New data and analyses confirm the efficacy and safety of OFEV®(nintedanib*) for the treatment of IPF beyond 52 weeks and for distinct subgroups

  • Effect of nintedanib* on slowing disease progression was maintained for up to 76 weeks in the TOMORROW trial
  • Long-term nintedanib* treatment in the INPULSIS®-ON extension study confirms manageable safety and tolerability profile for up to 33 months
  • Pooled analyses confirm efficacy of nintedanib* in patients with early IPF disease (forced vital capacity (FVC) > 90% predicted at baseline)
  • Nintedanib* is the first targeted treatment for IPF to consistently demonstrate its efficacy in two identically designed Phase III trials and these long-term and pooled analyses confirm and strengthen its value for IPF patients

Ingelheim, Germany, May 18, 2015 – Boehringer Ingelheim announced new data and analyses for OFEV® (nintedanib*) reinforcing its efficacy, safety and tolerability in a broad range of patients with idiopathic pulmonary fibrosis (IPF). These findings were presented at the American Thoracic Society (ATS) 2015 International Conference in Denver, United States. IPF is a debilitating and fatal lung disease, with a median survival of 2–3 years after diagnosis.1 It causes progressive scarring of the lungs, resulting in continual and irreversible deterioration in lung function and difficulty breathing.2

"As IPF is a life-threatening and progressive disease, patients will be on life-long treatment to manage their disease. It is important to assess and continue to monitor the efficacy and safety of OFEV® in these patients," said Professor Bruno Crestani, Professor of Pneumology and Deputy Dean for Research at the Paris Diderot University School of Medicine, France. "These data strengthen the evidence supporting the efficacy, safety and tolerability of OFEV® and further our understanding of treating this complex disease."

The new descriptive analyses on long-term treatment with nintedanib* in the Phase II TOMORROW trial (NCT01170065; abstract A1019)3 was presented at the conference. Following the placebo-controlled 52 week treatment phase of the trial (period 1), patients were given the option to continue blinded treatment (period 2) until the last patients had finalized the 52 week treatment period.

Overall, the analyses across both periods showed:

  • Average observed change in decline in forced vital capacity (FVC) or the amount of air that can be exhaled after maximum inhalation (a measure of IPF disease progression), was consistently lower in the nintedanib* 150 mg bid group than in the comparator group (-3.1% vs. -6.3% from baseline to week 76)
  • A lower proportion of patients in the nintedanib* 150 mg bid group versus the comparator group had at least 1 acute IPF exacerbation (a sudden and severe worsening of IPF) (4.7% vs. 19.5 % of patients)
  • The safety and tolerability of nintedanib 150 mg bid was similar between periods 1 and 2.

Worldwide, IPF affects as many as 14–43 people per 100,000 4,5 , most commonly over the age of 50.6

Dr Martin Kolb, Director, Division of Respiratory, Department of Medicine, McMaster University, Canada added: "The unique data from post-hoc subgroup analyses from the pooled INPULSIS® clinical trials demonstrate a consistent effect of OFEV® in patients with different degrees of lung function impairment and patients with different radiologic patterns in imaging tests at baseline (no honeycombing and no confirmation of diagnosis in lung biopsy vs. patients with honeycombing and/or biopsy confirmation of diagnosis). The results presented highlight the importance of early detection and timely treatment of patients with IPF. In addition, the data presented at the conference includes a wide range of patient types which are representative of patients seen in clinical practice."

In a post-hoc analysis of the INPULSIS® trials (NCT01335464 and NCT01335477; abstract A1021),7 nintedanib* showed a consistent effect on reducing the annual rate of FVC decline, a measure of disease progression, whether patients had varying degrees of lung function impairment (i.e. FVC of > 90% predicted or ≤ 90% predicted.). Patients with early disease benefited in a similar way from treatment with nintedanib* compared to patients with more advanced disease.

The abstracts presented at the conference can be downloaded here by searching for the abstract numbers listed.

Two further abstracts were presented at the conference including:

  • An analysis of the open-label extension of the Phase III INPULSIS® trials – INPULSIS®-ON (NCT01619085; abstract A1020)8 that confirmed the manageable safety and tolerability profile of nintedanib* in patients exposed to nintedanib* up to 33 months
  • A post-hoc analysis of the INPULSIS trials (NCT01335464 and NCT01335477; abstract A1022),9 that showed the consistent effect of nintedanib* on reducing the annual rate of FVC decline, a measure of disease progression, in patients with different radiologic patterns at baseline, provided that they met the IPF diagnostic criteria required for trial participation.

Notes to Editor

About the INPULSIS® Phase III trials with OFEV® (nintedanib*)
The double blind, randomised, placebo-controlled trials involving 1,066 patients across 24 countries evaluated the effect of oral nintedanib* 150 mg twice daily on the annual rate of decline in forced vital capacity (FVC) in patients with IPF over 52 weeks. The trials had an identical design, matched dosing, inclusion criteria and endpoints.10,11 The primary endpoint was the annual rate of decline in FVC (expressed in mL over 52 weeks). Key secondary endpoints were: change from baseline in health-related quality of life, as assessed by the Saint George’s Respiratory Questionnaire (SGRQ) and time to first acute IPF exacerbation.

Key results showed:11

  • Nintedanib* slowed disease progression in IPF by reducing the annual decline in lung function by 50% compared to patients taking placebo
  • Nintedanib* significantly reduced the risk of adjudicated acute exacerbations‡ by 68% in the pooled data set
  • There was a significant benefit of nintedanib* versus placebo in change in SGRQ total score in INPULSIS®-2, but no significant difference between groups in INPULSIS®-1

In both INPULSIS® trials, the most common adverse events were gastrointestinal in nature, of mild or moderate intensity, generally manageable and rarely leading to treatment discontinuation.11 The proportion of patients with serious adverse events was similar in all groups.11 The most frequent adverse event in the nintedanib* groups was diarrhoea, reported in 62% vs. 19% (INPULSIS®-1) and 63% vs. 18% (INPULSIS®-2) of patients in the nintedanib* vs. placebo groups, respectively. Less than 5% of patients in the nintedanib* groups of INPULSIS®-1 and INPULSIS®-2 discontinued treatment due to this event.11

About the INPULSIS®-ON open label extension trial
Patients who completed the 52-week treatment period and a 4-week follow-up period in the INPULSIS® trials were invited to receive open-label treatment with nintedanib* as part of an extension trial to assess the long-term safety and tolerability of nintedanib*. The INPULSIS®-ON (Clinicaltrial.gov trial identifier: NCT01619085) trial included 734 patients and is currently ongoing.

About the TOMORROW trial
The Phase II TOMORROW trial was a 12-month, randomised, double-blind, placebo-controlled trial conducted at 92 sites in 25 countries.12 The trial evaluated the safety and efficacy of oral nintedanib* at four dosage levels in 432 patients diagnosed with IPF, consistent with the criteria published by the American Thoracic Society (ATS) and European Respiratory Society (ERS).12

The primary endpoint of the TOMORROW trial was annual rate of decline in forced vital capacity (FVC).12 Secondary endpoints included acute IPF exacerbations, quality of life measured with the St. Georges Respiratory Questionnaire (SGRQ) and total lung capacity.12 In patients treated with 150 mg twice daily nintedanib*, FVC declined by 60 millilitres per year as compared with 190 millilitres per year in patients treated with placebo, a 68.4% reduction in the rate of loss with nintedanib*.12 This dose also resulted in a lower incidence of acute IPF exacerbations versus placebo (2.4 versus 15.7 per 100 patient years; p=0.02)12 and was also associated with a preserved quality of life when compared to placebo as measured by the SGRQ.

Gastrointestinal side effects were common in the nintedanib* 150 mg bid group, but the majority of these effects were of mild or moderate intensity.12 Severe adverse events occurred with similar frequency in the placebo and active-treatment groups but numerically lower in the 150 mg twice daily dose group.12

About OFEV® (nintedanib*)
Nintedanib* is a small molecule tyrosine kinase inhibitor developed by Boehringer Ingelheim for IPF.11 OFEV®, one capsule twice a day, slows disease progression by reducing the annual rate of decline in lung function by 50% in a broad range of IPF patient types.11 This includes patients with early disease (FVC >90% pred), limited radiographic fibrosis (no honeycombing) on high resolution computed tomography (HRCT) and those with emphysema.11 Only nintedanib* reduces adjudicated acute IPF exacerbations‡ by 68%.11 This can be crucial given that approximately 50% of patients hospitalised for an acute IPF exacerbation die during hospitalisation.13 Side effects with nintedanib* can be effectively managed in most patients.11

Nintedanib* targets growth factor receptors, which have been shown to be involved in the mechanisms by which pulmonary fibrosis occurs. Most importantly nintedanib* inhibits platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor receptor (VEGFR).11,14,15 It is believed that nintedanib* reduces disease progression in IPF and slows the decline in lung function by blocking the signalling pathways that are involved in fibrotic processes.11,14,16

  • The European Commission approved OFEV® for the treatment of IPF on 15 January 2015, following an expedited review and positive CHMP opinion on 20 November 2014
  • The FDA approved OFEV® for the treatment of IPF on 15 October 2014
  • On 21 November 2014, the European Commission granted EU marketing authorisation for Vargatef®(nintedanib*) in combination with docetaxel for the treatment of adult patients with locally advanced, metastatic or locally recurrent non-small cell lung cancer of adenocarcinoma tumour histology, after first-line chemotherapy

About idiopathic pulmonary fibrosis
IPF is a chronic, progressive, severely debilitating and ultimately lethal lung disease for which there are limited treatment options.1 IPF affects as many as 14–43 people per 100,000 worldwide.4,5 IPF is characterised by progressive scarring of lung tissue and loss of lung function over time.14,17 Development of scarred tissue is called fibrosis.1 Over time, as the tissue thickens and stiffens with scarring, the lungs lose their ability to take in and transfer oxygen into the bloodstream and vital organs do not get enough oxygen.2 As a result, individuals with IPF experience shortness of breath, a non-productive cough and often have difficulty participating in everyday physical activities.18 Acute IPF exacerbations are defined as rapid deteriorations of symptoms within days or weeks. These events can occur at any point in the course of the disease, even at first presentation. All patients with IPF are at risk of acute IPF exacerbations.13

Boehringer Ingelheim
The Boehringer Ingelheim group is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, Boehringer Ingelheim operates globally with 146 affiliates and a total of more than 47,700 employees. The focus of the family-owned company, founded in 1885, is researching, developing, manufacturing and marketing new medications of high therapeutic value for human and veterinary medicine.

Social responsibility is an important element of the corporate culture at Boehringer Ingelheim. This includes worldwide involvement in social projects, such as the initiative “Making more Health” and caring for the employees. Respect, equal opportunities and reconciling career and family form the foundation of the mutual cooperation. In everything it does, the company focuses on environmental protection and sustainability.

In 2014, Boehringer Ingelheim achieved net sales of about 13.3 billion euros. R&D expenditure corresponds to 19.9 per cent of its net sales.

For more information please visit www.boehringer-ingelheim.com

Intended audiences:
This press release is issued from our Corporate Headquarters in Ingelheim, Germany and is intended to provide information about our global business. Please be aware that information relating to the approval status and labels of approved products may vary from country to country, and a country-specific press release on this topic may have been issued in the countries where we do business.

Footnotes

* Nintedanib is approved under the brand name OFEV® in the US and EU for use in patients with IPF. Nintedanib is under regulatory review by health authorities in other countries
‡ Adjudicated exacerbations was a pre-specified sensitivity analysis in the pooled data set. Time to first investigator-reported exacerbation was a secondary endpoint which was met in TOMORROW and INPULSIS®-2 but not in INPULSIS®-1

Referências

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  2. Collard H, et al. Acute Exacerbations of Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med. 2007;176:636–643.
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