Poster Number GS-424020 – A Novel Mutual Prodrug of Salmeterol and Desisobutrylciclesonide Attenuates Acute Bronchoconstriction in the Absence of Cardiovascular Side-Effects in Ragweed Sensitized and Naïve Dogs Gilead Sciences, Inc. American Thoracic Society 199 East Blaine St. International Conference EG Barrett,1 K Rudolph,1 C Royer,1 P Kuehl,1 B Lu,2 MR Wright,2 WR Baker,3 and CD Wright3 Seattle, Washington 98102 May 14-19, 2010 Tel: (206) 832-2020 New Orleans, Louisiana, USA Lovelace Respiratory Research Institute, Albuquerque, NM; Gilead Sciences, Inc.; 2Foster City, CA and 3Seattle, WA Fax: (206) 832-1965 Abstract Results Rationale: GS-424020 is a novel mutual prodrug of salmeterol and desisobutrylciclesonide for use by inhaled delivery to the lung, where it is cleaved to its components. The prodrug is designed to allow local metabolism to the active forms of the parent constituents Figure 1. Allergen-Induced Bronchoconstriction in Ragweed-Sensitized Sogs Figure 4. Inhaled LABA Induces Heart Rate Increases in Dogs Inhaled GS-424020 Does Not Result in Systemic Exposure to LABA in Dogs
at the site of action while eliminating side effects by escape to systemic circulation. Methods: Vehicle, salmeterol, ciclesonide and GS-424020 were given by inhalation to ragweed (RW)-sensitized dogs 1 hr prior GS-424020 Dose
to challenge with ragweed. The dogs were challenged with a previously determined dose of ragweed that led to an immediate
bronchoconstriction (~300 – 400% increase in airway resistance). Changes in airway resistance were continuously measured for up
20 μg/kg 60 μg/kg 100 μg/kg 200 μg/kg 360 μg/kg
to 20 minutes after the peak response to inhaled ragweed. Additionally, naive dogs were instrumented with telemeters to measure
changes in heart rate. Dogs were treated with vehicle, salmeterol, ciclesonide and GS-424020 by inhalation and then monitored for 4 hr.
(nM•hr) 20.0 ± 8.8
Periodic blood samples were collected to determine systemic drug levels. GS-424020
74.9 ± 52.9 91.3 ± 25.5 125 ± 75.0 281 ± 93.1
Results: Treatment with GS-424020 (20 μg/kg) or salmeterol (10 μg/kg) led to a signifi cant reduction in RW-induced bronchoconstriction,
69 and 71%, respectively (p<0.001). There was no signifi cant effect with ciclesonide alone. Salmeterol at 1, 3, and 10 μg/kg led
AUC (nM•hr)
to a signifi cant increase in heart rate (HR) in naive dogs (mean HR over 4 hr; vehicle = 72, salmeterol = 110*, 132* and 166** BPM,
Des-Ciclesonide
respectively; *p<0.01; **p<0.001) while GS-424020 at 20, 60, 100, 200 and 360 μg/kg led to an average HR of 81, 87, 102*, 105**,
and 87, respectively (*p<0.05; **p<0.01). Elevated HR following salmeterol treatment was associated with signifi cant blood levels of drug
(2.4, 10.7, 22.9; AUC ; nM•hr) while blood levels of salmeterol after GS-424020 administration were below the limit of detection. (nM•hr) Conclusions: These results indicate that inhaled GS-424020 inhibits immediate RW-induced bronchoconstriction, as well as salmeterol Salmeterol
alone or salmeterol+ciclesonide in combination while inducing minimal cardiovascular effects at effi cacious doses. Mutual Prodrug Concept for Asthma Treatment
Limits of Quantitation: GS-424020 (1 nM); Des-ciclesonide (2 nM); Salmeterol (1 nM)
Vehicle, salmeterol, ciclesonide and GS-424020 were given by inhalation to ragweed (RW)-sensitized dogs 1 hr
• Inactive, single molecule, new molecular entity with:
prior to challenge with ragweed. The dogs were challenged with a previously determined dose of ragweed that led
Figure 6. Inhaled LABA Induces Decreased Serum Levels of Glucose
to an immediate bronchoconstriction (~300 – 400% increase in airway resistance). Changes in airway resistance
– Anti-infl ammatory properties of an inhaled corticosteroid and bronchodilation properties
and Potassium in Dogs: No Effect of GS-424020
were continuously measured for up to 30 minutes after the peak response to inhaled ragweed.
of a long acting β adrenergic receptor agonist (ICS/LABA) combination
Statistical analysis by repeated measures ANOVA with Bonferroni’s multiple comparison post-test
– Anti-infl ammatory effi cacy superior to current ICS/LABA combinations
Figure 2. GS-424020 and Salmeterol Exhibit Equivalent Bronchodilation Activity
– Amphiphilic, large molecular weight compound for long pulmonary residence time
in Dogs Sensitized and Challenged with Ragweed
– Rapidly cleared when absorbed through the lung thus minimizing adverse events
Inhaled LABA Results in Dose-Dependent Increase in Plasma Levels in Dogs
• Planned metabolic break down in the lung to active components
Salmeterol Dose
• Systemic exposure of component drugs is minimized
10 μg/kg AUC (nM•hr) Objectives Salmeterol
• GS-424020 is a novel mutual prodrug of salmeterol and desisobutrylciclesonide that is
enzymatically cleaved in the lung to its components
• It is designed to allow local metabolism to the active forms of the parent constituents at the
site of action, thus increasing retention in the lung while eliminating side effects by escape
Figure 5. Inhaled GS-424020 Does Not Induce Heart Rate Increases in Dogs
to systemic circulation due to its prodrug form
Statistical analysis by repeated measures ANOVA
• The purpose of this study was to evaluate the effi cacy and cardiovascular safety profi le
With Bonferroni’s multiple comparison post test
Dotted line: lower limit of reference values
of GS-424020 in ragweed sensitized Beagle dogs
10 mg/kg 3 mg/kg 10 mg/kg 6 mg/kg 20 mg/kg
Structure of GS-424020
Statistical analysis by paired two-tailed t-test
Salmeterol Conclusions Figure 3. Effects of Inhaled GS-424020 and LABA on Heart Rate in Naive Beagle Dogs Effi cacy • GS-424020 and Salmeterol exhibit equivalent bronchodilation activity in dogs sensitized and challenged with ragweed • Salmeterol (inhaled) induces heart rate increases in dogs • Increased heart rates are associated with increased systemic levels of Salmeterol • GS-424020 (inhaled) does not induce heart rate increase,
Additionally, naive Beagle dogs were instrumented with Data Sciences International D70-PCT telemeters (no less
consistent with lack of systemic exposure to Salmeterol
than 12 months prior to this study) in order to continuously monitor changes in heart rate. Dogs were treated with
[5-[1-hydroxy-2-[6-(4-phenylbutoxy)hexylamino]ethyl]-2-phosphonooxybenzyl]-(diethyl)-[[11β,16α]-[[15,16-((R)-
• GS-424020 (inhaled) does not induce decreased serum levels of
vehicle, salmeterol, ciclesonide and GS-424020 by inhalation and then monitored for 4 hr. Periodic blood samples
Statistical analysis by repeated measures ANOVA with Bonferroni’s multiple comparison post-test
cyclohexylmethylene)bis(oxy)]-11-hydroxypregna-1,4-diene-3,20-dion-21-yl]carbonylmethyl]ammonium chloride
were collected to determine systemic drug levels
glucose and potassium associated with Salmeterol treatment
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ROBERT KEVIN BLACKBURN EXPERIENCE Mass Spectrometry Laboratory Supervisor (Feb 2007 – Present) Molecular and Structural Biochemistry, North Carolina State University, Raleigh, NC Investigator (April 2001 – December 2006) Disease and Biomarker Proteomics, GlaxoSmithKline, Inc., Research Triangle Park, NC Research Scientist (August 1994-March 2001) Department of St