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Monday, September 8, 2014

Boehringer Ingelhem presents data of its clinical trial WISDOM on new COPD drug at ERS meeting

 Boehringer Ingelheim Presents Pivotal Phase III Data for the Investigational Fixed-Dose Combination of Tiotropium + Olodaterol in COPD
Additionally, data from the WISDOM trial on stepwise withdrawal of ICS in COPD was also presented at ERS.

RIDGEFIELD, Conn., September 8, 2014 – 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 μg, tiotropium 2.5 μg, tiotropium 5 μg, tiotropium + olodaterol FDC 2.5/5 μg or tiotropium + olodaterol FDC 5/5 μg. 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 μg) 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 μg as compared to those receiving olodaterol 5 μg and tiotropium 5 μg 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 μg 140 +6.8
T+O 2.5/5 μg 118 +6.2
Olodaterol 5 μg 55 +5.1
Tiotropium 2.5 μg 73 +5.7
Tiotropium 5 μg 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 μg: 74.0 percent; T+O FDC 2.5/5 μg: 74.7 percent; tiotropium 5 μg: 73.3 percent; tiotropium 2.5 μg: 73.4 percent; olodaterol 5 μg: 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 μg once daily, salmeterol 50 μg twice daily and fluticasone 500 μg 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.

For more information please visit http://www.us.boehringer-ingelheim.com
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New Phase III Study Shows Investigational Tiotropium Improves Lung Function in Adolescent Patients with Symptomatic Asthma

RIDGEFIELD, Conn., September 8, 2014 – Boehringer Ingelheim today presented new data from the company's Phase III trial program (UniTinA-asthma®) evaluating tiotropium in asthma, including the first study assessing the efficacy and safety of tiotropium in adolescent patients with symptomatic asthma. These data were unveiled during an oral session at the European Respiratory Society (ERS) International Congress 2014 in Munich, Germany. Tiotropium is being studied to determine its efficacy and safety in treating asthma patients and is not currently approved for this indication.
The first presentation of Phase III results from the RubaTinA-asthma® (NCT01257230) study demonstrated tiotropium's potential benefit among adolescents with moderate persistent asthma. The data presented at ERS show tiotropium 5 μg delivered via the Respimat® inhaler statistically significantly improved lung function, as measured by forced expiratory volume in one second (FEV1) response, in adolescent patients with asthma who remain symptomatic.
"Asthma is a leading cause of chronic illness among young people in the U.S.," said Mark Vandewalker, MD, director, Clinical Research of the Ozarks, Columbia, Missouri. "The results of this Phase III trial provide important insight into the potential role of investigational tiotropium in treating adolescent patients who require additional asthma control despite treatment with usual maintenance therapy."
In the Phase III RubaTinA-asthma® study, adolescent asthma patients (12-17 years) were randomized to receive once-daily tiotropium 5 μg, tiotropium 2.5 μg or placebo as add-on to inhaled corticosteroids (ICS) maintenance therapy over 48 weeks. The primary endpoint was peak FEV1—a measure of the amount of air exhaled in one second—within three hours of dosing (FEV1(0-3h) response), evaluated at Week 24. Additional endpoints included other breathing measurement tests, evaluations of symptom control and assessments of adverse events (AEs).
Tiotropium 5 μg delivered via the Respimat® inhaler demonstrated statistically significant improvement across lung function measurements, as compared to placebo, at 24 and 48 weeks.
Tiotropium Respimat 5 μg Tiotropium Respimat 2.5 μg
24 weeks 48 weeks 24 weeks 48 weeks
Mean Peak FEV1 (0–3h) 174 mL
(p=0.0005)
134 mL
(p=0.0085)
174 mL
(p=0.0006)
176 mL
(p=0.0007)
Trough FEV1 117 mL
(p=0.0320)
157 mL
(p=0.0044)
84 mL
(p=0.1307)
137 mL
(p=0.0154)
PEFam ± SE* 15.82 L/min ± 6.87
(p=0.02)
19.62 L/min ± 7.02
(p<0.01)
9.72 L/min ± 7.04
(p=0.17)
14.04 L/min ± 7.17
(p=0.05)
PEFpm ± SE* 16.69 L/min ± 6.73
(p=0.01)
18.21 L/min ± 6.85
(p<0.01)
12.25 L/min ± 6.90
(p=0.08)
15.27 L/min ± 7.05
(p=0.03)
*Adjusted mean difference plus/minus standard error
Overall, AEs were reported in 62.7 percent of those treated with tiotropium 5 μg, 63.2 percent of those treated with tiotropium 2.5 μg and 59.4 percent of those in the placebo group. The most common individual AEs were asthma, nasopharyngitis, viral respiratory tract infection and headache.
"Finding new therapies for the growing number of people living with and affected by asthma is an important priority for Boehringer Ingelheim," said Tunde Otulana, MD, senior vice president, Clinical Development and Medical Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. "We are encouraged by these latest data from the UniTinA-asthma® program and they are an important addition to the growing data supporting the potential use of tiotropium in treating asthma patients across ages and severities. These data indicate tiotropium's potential benefit in asthma may be extended to adolescents who continue to need additional treatment options for their asthma."
Additional Data Presented at ERS 2014
During the same oral session today, Boehringer Ingelheim presented data from a secondary analysis of six Phase III studies from the UniTinA-asthma® clinical trial program involving adults with symptomatic asthma. In the six studies, once-daily tiotropium was given as add-on treatment to patients with varying severities of asthma who remained symptomatic despite maintenance therapy of ICS or ICS/long-acting beta agonist (LABA).
To measure asthma control, investigators looked at the Asthma Control Questionnaire (ACQ-7) score of patients in previous Phase III studies of tiotropium in asthma. The definition of responder used in this trial was characterized as patients with an improvement in responder rate of ≥ 0.5 for the ACQ.
Data from the analysis demonstrate that the addition of once-daily tiotropium delivered via the Respimat® inhaler to maintenance asthma therapy is associated with an improvement in asthma control responder rate, as measured by the ACQ-7, among adult patients with mild, moderate and severe symptomatic asthma.

ACQ-7 Responder Rate n (%)
Tiotropium Respimat
5 μg
Tiotropium Respimat
2.5 μg
Placebo Respimat
PrimoTinA – Week 48 (NCT00772538/6984) 263 (58.1) -- 205 (45.2)
MezzoTinA – Week 24
(NCT01172808/2821)
330 (64.3) 332 (64.5) 299 (57.7)
GraziaTinA – Week 12
(NCT01316380)
90 (58.1) 91 (59.1) 91 (58.7)
CadenTinA– Week 52
(NCT01340209)
87 (76.3) 81 (71.1) 41 (73.2)

Additionally at ERS 2014, a pooled study evaluating the safety of tiotropium compared to placebo in five Phase III and one Phase II trial was presented. In the six trials, adults with asthma received tiotropium delivered via the Respimat® inhaler as add-on to at least ICS maintenance therapy.
Adverse Event Occurring in >2 percent of Patients
Tiotropium Respimat 5 μg Tiotropium Respimat 2.5 μg Placebo Respimat
Any AE 58.3 percent 52.0 percent 61.3 percent
Serious AE 4.1 percent 1.8 percent 4.4 percent

The most common individual AEs were asthma, peak expiratory flow (PEF) rate decrease and nasopharyngitis.

About the UniTinA-Asthma® Clinical Trial Program
The comprehensive Phase III trial program, UniTinA-asthma®, includes a number of clinical trials in adults, adolescents and pediatric patients across different asthma severities who remain symptomatic on maintenance treatment with at least inhaled corticosteroid (ICS). The program includes over 4,000 patients in more than 150 sites globally.

About Asthma
Asthma is a chronic disease characterized by airway inflammation and bronchoconstriction. When a person with asthma comes into contact with an asthma trigger (e.g. infections, pollen, smoke), their airways can become inflamed, swollen and constricted and excess mucus is produced. These reactions can cause the airways to become narrower and irritated, making it difficult to breathe. People suffering from asthma experience recurrent episodes of wheezing, breathlessness, chest tightness and coughing. Asthma attacks occur when symptoms become more intense or frequent.

As of December 2012, an estimated 300 million people worldwide suffer from asthma. Estimates have shown that the number of people with asthma could grow by an additional 100 million people worldwide by 2025.

By avoiding asthma triggers, one can help to reduce the severity of asthma. Although asthma cannot be cured, appropriate management can control the disease in many patients. Despite current treatment options, approximately 40 percent of patients with asthma remain symptomatic.

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.

For more information please visit http://www.us.boehringer-ingelheim.com
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