New Sub-Analyses Presented for STIOLTO RESPIMAT Across a Range of COPD Patient-Reported Outcomes Measures

RIDGEFIELD, Conn., and MONTREAL, Oct. 27, 2015 /PRNewswire/ -- Boehringer Ingelheim Pharmaceuticals, Inc. today announced the presentation of several new post-hoc analyses from the TONADO® 1&2 and OTEMTO® 1&2 studies at the American College of Chest Physicians Annual Meeting (CHEST 2015) in Montreal. One analysis showed significant lung function improvement, as measured by FEV₁ AUC_0–3, with once daily STIOLTO RESPIMAT across a range of age groups of COPD patients (adult patients less than 65 years, 65- less than 75 years, 75- less than 85 years and greater than or equal to 85 years).

In addition, there were two analyses which showed treatment with STIOLTO RESPIMAT reduced the frequency of night-time rescue medication use, as measured by puffs needed per night, and improved the score of Transition Dyspnea Index (TDI), which is a measure of severity of shortness of breath, in COPD patients, compared to tiotropium, olodaterol or placebo. 

"The results from these pre-planned subgroup analyses of the TONADO® 1&2 and OTEMTO® 1&2 studies provide additional insights into STIOLTO RESPIMAT as an effective treatment option for adult COPD patients across a range of ages, who are most commonly taking a maintenance medicine," said Gary T. Ferguson, MD, Pulmonary Research Institute of Southeast Michigan, Farmington Hills, Michigan, and study investigator. "These data, along with the additional post-hoc analyses presented at the meeting, add to our understanding of STIOLTO RESPIMAT's benefits to COPD patients compared to tiotropium, olodaterol, and placebo."

STIOLTO RESPIMAT was approved in May 2015 for the long-term, once-daily maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema. STIOLTO RESPIMAT is not indicated to treat asthma or acute deterioration of COPD. 

Long-acting beta2-adrenergic agonists, such as olodaterol, one of the active ingredients in STIOLTO RESPIMAT, increase the risk of asthma-related death. STIOLTO RESPIMAT is not indicated for asthma and should not be initiated in acutely deteriorating COPD patients or for the relief of acute symptoms. STIOLTO RESPIMAT is contraindicated in patients with a hypersensitivity to tiotropium, ipratropium, olodaterol, or any component of this product. As with other inhaled medicines, STIOLTO RESPIMAT may cause paradoxical bronchospasm, which means breathing or wheezing worsen, that may be life-threatening. The most common adverse reactions were nasopharyngitis (common cold), cough and back pain.

Please see complete Important Safety Information below.

Key findings include:

• In the subgroup analysis of the replicate, double-blind, parallel-group 52 week TONADO® 1&2 (NCT01431274/NCT01431287) and 12 week OTEMTO® 1&2 (NCT01964352/NCT02006732) studies, once-daily STIOLTO RESPIMAT increased FEV₁ AUC_0-3, a key measure of lung function, across a range of adult COPD patients, compared to tiotropium, olodaterol or placebo. Adjusted mean results were consistent between studies: [Abstract 740A]   
  • T+O 5/5 µg: 0.120 L and 0.151 L in patients <65, T+O 5/5 µg: 0.104 L and 0.096 L in patients 65-<75, and T+O 5/5 µg: 0.085 L and 0.126 L in patients 75-<85 (all comparisons p<0.0001) in TONADO 1&2.
  • T+O 5/5 µg: 0.116 L (P=0.0003) and 0.376 L (p<0.0001)  in patients <65, T+O 5/5 µg: 0.120 L and 0.292 L (both p<0.0001) in patients 65-<75, and T+O 5/5 µg: 0.085 L (p=0.18) and 0.301 L (p<0.0001) in patients 75-<85 in OTEMTO 1. 
  • T+O 5/5 µg: 0.094 L (P=0.004) and 0.322 L (p<0.0001)  in patients <65, T+O 5/5 µg: 0.120 L and 0.303 L (both p<0.0001) in patients 65-<75, and T+O 5/5 µg: 0.092 L (p=0.21) and 0.174 L (p=0.24) in patients 75-<85 in OTEMTO 2. 
• In a post-hoc analysis of the TONADO® 1&2 and OTEMTO® 1&2 studies, treatment with once-daily STIOLTO RESPIMAT significantly reduced night-time rescue medication use compared to tiotropium, olodaterol or placebo  (At week 52: -0.55 puffs/night for T+O 5/5 µg versus T 5 µg (p<0.0001), and -0.28 for T+O 5/5 µg versus O 5 µg (p=0.0014) in TONADO 1&2.  At week 12: -1.00 for T+O 5/5 µg versus placebo (p<0.0001) and -0.42 for T+O 5/5 µg versus T 5 µg (p=0.0002) in OTEMTO 1&2). [Abstract 731A]   
• In an additional post-hoc analysis of TONADO® 1&2 and OTEMTO® 1&2, a significant increase was seen in TDI focal score with once-daily STIOLTO RESPIMAT compared to tiotropium, olodaterol or placebo (At week 24: 0.356 for T+O 5/5 µg versus T 5 µg (p=0.0082) and 0.420 for T+O 5/5 µg versus O 5 µg (p=0.0019) in TONADO 1&2. At week 12: 1.623 for T+O 5/5 µg versus placebo (p<0.0001), and 0.594 for T+O 5/5 µg versus T 5 µg (p=0.0019) in OTEMTO 1&2). [Abstract 726A]   

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. In OTEMTO® 1&2, the incidence of AEs was similar between treatment groups, with no increase in incidence with STIOLTO RESPIMAT compared to tiotropium alone or placebo. The most common adverse reactions in the OTEMTO 1&2 studies were nasopharyngitis, COPD and cough.

"As a leader in COPD care for more than 40 years in the U.S., we're encouraged by these data as we continue to explore the potential benefits of STIOLTO RESPIMAT for COPD patients," said Danny McBryan, MD, vice president, Clinical Development & Medical Affairs, Respiratory, Boehringer Ingelheim Pharmaceuticals, Inc.

The OTEMTO® 1&2 and TONADO® 1&2 trials are part of the more than 15,000 patient TOviTO® Phase III clinical trial program investigating the efficacy and safety of STIOLTO RESPIMAT in COPD. The results build on the pivotal Phase III TONADO® trials that demonstrated STIOLTO RESPIMAT provides significant improvements in lung function (as measured by FEV₁ AUC_0-3hr and trough FEV₁ response) compared to tiotropium RESPIMAT and olodaterol RESPIMAT across a broad range of disease severities (GOLD 2-4), including those with early stage disease.

For additional information, please visit: https://www.Stiolto.com/how-it-works.

About the RESPIMAT® Inhaler
The RESPIMAT is the platform inhaler for the Boehringer Ingelheim respiratory therapies. Only the RESPIMAT inhaler actively delivers a slow-moving mist that helps patients inhale the medication. 

The RESPIMAT inhaler delivers medication independent of inspiratory effort. As with all inhaled drugs, the actual amount of drug delivered to the lung may depend on patient factors, such as coordination between actuation of the inhaler and inspiration through the delivery system. The duration of inhalation should be at least as long as the spray duration (1.5 seconds).

INDICATION for STIOLTO RESPIMAT
Stiolto Respimat (tiotropium bromide and olodaterol) Inhalation Spray is a combination of tiotropium, an anticholinergic, and olodaterol, a long-acting beta2-adrenergic agonist (LABA), indicated for the long-term, once-daily maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

Important Limitations of Use
STIOLTO is NOT indicated to treat acute deterioration of COPD and is not indicated to treat asthma. 

IMPORTANT SAFETY INFORMATION for STIOLTO RESPIMAT

WARNING: ASTHMA-RELATED DEATH
Long-acting beta2-adrenergic agonists (LABA) such as olodaterol, one of the active ingredients in STIOLTO RESPIMAT, increase the risk of asthma-related death. Data from a large, placebo-controlled US study that compared the safety of another long-acting beta2-adrenergic agonist (salmeterol) with placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol. This finding with salmeterol is considered a class effect of all LABA, including olodaterol, one of the active ingredients in STIOLTO RESPIMAT. The safety and efficacy of STIOLTO RESPIMAT in patients with asthma have not been established. STIOLTO RESPIMAT is not indicated for the treatment of asthma.

CONTRAINDICATION
All LABA are contraindicated in patients with asthma without use of a long-term asthma control medication. STIOLTO is contraindicated in patients with hypersensitivity to tiotropium, ipratropium (atropine derivatives), olodaterol, or any component of this product. 

In clinical trials and postmarketing experience with tiotropium, immediate hypersensitivity reactions, including angioedema (including swelling of the lips, tongue, or throat), itching, or rash have been reported. Hypersensitivity reactions were also reported in clinical trials with STIOLTO.

WARNINGS AND PRECAUTIONS
STIOLTO should not be initiated in patients with acutely deteriorating COPD, which may be a life-threatening condition, or used as rescue therapy for acute symptoms. Acute symptoms should be treated with an inhaled short-acting beta2-agonist. Patients who have been taking inhaled, short-acting beta2-agonists on a regular basis should discontinue the regular use of these drugs and use them only for acute respiratory symptoms.

STIOLTO should not be used more often or at higher doses than recommended, or in conjunction with other LABA as an overdose may result.

Immediate hypersensitivity reactions, including urticaria, angioedema, rash, bronchospasm, anaphylaxis, or itching may occur after administration of STIOLTO. If such a reaction occurs, discontinue therapy with STIOLTO and consider alternative treatments. Patients with a history of hypersensitivity reactions to atropine or its derivatives should be closely monitored for similar hypersensitivity reactions to STIOLTO.

If paradoxical bronchospasm occurs, STIOLTO should be discontinued immediately.

STIOLTO can produce a clinically significant cardiovascular effect in some patients, as measured by increases in pulse rate, systolic or diastolic blood pressure, and/or symptoms. If such effects occur, STIOLTO may need to be discontinued.   

Use caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, ketoacidosis, in patients with known or suspected prolongation of the QT interval, and in patients who are unusually responsive to sympathomimetic amines.

Use with caution in patients with narrow-angle glaucoma. Instruct patients to contact a physician immediately if signs or symptoms of acute narrow-angle glaucoma develop (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema).

Use with caution in patients with urinary retention, which can be associated with symptoms like difficulty passing urine and painful urination in patients with prostatic hyperplasia or bladder-neck obstruction. Instruct patients to consult a physician immediately should any of these signs or symptoms develop.

Patients with moderate to severe renal impairment (creatinine clearance of ≤60 mL/min) treated with STIOLTO should be monitored closely for anticholinergic side effects.

Be alert to hypokalemia, which has the potential to produce adverse cardiovascular effects. Be alert to hyperglycemia.

ADVERSE REACTIONS
The most common adverse reactions with STIOLTO (>3% incidence and higher than any of the comparators – tiotropium and/or olodaterol) were: nasopharyngitis, 12.4% (11.7%/12.6%), cough, 3.9% (4.4%/3.0%), and back pain, 3.6% (1.8%/3.4%).

DRUG INTERACTIONS

• Use caution if administering adrenergic drugs because sympathetic effects of olodaterol may be potentiated.
• Concomitant treatment with xanthine derivatives, steroids, or diuretics may potentiate any hypokalemic effect of olodaterol.
• Beta agonists, such as olodaterol, can acutely worsen the ECG changes and/or hypokalemia that may result from administration of non-potassium sparing diuretics. The action of adrenergic agents on the cardiovascular system may be potentiated by monoamine oxidase inhibitors or tricyclic antidepressants or other drugs known to prolong the QTc interval. Therefore beta-agonists should be used with extreme caution in patients being treated with these drugs. Drugs that prolong the QTc interval may be associated with an increased risk of ventricular arrhythmias.
• Beta-blockers should be used with caution as they can inhibit the therapeutic effect of beta agonists which may produce severe bronchospasms in patients with COPD. However, under certain circumstances, e.g. as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-blockers in patients with COPD. In this setting, cardio selective beta-blockers could be considered, although they should be administered with caution.
• Avoid co-administration of STIOLTO with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects.

STIOLTO is for oral inhalation only. The STIOLTO cartridge is only intended for use with the STIOLTO RESPIMAT inhaler.

Inform patients not to spray STIOLTO into the eyes.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

Please click for full Prescribing Information, Medication Guide and Instructions for Use for STIOLTO RESPIMAT.  

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, treatments and patient-centric support services, the Boehringer Ingelheim (BI) lung health portfolio is designed to help address the challenges people living with a lung disease face every day. 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 make a difference in the lives of patients with COPD, asthma, lung cancer, idiopathic pulmonary fibrosis and other respiratory diseases.

About Boehringer Ingelheim Pharmaceuticals, Inc.
Boehringer Ingelheim Pharmaceuticals, Inc., based in Ridgefield, CT, is the largest U.S. subsidiary of Boehringer Ingelheim Corporation.

Boehringer Ingelheim is one of the world's 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, the company operates globally with 146 affiliates and more than 47,000 employees. Since its founding in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel treatments for human and veterinary medicine.

Boehringer Ingelheim is committed to improving lives and providing valuable services and support to patients and families.  Our employees create and engage in programs that strengthen our communities. To learn more about how we make more health for more people, visit our Corporate Social Responsibility Report.

In 2014, Boehringer Ingelheim achieved net sales of about $16.96 billion dollars (13.3 billion euros). R&D expenditure corresponds to 19.9 percent of its net sales.

For more information please visit www.us.boehringer-ingelheim.com, or follow us on Twitter @BoehringerUS.

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