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Indacaterol : A Novel Beta2-agonist for Asthma and COPD
By Novartis Pharmaceuticals
May 24, 2005, 10:54
Novartis' development compound indacaterol (QAB149) may provide a new standard for beta2-agonist therapy in
patients with asthma and chronic obstructive pulmonary disease (COPD), according to data presented at the centenary meeting of the American Thoracic Society (ATS) this week. The collective data from Phase II studies show
indacaterol provides bronchodilation for up to 24-hours, with convenient once-daily dosing.
"Respiratory disease is an important therapeutic area of focus at Novartis," said Alex Gorsky, Chief Operating Officer, Novartis Pharmaceuticals Corporation. "We have designed an ambitious development program for indacaterol and other compounds, such as the recently licensed anticholinergic AD237. We look forward to making new single and combination treatments available for the millions of patients who need them."
Results in Patients
A randomized, double-blind, dose-ranging study (50, 100, 200, 400 ug or placebo) in 42 patients with intermittent or mild to moderate persistent asthma demonstrated effective 24-hour bronchodilation within five minutes and a favorable safety profile with once-daily dosing. Improvements in efficacy were generally dose dependent, while safety and tolerability were similar to placebo.(i)
"Despite advances in the management of these chronic conditions, the numbers of individuals affected by asthma and COPD are large and growing," said James Donohue, M.D., Professor of Medicine, Chief, Division of Pulmonary Critical Care, University of North Carolina School of Medicine. "These data show indacaterol has significant therapeutic potential, including single-dose 24-hour control, for asthma and COPD patients."
A further randomized, double-blind, placebo-controlled, parallel-group, multicenter study involving 156 patients aged 13-75 demonstrated that indacaterol was shown to have a favorable cardiovascular safety profile, with no clinically significant effect on ECG measurements, vital signs or laboratory tests commonly affected by long-duration beta2-agonists.
No clinically notable changes occurred in the mean QTc intervals for any treatment group at any time point (calculated using Fridericia's formula). No clinically or statistically significant changes in serum potassium and blood glucose, or evidence of dose-related increases in adverse events were detected. In addition, no serious adverse events occurred in any active treatment group.(ii)
Indacaterol pre-clinical studies
In addition, extensive pre-clinical studies involving indacaterol also were presented. In isolated human bronchi, indacaterol provides effective bronchodilation with a longer duration of action than albuterol and formoterol
and an onset of action more rapid than salmeterol and comparable to albuterol.
At resting tone, the onset of action of indacaterol (9.2 plus or minus 1.5min, n=8) was not significantly different from that of formoterol (5.8 plus or minus 0.8min, n=8) and albuterol (11.0 plus or minus 3.6min, n=8) but was significantly faster than that of salmeterol (18.0 plus or minus 3.5min, n=8; p less than 0.05).(iii)
In addition, indacaterol was shown to be a potent beta2-agonist that, in contrast to salmeterol, does not antagonize the bronchorelaxant effect of a short-acting beta2-agonist.
Other pre-clinical data demonstrate that indacaterol provides a long duration of action and fast onset in vitro and in vivo in the guinea-pig. The risk of tachyphylaxis, or rapidly decreasing response to a drug, was assessed
in once-daily intratracheal (IT) dosing of indacaterol compared with formoterol and salmeterol. Conscious guinea-pigs were then challenged with aerosolized 5-HT (175ug/mL, 1 min) 2 hours after beta2-agonist exposure following both single and 5 daily IT treatments and bronchoconstriction
quantified by plethysmography. No tachyphylaxis was observed with indacaterol, formoterol or salmeterol.(iv)
Significant Disease Burden
COPD incurs a significant burden on the U.S. healthcare system in terms of number of visits and medications prescribed. Among the papers presented at the ATS meeting was an analysis of data from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey conducted by a team of researchers from Novartis Pharmaceuticals, Rutgers University and Duke University that assessed the disease burden. Results showed that during 2002, 9.9 million ambulatory visits were made to physician offices, outpatient departments and emergency departments in the U.S., representing a 50.1% increase from 2001. In addition, the annual rate of visits for COPD across
all settings was 34.4 visits per 1,000 persons in the U.S. population.(v)
"Asthma-related suffering, cost and death can be greatly reduced through treatment with effective medications," said Mike Tringale, M.S.M., Director of Marketing and Communications at the Asthma and Allergy Foundation of America. "We look forward to seeing what benefit this new treatment will provide and to having a new treatment option for patients."
About Asthma and COPD
Exploring new treatments for asthma and COPD is critical. Despite a wide range of currently available therapeutic options, respiratory diseases affect millions of patients around the world. For example, asthma, which affects
more than 23 million people in the U.S., is the sixth most common chronic condition overall. In addition, the estimated number of asthma-related deaths is approximately 5,000 per year.(vi) COPD is presently the fourth leading
cause of death worldwide and is expected to be the third leading cause of death by 2020. While COPD death rates are very low under the age of 45, complications and deaths increase steeply with age.(vii)
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