Boehringer Ingelheim Presents Pivotal Phase III Data for the Investigational Fixed-Dose Combination of Tiotropium + Olodaterol in COPD

RIDGEFIELD, Conn. -- Boehringer Ingelheim today presented the first data from the pivotal Phase III TONADO™ 1&2 studies (NCT01431274/NCT01431287) for the fixed-dose combination (FDC) of tiotropium plus olodaterol delivered via the Respimat® inhaler in patients with moderate to very severe chronic obstructive pulmonary disease (COPD). The data were presented at the European Respiratory Society (ERS) International Congress 2014 in Munich.

Once-daily tiotropium + olodaterol FDC is an investigational combination that includes the long-acting muscarinic antagonist (LAMA) tiotropium with olodaterol, a long-acting beta agonist (LABA), delivered via the propellant-free Respimat® inhaler, which generates a slow-moving mist.

The pivotal 52-week TONADO™ 1&2 studies included more than 5,500 patients with COPD. Results showed that lung function, as measured by trough forced expiratory volume in one second (FEV1), improved in patients receiving tiotropium + olodaterol FDC delivered via the Respimat® inhaler, and that St. George's Respiratory Questionnaire (SGRQ) total score was affected favorably compared to those receiving olodaterol or tiotropium alone.

"The results from the TONADO™ studies showed that the combination has the potential to improve lung function compared to the individual components alone in people with COPD," said Gary T. Ferguson, MD, Pulmonary Research Institute of Southeast Michigan, Livonia, Michigan. "Approximately 15 million Americans have been told by a healthcare provider they have COPD, and this drug combination provides a potential new maintenance treatment option for people with COPD."

TONADO™ 1&2 were 52-week, double-blind, parallel-group studies in which patients with moderate to very severe COPD were randomized to receive olodaterol 5 mcg, tiotropium 2.5 mcg, tiotropium 5 mcg, tiotropium + olodaterol FDC 2.5/5 mcg or tiotropium + olodaterol FDC 5/5 mcg. Primary efficacy endpoints were change from baseline in trough FEV1, FEV1 area under the curve from 0–3 hours and SGRQ total score after 24 weeks. These studies are part of a large Phase III clinical trial program (TOviTO®) for tiotropium + olodaterol FDC, which includes more than 7,000 people with varying severities of COPD worldwide.

In a combined analysis presented at ERS, tiotropium + olodaterol FDC (5/5 mcg) resulted in statistically significant improvements in lung function compared to the individual components (P < 0.001 for each study). The improvement in total SGRQ score for patients treated with tiotropium + olodaterol FDC 5/5 mcg as compared to those receiving olodaterol 5 mcg and tiotropium 5 mcg separately was also statistically significant (P < 0.05 in both cases), but not clinically meaningful.

 

Trough FEV1 responses (mL)

at 24 weeks

SGRQ total score change (points)

at 24 weeks

T+O 5/5 mcg

140

+6.8

T+O 2.5/5 mcg

118

+6.2

Olodaterol 5 mcg

55

+5.1

Tiotropium 2.5 mcg

73

+5.7

Tiotropium 5 mcg

80

+5.6

A combined analysis of TONADO™ 1&2 showed the percentage of patients experiencing any adverse event (AE) in the studies were T+O FDC 5/5 mcg: 74.0 percent; T+O FDC 2.5/5 mcg: 74.7 percent; tiotropium 5 mcg: 73.3 percent; tiotropium 2.5 mcg: 73.4 percent; olodaterol 5 mcg: 76.6 percent.

"The TONADO™ results, together with the VIVACITO™ data presented at a major medical meeting earlier this year, formed the basis of the recent regulatory submission to the U.S. Food & Drug Administration for tiotropium + olodaterol FDC delivered via the Respimat® inhaler," said Tunde Otulana, MD, senior vice president, Clinical Development and Medical Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. "We're encouraged by these findings as we continue to investigate additional options for people living with COPD across different severities."

Additional Data Presented at ERS 2014 
Also presented at ERS for the first time, were data from the 52-week WISDOM (Withdrawal of Inhaled Steroids During Optimised bronchodilator Management) trial. These data were simultaneously published in the New England Journal of Medicine.

The WISDOM study evaluated stepwise withdrawal of inhaled corticosteroids (ICS) in severe to very severe COPD patients with a history of exacerbation. WISDOM was a 12-month, double-blind, parallel-group, active-controlled study in which all patients received triple therapy (tiotropium 18 mcg once daily, salmeterol 50 mcg twice daily and fluticasone 500 mcg twice daily) for a six-week run-in period. Patients were randomized 1:1 to continue triple therapy or stepwise withdrawal of ICS over 12 weeks (dose reduction every six weeks). The primary endpoint was time to first moderate or severe on-treatment exacerbation.

The WISDOM data show that in patients with severe to very severe COPD and a history of exacerbation, the risk of moderate/severe exacerbations during one year of follow-up was non-inferior between those patients who continued on ICS and those where ICS therapy was withdrawn in a stepwise manner, as long as patients continued to receive maintenance treatment with tiotropium and a LABA. 

 

ICS

(n=1243)

ICS Withdrawal
(n=1242)

Patients with an Event (%)

550 (44.2)

580 (46.7)

Median Time to First Event  for first 25% of patients (days/95% CI)

107 days (94, 124)

110 days (99, 120)

The number of patients experiencing any AE was 70.8 percent for those who continued on ICS and 71.7 percent for those where ICS was withdrawn. In the trial, the rate of pneumonia and major adverse cardiac events (MACE) for the ICS withdrawal and ICS-continued treatment groups was pneumonia: 5.5 percent and 5.8 percent, respectively; and MACE: 2.2 percent and 2.0 percent, respectively.

About COPD 
Chronic obstructive pulmonary disease (COPD) is a term including chronic bronchitis and/or emphysema. This disease can make breathing harder because less air is able to flow in and out of the lungs. Chronic lower respiratory diseases, which include COPD, are the third leading cause of death in the United States, and approximately 15 million Americans have been told by a healthcare provider that they have COPD.

The most common symptom of COPD is shortness of breath, especially with physical activities. Coughing, with or without mucus production, is also a common symptom of COPD. These symptoms can be misunderstood as signs of aging.  COPD is usually associated with progressive airway damage and loss that cause breathing to get more difficult.

Leading Respiratory Forward
Through research, Boehringer Ingelheim (BI) has developed drug therapies to help patients with lung diseases. Leveraging the company's cutting edge science and leadership in chronic obstructive pulmonary disease (COPD), BI is researching new treatment approaches where needs persist. It is the company's goal to help patients with COPD, asthma, lung cancer, and idiopathic pulmonary fibrosis.

About Boehringer Ingelheim Pharmaceuticals, Inc.
Boehringer Ingelheim Pharmaceuticals, Inc., based in Ridgefield, CT, is the largest U.S. subsidiary of Boehringer Ingelheim Corporation (Ridgefield, CT) and a member of the Boehringer Ingelheim group of companies.

The Boehringer Ingelheim group is one of the world's 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 142 affiliates and more than 47,400 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel medications of high therapeutic value for human and veterinary medicine.

Social responsibility is a central element of Boehringer Ingelheim's culture. Involvement in social projects, caring for employees and their families, and providing equal opportunities for all employees form the foundation of the global operations. Mutual cooperation and respect, as well as environmental protection and sustainability are intrinsic factors in all of Boehringer Ingelheim's endeavors.

In 2013, Boehringer Ingelheim achieved net sales of about $18.7 billion (14.1 billion euro). R&D expenditure in the Prescription Medicines business corresponds to 19.5% of its net sales.

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