either as single or divided doses offered improvement in efficacy numerically in severe asthma patients.

Active-comparator Studies

In all of the active comparator studies, ciclesonide was as effective as the other inhaled corticosteroids (fluticasone, beclomethasone, budesonide) in comparable doses. The non-inferiority status of ciclesonide was demonstrated by the lung function variables FEV₁ and morning PEF.

Long-term Studies

Maintenance of efficacy was established in four long-term extension studies ranging from 40 weeks to one year in duration. All lung function variables were stable throughout the long-term studies.

3.3.4 Clinical Safety

The clinical studies provided safety data from approximately 6300 asthma patients treated with the medicinal ingredient, ciclesonide. Some studies were up to 12 weeks duration others were long-term. Approximately 1700 patients were treated with ciclesonide in the long-term studies up to one year.

In general, the safety profile of ciclesonide is the same as for other inhaled corticosteroids. Adverse events were within the expected range for a population of patients with asthma. The main adverse events were related to the upper respiratory tract (nasopharyngitis, upper respiratory tract infection, sinusitis, allergic rhinitis, influenza, hoarseness), asthma aggravation, and headache. Studies did show that there was good oropharyngeal tolerability with ciclesonide. Fewer cases of oral candidiasis appeared in ciclesonide-treated patients as compared to active controls.

An overview of the effects of ciclesonide on the HPA axis showed that ciclesonide did not have significant influence on serum and urinary cortisol levels compared to placebo. Even at high doses, ci clesonide did not appear to affect serum or urinary cortisol levels. The fact that there was no evidence of drug-related cortisol suppression as well as no significant effect on bone formation or resorption at doses 1600 μg/day suggests that inhaled ciclesonide up to 1600 μg/day can be considered to have no significant effect on bones in the large majority of adult patients with asthma.

Concerns about ocular safety were raised when two studies were reported that suggested a higher incidence of lens opacities in ciclesonide-treated patients. These concerns resulted in the issuance of a Notice of Non-compliance. It was noted that these studies had problems with the eye-examination procedures. Therefore, a well-designed, long-term comparative study was conducted specifically designed to determine the potential for cataract formation with inhaled ciclesonide use in comparison with other inhaled corticosteroids, to be submitted in the refile submission.

This study was a multicentre, randomized, double-blind, active-controlled, parallel group, one year, Phase III study intended to compare the effects of inhaled ciclesonide 640 ug/day and beclomethasone 640 ug/day on lens opacification in adult patients with moderate to severe persistent asthma. A total of 1568 subjects were randomized and treated with double-blind study medication (ciclesonide 785; beclomethasone 783 subjects). The following variables were assessed: lens opacity formation, interocular pressure and visual acuity. Lens opacification was evaluated by slit lamp examination. The highly sensitive and well-characterized Lens Opacity Classification system was used to determine changes in lens opacity. Interocular pressure and visual acuity were assessed using standardized methods. With regards to lens opacity measurements, a very low threshold was defined to assure detection of even slight changes in lens opacification. An Independent Data Monitoring Committee was formed to monitor safety throughout the double-blind treatment phase.

The study demonstrated that there were no significant differences between the effects of ciclesonide and beclomethasone with respect to the occurrence of lens opacification. There was one case of cataract surgery in the beclomethasone group; none in the ciclesonide group. The changes from baseline in median intra-ocular pressure and best-corrected visual acuity score were comparable between ciclesonide and beclomethasone, and were not clinically relevant. No single case of glaucoma was reported. In conclusion, this study demonstrated no safety concerns regarding ciclesonide and ocular toxicity.