Clinical Trials

Date: 2017-05-27

Type of information: Publication of results in a medical journal

phase: 3

Announcement: presentation of results at the 2017 American Thoracic Society (ATS) conference

Company: Boehringer Ingelheim (Germany)

Product: Ofev® (nintedanib)

Action mechanism:

• kinase inhibitor/ tyrosine kinase inhibitor. Nintedanib targets three growth factors: the vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR) and platelet-derived growth factor receptor (PDGFR). These receptors have been shown to be potentially involved in pathomechanisms of pulmonary fibrosis. By blocking these signaling pathways that are involved in fibrotic processes, it is hypothesized that there may be potential to reduce disease progression, and thereby slow the decline of lung function.
• Ongoing research is being conducted for the treatment of Ofev®in patients with idiopathic pulmonary fibrosis and other interstitial lung diseases. Nintedanib is also being investigated for the treatment of systemic sclerosis with associated interstitial lung disease (SSc-ILD), as well as progressive fibrosing interstitial lung disease (PF-ILD). Additionally, the first Phase IV trial following the approval of Ofev® for the treatment of idiopathic pulmonary fibrosis is completed and will add evidence to the safety and tolerability of nintedanib with add-on pirfenidone. Results from the 12 week, randomised INJOURNEY® trial will be presented at an upcoming international medical congress.

Disease: idiopathic pulmonary fibrosis (IPF)

Therapeutic area: Lung diseases - Respiratory diseases

Country:

Trial details:

• The Phase 3 INPULSIS™trials (INPULSIS™-1 and INPULSIS™-2) are double-blind, randomized and placebo-controlled trials that evaluated the effect of oral nintedanib, 150 mg twice daily, on annual rate of decline in forced vital capacity FVC, in people with IPF over 52 weeks. A total of 1,061 (n=638, nintedanib vs. 423, placebo) people with IPF were enrolled in the two trials, including 513 people in INPULSIS™-1 (n=309, nintedanib vs. 204, placebo) and 548 in INPULSIS™-2 (n=329, nintedanib vs. n=219, placebo). The trials had an identical design, matched dosing, inclusion criteria, and endpoints.
• The primary endpoint was the annual rate of decline in FVC (expressed in mL over 52 weeks). There were two key secondary endpoints: change from baseline in health-related quality of life, as assessed by the SGRQ total score, and time to first acute exacerbation (days). Other secondary endpoints were respiratory mortality, overall survival, on-treatment survival, and time to death or lung transplant. Included were people over 40 years of age with a diagnosis of IPF within five years before enrollment based on the most recent American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS), and Latin American Thoracic Association (ALAT) IPF guideline for diagnosis and management.

Latest news:

• • On May 24, 2017, Boehringer Ingelheim announced the presentation of new analyses on the use of Ofev®(nintedanib) in treating idiopathic pulmonary fibrosis at the 2017 American Thoracic Society (ATS) conference. Abstracts presented at the conference support the established efficacy and safety data for Ofev®, and offer further insights into its effect on lung function in IPF patients.
• Pooled data from the two Phase III INPULSIS® trials showed that Ofev®-treated patients were twice as likely as those given placebo to experience an improvement or no decline in lung function, as measured by forced vital capacity, at week 52 (36.8%, Ofev® vs. 18.0%, placebo).1 A subgroup analysis of the open-label INPULSIS®-ON study demonstrated a similar annual rate of forced vital capacity decline over 96 weeks among Ofev®-treated patients, regardless of the dosage they received based on individual tolerability (150 mg twice daily, 100 mg twice daily, or both doses).2
• Additionally, a pooled analysis from the TOMORROW™ and INPULSIS® trials assessed the incidence rates for major adverse cardiovascular events (MACE) among patients treated with Ofev® and placebo. Most patients included in this analysis (90%) had a high cardiovascular  risk at baseline, including a history of fatty-plaque build-up in the arteries (called atherosclerosis) and/or at least one cardiovascular risk factor such as high blood pressure, diabetes or elevated blood cholesterol levels. Overall, the incidence of MACE was similar between the treatment groups both in patients with a high cardiovascular risk (3.5%, Ofev® and 3.3%, placebo) and low cardiovascular risk (4.5%, Ofev® and 5.3%, placebo) at baseline.
• A separate analysis presented at ATS examined data from the IPF-PRO patient registry at 18 pulmonary care sites to identify the clinical characteristics of idiopathic pulmonary fibrosis patients who have advanced lung function impairment. Most clinical studies have included idiopathic pulmonary fibrosis patients with mild to moderate lung function impairment, and investigators wanted to understand how patients with more advanced disease differed. Patients with advanced idiopathic pulmonary fibrosis at baseline had greater physical impairment versus patients with mild to moderate disease, including lower six-minute walk distance (320 feet vs. 397 feet). The more advanced idiopathic pulmonary fibrosis patients also had an increased prevalence of hypoxaemia (low blood oxygen), both at rest (36.6% vs. 7.4%) and while active (62.4% vs. 20.2%), requiring more supplemental oxygen, as well as a history of pulmonary arterial hypertension, or high blood pressure in the lungs (14.0% vs. 6.4%). In addition, health-related quality of life (HRQL) scores were significantly worse in those with advanced lung function impairment.
• • On June 27, 2016, Boehringer Ingelheim announced that new analysis of the INPULSIS® trials show for the first time that disease progression is similar in idiopathic pulmonary fibrosis patients identified using a broader diagnostic definition compared with the current diagnostic guidelines. The post-hoc analysis of these 1,061 patients has now been published in the American Journal of Respiratory and Critical Care Medicine.
• The INPULSIS® trials included patients with a classic diagnosis of IPF but also those patients with a clinical diagnosis of IPF who, in the absence of a surgical lung biopsy and honeycombing on HRCT, had a possible UIP pattern and the presence of traction bronchiectasis.1 Traction bronchiectasis is recognised as one of the most relevant CT signs of lung fibrosis.8 The analysis also shows that OFEV® is effective in slowing disease progression in both diagnostic subgroups which confirms the efficacy of OFEV® across a broad range of IPF patient types studied in Phase III and may be applicable to patients seen in clinical practice.
• The subgroup analysis showed that: In patients with confirmed UIP pattern, including honeycombing and/or biopsy, the adjusted annual rate of decline in forced vital capacity was ?108.7 mL/year in the nintedanib group and -225.7 mL/year in the placebo group (difference versus placebo of 117.0 mL/year). In patients with HRCT features of possible UIP pattern, with no honeycombing and no biopsy but the presence of traction bronchiectasis, the adjusted annual rate of decline in forced vital capacity was ?122.0 mL/year in the nintedanib group and -221.0 mL/year in the placebo (difference versus placebo of 98.9 mL/year). The treatment-by-subgroup interaction p-value was not significant (p=0.8139), indicating that the treatment effect of nintedanib was not different between the subgroups. The treatment effect in both subgroups was also consistent with the treatment effect in the overall pooled population. Adverse events were similar between subgroups.
• • On May 18, 2014, Boehringer Ingelheim announced the results of its two pivotal Phase 3 INPULSIS™ trials (INPULSIS™-1 and -2; NCT01335464 and NCT01335477), which were published online in the New England Journal of Medicine (NEJM) The INPULSIS™ trials evaluated the efficacy and safety of nintedanib, an investigational therapy being studied in people with idiopathic pulmonary fibrosis (IPF).
• INPULSIS™-1 and -2, which involved a total of 1,061 people with IPF, met the primary endpoint: reduction in the annual rate of decline in forced vital capacity over 52 weeks. In these trials, nintedanib reduced the annual rate of forced vital capacity decline compared to placebo by 48% in INPULSIS™-1 (-114.7 vs. -239.9 mL/year, respectively [95% CI: 77.7, 172.8]) and by 55% in INPULSIS™-2 (-113.6 vs. -207.3 mL/year, respectively [95% CI: 44.8, 142.7]). In both trials, the most prevalent adverse events (AE) were gastrointestinal. Diarrhea was the most frequent AE in the nintedanib groups compared to the placebo groups, and was reported in 61.5% vs. 18.6% of participants in INPULSIS™-1 and 63.2% vs. 18.3% of participants in INPULSIS™-2. Most cases were mild to moderate in intensity (93.7% in INPULSIS™-1 and 95.2% in INPULSIS™-2). In both trials, about 4.5% of people who used nintedanib discontinued treatment due to diarrhea (n=28 of 638). In these clinical trials, investigators had the option of dose reduction or dose interruption to help manage diarrhea. Nausea was the second most common adverse event among patients treated with nintedanib versus placebo, occurring in 22.7% vs. 5.9% of participants in INPULSIS™-1 and 26.1% vs. 7.3% of participants in INPULSIS™-2.
• The absolute change from baseline in forced vital capacity at 52 weeks, a pre-specified secondary endpoint, for nintedanib versus placebo was 109.9 mL in INPULSIS™-1 (-95.1 mL, nintedanib vs. -205.0 mL, placebo [95% CI: 71.3, 148.6]) and 109.8 mL in INPULSIS™-2 (-95.3 mL, nintedanib vs. -205.0 mL, placebo [95% CI: 70.9, 148.6]).
• The proportion of forced vital capacity responders was also measured based on the number of patients who had an absolute decline in FVC of less than 5%, as well as an absolute decline in forced vital capacity of less than 10% at 52 weeks.
• In both trials, more patients treated with nintedanib versus placebo had an absolute decline in forced vital capacity of less than 5%:
• INPULSIS™-1: 52.8% vs. 38.2%, respectively; OR 1.85 [95% CI: 1.28, 2.66]
• INPULSIS™-2: 53.2% vs. 39.3%, respectively; OR 1.79 [95% CI: 1.26, 2.55]
• More nintedanib versus placebo patients had an absolute decline in forced vital capacity of less than 10% in the INPULSIS™-1 trial (70.6% vs. 56.9%, respectively; OR 1.91 [95% CI: 1.32, 2.79]) This difference did not reach statistical significance in the INPULSIS™-2 trial (69.6% vs. 63.9%, respectively; OR 1.29 [95% CI: 0.89, 1.86])
• In INPULSIS™-2, there was a significant increase in time to first acute exacerbation in the nintedanib group compared with placebo (HR 0.38 [95% CI: 0.19, 0.77]). In addition, the proportion of patients with at least one investigator-reported acute exacerbation was lower in the nintedanib group (3.6%) compared with placebo (9.6%).
• In INPULSIS™1, there was no difference between the nintedanib and placebo groups in time to first acute exacerbation (HR 1.15 [95% CI: 0.54, 2.42]), and the proportion of patients with at least one investigator-reported acute exacerbation was comparable between the nintedanib and placebo groups (6.1% vs. 5.4%, respectively).
• In the pre-specified pooled analysis, there was no significant difference between nintedanib and placebo in time to first investigator-reported acute exacerbation (HR 0.64 [95% CI: 0.39, 1.05]). The proportion of patients with at least one investigator reported acute exacerbation was 4.9% in the nintedanib group versus 7.6% in the placebo group. A pre-specified sensitivity analysis based on adjudicated acute exacerbations (confirmed or suspected) in the pooled data was conducted and showed a benefit of nintedanib compared with placebo (HR 0.32 [95% CI: 0.16, 0.65]).
• In INPULSIS™-2, there was a significantly smaller increase in SGRQ total score with nintedanib versus placebo at week 52, which is consistent with less deterioration in health-related quality of life (2.80 versus 5.48; difference of -2.69 [95% CI: -4.95, -0.43]). In INPULSIS™-1, there was no difference between the treatment groups in adjusted mean change from baseline at week 52 in SGRQ total score (4.34, nintedanib vs. 4.39, placebo [95% CI: -2.50, 2.40]).
• A higher proportion of patients in the nintedanib groups versus placebo experienced elevations in liver enzymes. In INPULSIS™-1, 15 patients (4.9%) in the nintedanib group and 1 patient (0.5%) on placebo experienced ALT and/or AST elevations of =3x ULN. In INPULSIS™-2, 17 patients (5.2%) in the nintedanib group and 2 patients (0.9%) on placebo experienced ALT and/or AST elevations of =3x ULN.
• Overall, the proportions of people experiencing serious adverse events was similar in the nintedanib and placebo groups (31.1% vs. 27.0% in INPULSIS™-1; 29.8% vs. 32.9% in INPULSIS™-2, respectively). A total of 65 nintedanib patients (21.0%) and 22 (10.8%) placebo patients in INPULSIS-1 and 58 nintedanib patients (17.6%) and 33 placebo patients (15.1%) in INPULSIS-2 discontinued study medication due to adverse events.
• • On September 26, 2012, Boehringer Ingelheim has announced that clinical trial enrollment has completed for two phase III studies evaluating the safety and efficacy of nintedanib in patients with idiopathic pulmonary fibrosis, being studied at a twice-daily oral dose. The trials have enrolled a total of 970 patients in 20 countries. The first patients entered the trials in April and May 2011, respectively.

Is general: Yes