FDA Approves Boehringer Ingelheim’s OFEV^® (nintedanib) as First Kinase Inhibitor to Treat Idiopathic Pulmonary Fibrosis

RIDGEFIELD, Conn., October 15, 2014 – Boehringer Ingelheim Pharmaceuticals, Inc. today announced that the U.S. Food and Drug Administration (FDA) approved OFEV^® (nintedanib) capsules for oral use for the treatment of idiopathic pulmonary fibrosis (IPF). Granted Breakthrough Therapy designation during its review by the FDA, OFEV, capsules for oral use, taken twice daily, is the only kinase inhibitor approved to treat IPF. OFEV will be available to patients within 10 days.

IPF is a rare and fatal lung disease that affects as many as 132,000 Americans. Most people with IPF only live three to five years after diagnosis. IPF typically affects men over the age of 65.

“While the cause of IPF is unknown and there is no known curative treatment, the unfortunate patients confronted with the disease and physicians caring for patients in the U.S. have been anxiously awaiting FDA-approved treatments,” said Ganesh Raghu, M.D., Professor of Medicine, University of Washington in the Division of Pulmonary and Critical Care Medicine and Director of Center for Interstitial Lung Diseases at University of Washington Medical Center, Seattle, WA. “In three clinical trials, nintedanib slowed lung function decline compared to placebo. This approval is a welcome development for patients and caregivers and it provides hope for those who are living with this devastating disease.”

Decline in lung function, the primary endpoint, was measured by Forced Vital Capacity (FVC in mL) over one year (annual rate of decline) versus placebo. FVC is the volume of air that can be forcibly exhaled after full inhalation.

In research, Boehringer Ingelheim discovered that nintedanib, a kinase inhibitor, blocks growth factor receptors implicated in IPF – including the vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR) and platelet-derived growth factor receptor (PDGFR).

“This approval is a major milestone in IPF with OFEV demonstrating a significant impact on the slowing of lung function decline and a significant reduction in the risk of a first acute exacerbation of IPF over 52 weeks,” said Tunde Otulana, M.D., a pulmonologist and senior vice president, Clinical Development and Medical Affairs at Boehringer Ingelheim. “As a research-driven pharmaceutical company, moments like these, when we can bring a treatment option to patients who are very much in need, makes us extremely proud and inspires us to continue our quest for effective therapies to positively impact patients’ lives.” 

To support people living with IPF who will be prescribed OFEV, Boehringer Ingelheim has developed OPEN DOORS^™ – a comprehensive patient support program that will provide a broad range of financial and nursing support services. Accessible through www.OFEV.com and at 1-866-673-6366, OPEN DOORS^™ services and resources include:

• Access to nurse support 24 hours a day, 7 days a week
• Assistance in finding financial resources to support access to OFEV
• Access to information about IPF and assistance in identifying local resources, such as support groups

The most common adverse reactions (occurring in greater than or equal to 5%) in OFEV-treated patients compared to those taking placebo were diarrhea (62% vs. 18%), nausea (24% vs. 7%), abdominal pain (15% vs. 6%), liver enzyme elevation (14% vs. 3%), vomiting (12% vs. 3%), decreased appetite (11% vs. 5%), weight decrease (10% vs. 3%), headaches (8% vs. 5%) and hypertension (5% vs. 4%). 

About the OFEV^® Pivotal Trials
The approval of OFEV is based on findings from one Phase 2 trial (TOMORROW^™; NCT00514683) and two Phase 3 trials (INPULSIS^™-1 and INPULSIS^™-2; NCT01335464 and NCT01335477), which were randomized, double-blind, placebo-controlled trials comparing OFEV 150 mg twice daily to placebo for 52 weeks. Both INPULSIS^™ trials were identically designed while the TOMORROW^™ study design was similar. The Phase 2 trial and two Phase 3 trials are referred to as Study 1, Study 2, and Study 3, respectively, in the product label.

The primary focus of the trials, which involved more than 1,200 people with IPF, was to evaluate OFEV’s effectiveness on slowing the decline in lung function, as measured by FVC over one year versus placebo.

All three trials demonstrated a consistent, statistically significant reduction in annual rate of decline in FVC with OFEV versus placebo.

• Study 1 (n=167):  68% relative reduction (-60 vs. -191 ml/year)
• Study 2 (n=513):  52% relative reduction (-115 vs. -240 ml/year)
• Study 3 (n=548):  45% relative reduction (-114 vs. -207 ml/year)

A secondary endpoint from the studies included time to first acute IPF exacerbation (i.e., a sudden and severe worsening of IPF). Time to first acute IPF exacerbation was adjudicated (i.e., determined by a committee of doctors based on patient health records) in Studies 2 and 3, and investigator-reported (as determined by the patient's doctor) in Study 1. In Study 1 and Study 3, the risk of first acute IPF exacerbation over 52 weeks was significantly reduced in patients receiving OFEV compared to placebo. In Study 2, there was no difference between the treatment groups.

• In Study 1: Hazard Ratio: 0.16, 95% CI: 0.04, 0.71
• In Study 3: Hazard Ratio: 0.20, 95% CI: 0.07, 0.56
• In Study 2: Hazard Ratio: 0.55, 95% CI: 0.20, 1.54

Survival was evaluated for OFEV compared to placebo in Studies 2 and 3. The studies did not show a statistically significant difference in all-cause mortality (death due to any cause) between OFEV and placebo.

• Study 2 & 3: Hazard Ratio: 0.70, 95% CI: 0.43, 1.12

For most patients experiencing diarrhea, nausea and vomiting, these events were mild to moderate in intensity, and diarrhea occurred within the first three months of treatment. Investigators had the option of symptomatic treatment, dose reduction, treatment interruption or discontinuation to manage adverse events in clinical trials. Diarrhea led to permanent dose reduction in 11% of OFEV-treated patients (vs. 0% on placebo) and treatment discontinuation in 5% of patients taking OFEV compared to less than 1% of placebo-treated patients. Nausea and vomiting led to discontinuation of OFEV in 2% and 1% of patients, respectively.

Patient support offered by Boehringer Ingelheim includes a comprehensive side effect management program to assist patients taking OFEV who experience adverse reactions.

The most frequent serious adverse reactions reported in patients treated with OFEV, more than placebo, were bronchitis (1.2% vs. 0.8%) and myocardial infarction (1.5% vs. 0.4%). The most common adverse events leading to death in patients treated with OFEV, more than placebo, were pneumonia (0.7% vs. 0.6%), lung neoplasm malignant (0.3% vs. 0%), and myocardial infarction (0.3% vs. 0.2%). In the predefined category of major adverse cardiovascular events (MACE) including myocardial infarction, fatal events were reported in 0.6% of OFEV treated patients and 1.8% of placebo-treated patients.

About OFEV^® (nintedanib) capsules for oral use

Indication and Usage

OFEV is indicated for the treatment of idiopathic pulmonary fibrosis (IPF).

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Elevated Liver Enzymes
The safety and efficacy of OFEV has not been studied in patients with moderate (Child Pugh B) or severe(Child Pugh C) hepatic impairment.  Treatment with OFEV is not recommended in patients with moderate or severe hepatic impairment.

In clinical trials, administration of OFEV was associated with elevations of liver enzymes (ALT, AST, ALKP, GGT) and bilirubin. Liver enzyme increases were reversible with dose modification or interruption and not associated with clinical signs or symptoms of liver injury.

Conduct liver function tests (ALT, AST, and bilirubin) prior to treatment with OFEV, monthly for 3 months, and every 3 months thereafter, and as clinically indicated. Dosage modifications, interruption, or discontinuation may be necessary for liver enzyme elevations. 

Gastrointestinal Disorders
Diarrhea
Diarrhea was the most frequent gastrointestinal event reported in 62% versus 18% of patients treated with OFEV and placebo, respectively.  In most patients, the event was of mild to moderate intensity and occurred within the first 3 months of treatment. Diarrhea led to permanent dose reduction in 11% of patients treated with OFEV compared to 0 placebo-treated patients. Diarrhea led to discontinuation of OFEV in 5% of the patients compared to <1% of placebo-treated patients.

Dosage modifications or treatment interruptions may be necessary in patients with adverse reactions of diarrhea. Treat diarrhea at first signs with adequate hydration and antidiarrheal medication (e.g., loperamide), and consider treatment interruption if diarrhea continues. OFEV treatment may be resumed at the full dosage (150 mg twice daily), or at the reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage. If severe diarrhea persists despite symptomatic treatment, discontinue treatment with OFEV.

Nausea and Vomiting
Nausea was reported in 24% versus 7% and vomiting was reported in 12% versus 3% of patients treated with OFEV and placebo, respectively.  In most patients, these events were of mild to moderate intensity. Nausea led to discontinuation of OFEV in 2% of patients. Vomiting led to discontinuation of OFEV in 1% of the patients.

For nausea or vomiting that persists despite appropriate supportive care including anti-emetic therapy, dose reduction or treatment interruption may be required.  OFEV treatment may be resumed at the full dosage (150 mg twice daily), or at the reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage. If severe nausea or vomiting does not resolve, discontinue treatment with OFEV.

Embryofetal Toxicity
OFEV is Pregnancy category D.  It can cause fetal harm when administered to a pregnant woman. If OFEV is used during pregnancy, or if the patient becomes pregnant while taking OFEV, the patient should be advised of the potential hazard to a fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with OFEV and to use adequate contraception during treatment and at least 3 months after the last dose of OFEV.

Arterial Thromboembolic Events
Arterial thromboembolic events have been reported in patients taking OFEV. In clinical trials, arterial thromboembolic events were reported in 2.5% of patients treated with OFEV and 0.8% of placebo-treated patients. Myocardial infarction was the most common adverse reaction under arterial thromboembolic events, occurring in 1.5% of OFEV-treated patients compared to 0.4% of placebo-treated patients. Use caution when treating patients at higher cardiovascular risk including known coronary artery disease. Consider treatment interruption in patients who develop signs or symptoms of acute myocardial ischemia.

Risk of Bleeding
Based on the mechanism of action (VEGFR inhibition), OFEV may increase the risk of bleeding. In clinical trials, bleeding events were reported in 10% of patients treated with OFEV and in 7% of patients treated with placebo. Use OFEV in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk.

Gastrointestinal Perforation
Based on the mechanism of action, OFEV may increase the risk of gastrointestinal perforation. In clinical trials, gastrointestinal perforation was reported in 0.3% of patients treated with OFEV, compared to 0 cases in the placebo-treated patients. Use caution when treating patients who have had recent abdominal surgery. Discontinue therapy with OFEV in patients who develop gastrointestinal perforation. Only use OFEV in patients with known risk of gastrointestinal perforation if the anticipated benefit outweighs the potential risk.

ADVERSE REACTIONS

• Adverse reactions reported in ³5% of patients treated with OFEV and more commonly than in patients treated with placebo included diarrhea (62% vs. 18%), nausea (24% vs.7%), abdominal pain (15% vs 6%), liver enzyme elevation (14% vs 3%), vomiting (12% vs 3%), decreased appetite (11% vs 5%), weight decreased (10% vs 3%), headache (8% vs 5%), and hypertension (5% vs 4%).
• The most frequent serious adverse reactions reported in patients treated with OFEV, more than placebo, were bronchitis (1.2% vs. 0.8%) and myocardial infarction (1.5% vs. 0.4%). The most common adverse events leading to death in patients treated with OFEV, more than placebo, were pneumonia (0.7% vs. 0.6%), lung neoplasm malignant (0.3% vs. 0%), and myocardial infarction (0.3% vs. 0.2%).  In the predefined category of major adverse cardiovascular events (MACE) including MI, fatal events were reported in 0.6% of OFEV-treated patients and 1.8% of placebo-treated patients.

DRUG INTERACTIONS
P-glycoprotein (P-gp) and CYP3A4 Inhibitors and Inducers
Coadministration with oral doses of a P-gp and CYP3A4 inhibitor, ketoconazole, increased exposure to nintedanib by 60%. Concomitant use of potent P-gp and CYP3A4 inhibitors (e.g., erythromycin) with OFEV may increase exposure to nintedanib. In such cases, patients should be monitored closely for tolerability of OFEV. Management of adverse reactions may require interruption, dose reduction, or discontinuation of therapy with OFEV. Coadministration with oral doses of a P-gp and CYP3A4 inducer, rifampicin, decreased exposure to nintedanib by 50%. Concomitant use of P-gp and CYP3A4 inducers (e.g., carbamazepine, phenytoin, and St. John’s wort) with OFEV should be avoided as these drugs may decrease exposure to nintedanib.

Anticoagulants
Nintedanib is a VEGFR inhibitor, and may increase the risk of bleeding. Monitor patients on full anticoagulation therapy closely for bleeding and adjust anticoagulation treatment as necessary.

USE IN SPECIFIC POPULATIONS
Nursing Mothers

• Excretion of nintedanib and/or its metabolites into human milk is probable.  Because of the potential for serious adverse reactions in nursing infants from OFEV, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Hepatic Impairment

• Monitor for adverse reactions and consider dose modification or discontinuation of OFEV as needed for patients with mild hepatic impairment (Child Pugh A). Treatment of patients with moderate (Child Pugh B) and severe (Child Pugh C) hepatic impairment with OFEV is not recommended.

Smokers

• Smoking was associated with decreased exposure to OFEV, which may alter the efficacy profile of OFEV. Encourage patients to stop smoking prior to treatment with OFEV and to avoid smoking when using OFEV.

Please click here for full Prescribing Information, including Patient Information.

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 (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.

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