indacaterol
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indacaterol
SNAPSHOT
DEVELOPMENT PROFILE
SUMMARY
sidselrasmussen
Novartis  has developed and launched an inhaled once-daily formulation of  indacaterol (QAB-149; Onbrez Breezhaler; Hirobriz Breezhaler; Oslif Breezhaler; Arcapta Neohaler, Onbrize), a long-acting beta-2 agonist (LABA) and bronchodilator,  delivered with SkyePharma's SkyeHaler  multidose dry powder inhaler (presumed to be called Concept-1) [515635]. The product is indicated  in Europe for the maintenance bronchodilator treatment of airflow obstruction in adults with chronic obstructive pulmonary disease (COPD) [1178904], [1205254]. In the US the product is indicated for the long term, once-daily maintenance bronchodilator treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema [1205254].
By December 2009, the product had been launched in Germany as Onbrez Breezhaler [1061875], [1070827]; in August 2010, the product was launched  in the UK and Portugal [1355854],  [1384122].  In September 2011, the product (150-microg dose) was launched in Japan for COPD [1224226]; in December 2011, Eisai began co-marketing the drug with Novartis in Japan [1241372], [1259590]. In March 2012, the product was launched for COPD in the US as Arcapta Neohaler [1272925].
Novartis was developing the formulation for the potential treatment of asthma. In September 2007, Novartis initiated a p
hase III trial in  asthma patients; in August 2008, the trial was completed  [835922]. However, in March 2011, the company stated that it did not intend to seek an indication for asthma [1174333].
Novartis is also investigating  indacaterol in combination with NVA-237 (NVA-237/indacaterol fixed dose combination, Novartis).
The drug carries a boxed warning that LABAs increase the risk of asthma-related death and should not be used in asthmatics, unless with a long-term asthma control medication [1205007]. In July 2011, a risk evaluation and mitigation strategy (REMS) was approved, requiring an analysis of patients' understanding of the increased risk of asthma-related deaths and safe use of LABAs. In December 2012, the FDA released the drug from its REMS because the REMS had met its goals [1453236].
PATENTS AND GENERICS
In January 2014, patent protection for indacaterol was expected to expire in  2025 in the US (including patent term extension), 2024 in the EU (including extensions), 2025 in Japan  and in 2020 in other markets [1528447].
REGULATORY
THE US
In 2008, the drug was filed in the US for COPD [979537].  However, in October 2009, the FDA issued a Complete Response Letter requesting more information on the dosing of the drug. The company planned to assess the data on the drug with the agency to decide if further clinical trials were needed [1050324]. In April 2010, the company disclosed that all clinical studies to support resubmission had begun and in September 2010, data from additional studies were submitted to the FDA [1092088], [1144561]. By January 2011, the filing had been resubmitted [1161452]. In March 2011, the FDA's Pulmonary-Allergy Drug Advisory Committee recommended approval of indacaterol (75 microg) for the once-daily long-term bronchodilator maintenance treatment of airflow obstruction in COPD patients, including chronic bronchitis and/or emphysema. However, the panel recommended non-approval of the 150 microg dose [1174333]. In March 2011, the FDA extended its review period by 3 months. No additional data were requested [1178857]. In July 2011, the FDA approved the 75-microg dose of the drug (as Arcapta Neohaler) for the long-term maintenance bronchodilator treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema  [1205014], [1205007]. In March 2012, the product was launched [1272925].
In 2008, the drug was filed in the EU  for COPD [979537]. In September 2009, the CHMP recommended the drug for approval for the maintenance treatment of COPD at doses of 150 and 300 microg [1045417], [1045387]. In November 2009, the drug was approved in the EU for maintenance treatment for COPD under the tradename Onbrez Breezhaler [1061875], [1272925];  at that time,  the drug was approved in the Netherlands [1435875], and subsequently launched [
1435876];  at that time,  the drug was approved in the Czech Republic and subsequently launched [1445998], [1444818]; and also, the drug was approved in Latvia  and Estonia  [1457030], [1461521].  It had been launched in Germany by December 2009 [1070827]; at that time, the drug was approved in Iceland [1451030] and subsequently launched [1450511] and launched in Ireland and Denmark in March 2010 [1092088]; at that time, the drug was launched in Norway [1458163]. In  August 2010, the product was launched  in the UK [1355854] and in Portugal as Onbrez Breezhaler  [1384122]. In November 2010, it was launched  in France [1352172]. In  December 2010, the drug was launched in Sweden [1411516]. By April 2011, the product had been launched in more than 15 EU countries [1186339].  In June 2011, Chiesi launched the drug in Italy [1336159]. By November 2013, Onbrez Breezhaler had been launched in Spain for the treatment of COPD [1582942].
JAPAN
In July 2010, an NDA was filed for COPD in Japan [1125770]. In May 2011, indacaterol was recommended for approval in Japan [1206075]; approval was subsequently granted in July 2011 [1208512]. In September 2011, the 150-microg dose was launched for COPD under the brandname Onbrez Inhalation Capsules [1224226].
CHINA
By October 2010, a filing had been submitted in China [1141080]; by June 2012, the product had been approved in Chi
na [1309683].
REST OF THE WORLD
By September 2010, the drug had been approved in Australia, India, Indonesia and Korea, and a number of countries in Latin America [1132594]. In October 2010, the drug was approved as Onbrez Breezhaler inhalation powder (150 microg  doses) for the maintenance treatment of chronic obstructive pulmonary disease [1522857]. The product was assumed to be launched shortly after its approval there [1522858]. It was assumed that the drug was approved in Taiwan shortly after its approval there in October 2010 [1523932], [1509402]. By March 2011, indacaterol (150 and 300 microg  doses) had been approved in more than 50 countries worldwide [1174333]. In August 2012, the agent (as Onbrez Breezhaler) was launched in Korea [1452449].
By April 2012, the drug had been launched in Chile as Onbrize, presumably for COPD [1351928].
By July 2013, the product had been approved for the treatment of COPD in Canada as Onbrez Breezhaler. At that time, launch occurred [1451164], [1451118].
POSTMARKETING
In September 2012, pooled data from three clinical studies presented at the European Respiratory Society Congress in
Vienna, Austria, showed that in patients with more severe dyspnoea  a 300-microg dose of indacaterol was more effective than lower doses or tiotropium [1319448].
In February 2012, a phase IV, global, randomized, double-blind, parallel-group, 26-week trial
(NCT01555138; CQAB149B2401; 2011-003732-31; INSTEAD) began in Argentina, Columbia, Malaysia, Mexico and Europe in patients (expected n = 600) with moderate COPD and no exacerbations in the prior year switched from Seretide (salmeterol/fluticasone propionate 50/500 microg bid) to indacaterol (150 microg once daily). The primary endpoint was trough FEV1 at week 12 [1550517]. In April 2014, topline data from the 581-patient trial showed non-inferiority of indacaterol to Seretide [1550369].
PREMARKETING
PHASE III
In September 2007, Novartis initiated a 26-week, randomized, multicenter, double blind, parallel group, phase III study (NCT00529529; CQAB149B2338) to assess the safety of indacaterol (300 and 600 microg) in patients (over 12 years old, n = 750) with moderate to severe persistent asthma, using salmeterol (50 microg, bid) as an active control. The trial was no longer recruiting subjects by February 2008 and  it was completed in August 2008 [835922].
PHASE II
In November 2006, a placebo controlled, randomized, double blind, dose-ranging, phase II trial
(NCT00403754) was initiated in Japan in subjects (expected n = 40) with asthma. The subjects were to receive indacaterol (150, 300 and 600 microg) followed by salmeterol (50 microg bid). The primary endpoint was measured by the forced expiratory volume of breath in 1 s (FEV1) 22 to 24 h after treatment. The study was completed in November 2007 [885968].
In November 2003, Novartis presented data from a phase IIa crossover trial in 42 patients of age 24 to 64 years with mild to moderate asthma. In the study, each patient received 5 single dose treatments (1 day of treatment followed by 5 to 14 days of wash-out period) of either indacaterol 50 microg, 100 microg, 200 microg, 400 microg or placebo. Indacaterol was shown to have a rapid onset of action (as early as 5 min). At this time, a phase IIb program, including a dose-refining study, was planned to start in early 2004 [513950]. Similar data were reported in May 2005 at the American Thoracic Society (ATS) annual meeting in San Diego, CA [603221],  [606270].
In a clinical trial, once-daily dosing of 25  (n = 8), 300  (n = 8) and 600 microg (n = 8) of indacaterol all demonstrated a response in mild asthma patients compared to placebo [467458].
CHRONIC OBSTRUCTIVE PULMONARY DISEASE
PHASE III
In September 2012,  data from a double-blind placebo-controlled, 26-week study, randomized study in a predominantly Chinese population were presented at the European Respiratory Society Congress in Vienna, Austria. Patients (n = 563) with moderate-to-severe COPD received 150 or 300 microg indacaterol or placebo. Both drug doses significantly improved trough FEV1 versus placebo. Transition dyspnea index (TDI) total score at week 26 was superior to placebo for both drug doses,  as was percentage of pts with a clinically relevant TDI score. Both doses improved  St George's Respiratory Questionnaire (SGRQ) total score at week 26. Incidences of adverse events were similar with drug or placebo [1319454].
In May 2012, a phase IIIb, randomized, double-blind, parallel-group trial (NCT01604278; CNVA237A2316; 2011-005673-23; GLOW6) began in Belgium, Bulgaria, Greece, Hungary, Ireland, Russia, Slovakia, Spain, Turkey and the UK in patients (n = 671) with moderate to severe COPD to compare NVA-237 (50 microg) plus indacaterol (150 microg) with indacaterol (150 microg). The primary endpoint was trough FEV1 at week 12. In January 2013, the trial was completed [1409079]. In April 2013, results were reported, demonstrating that the primary endpoint was met and that NVA-237 plus indacaterol was superior to indacaterol alone; the combination resulted in a statistically significant improvement in FEV1 and a statistically significant reduction in dyspnea [1408736].