Nintedanib  media backgrounder

1. What is nintedanib?

Nintedanib* (OFEV^®) is a small molecule tyrosine kinase inhibitor (TKI) developed by Boehringer Ingelheim for idiopathic pulmonary fibrosis (IPF).¹ Nintedanib* is currently approved in the US, the European Union, Japan and other countries for the treatment of IPF.  It is an oral treatment, given as one capsule twice daily. It has been demonstrated to slow disease progression with an approximately 50% reduction compared with placebo in the lung function decline (as measured by forced vital capacity) across a range of IPF patient types.^1-7 The difference in annual rate of FVC decline between nintedanib and placebo groups in the pooled INPULSIS^® trials was 109.9 mL/year. ** ²

2. How does nintedanib work?

Nintedanib* targets growth factor receptors, which have been shown to be involved in the mechanisms by which pulmonary fibrosis occurs.^1,8 Most importantly nintedanib* inhibits platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor receptor (VEGFR).^8-10 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. ^9-11

3. Data overview

Nintedanib* has been studied in a comprehensive clinical trial programme including the Phase II TOMORROW dose finding trial, the Phase III INPULSIS^®-1 and -2 trials as well as the open-label INPULSIS^®-ON extension trial.

About the INPULSIS^®-1 and -2 clinical trials

INPULSIS^®-1 and -2 are two global Phase III trials which evaluated the efficacy and safety of nintedanib* in the treatment of IPF. The trials were identical in design, e.g. with matching dosing, inclusion criteria and endpoints.^2,12

The first results from INPULSIS^®-1 and -2 were presented at the American Thoracic Society (ATS) International Conference and published in the New England Journal of Medicine in May 2014.²

INPULSIS^® study design¹²

• Two randomised, double-blind, placebo-controlled, parallel-group trials in 1,066 patients recruited in 24 countries across the Americas, Europe, Asia and Australia
• 52-week treatment period followed by 4-week follow-up period
• 3:2 randomisation ratio for nintedanib*:placebo
• Oral nintedanib* 150 mg twice daily
• Temporary treatment interruption and/or dose reduction to 100 mg bid allowed to manage adverse events. After an adverse event had resolved, the dose could be reinstituted at 150 mg twice daily

​Key inclusion criteria¹²
Included were patients aged ≥40 years with a diagnosis of IPF established within five years before randomisation. Participants were required to have a forced vital capacity (FVC) ≥ 50% predicted, a carbon monoxide diffusion capacity (DLco) of 30-79% predicted, and to have undergone a chest high-resolution computerised (HRCT) scan ≤ 12 months before screening. The diagnosis of IPF was confirmed based on the central review of chest HRCT scans from all patients by an expert radiologist. Surgical lung biopsy specimens if available were also centrally evaluated by an expert pathologist.

Primary endpoint¹²
The primary endpoint was the annual rate of decline in FVC (mL/year).

Forced vital capacity (FVC)
FVC is a lung function test measuring the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. As IPF progresses, lung function gradually and irreversibly deteriorates and this is measured by FVC decline. For patients with IPF randomised to placebo arms of recent IPF clinical trials, the average annual decline in FVC is in the range of 150 mL to 200 mL, while in the general elderly population it is approximately 30–65 mL per year.^13-16 In the absence of another identifiable cause, a progressive decline of FVC in patients with IPF is regarded as a manifestation of disease progression.¹⁷ In addition, declines in FVC % predicted of >5% and >10% over 6–12 months are associated with a reduced survival time.^17-20

Secondary endpoints¹²
The key secondary endpoints were: 

• Time to first investigator-reported acute IPF exacerbation over 52 weeks
• Change from baseline in St. George’s Respiratory Questionnaire (SGRQ) total score over 52 weeks (expressed in points). The SGRQ is a self-administered questionnaire originally developed for chronic obstructive lung disease assessing health-related quality of life (with a value of 0 indicating no impairment at all and a value of 100 indicating the worst possible health-related quality of life).

INPULSIS^® results²
In the pre-specified pooled analysis of the two trials, nintedanib* reduced the decline in FVC by approximately 50% compared with placebo: the difference in annual rate of FVC decline between nintedanib and placebo groups was  109.9 ml/year.²

The annual rate of FVC decline in the two trials was:²

• INPULSIS^®-1: -114.7 mL (nintedanib*) vs. -239.9 mL (placebo)
• INPULSIS^®-2: -113.6 mL (nintedanib*) vs. -207.3 mL (placebo)

Nintedanib* showed a favourable but statistically non-significant trend in the pooled INPULSIS^® -1 and -2 data for time to first investigator-reported exacerbation. There was a statistically significant increase in the pre-specified sensitivity analysis of time to first adjudicated exacerbation.²

• Time to first investigator-reported exacerbation (pooled): Hazard ratio (HR): 0.64; 95% confidence interval (CI): 0.39 to 1.05; p=0.08
• Time to first adjudicated acute exacerbation (pooled): HR: 0.32; 95% CI: 0.16 to 0.65; p=0.001

In a post hoc analysis of the data from both INPULSIS^® -1 and -2 and TOMORROW (in patients with the licensed 150 mg starting dose) a statistically significant reduction in the risk of suffering one or more exacerbation as reported by the treated physician was seen.²¹

There was a significant, albeit small 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 trials, the most common adverse events were of gastrointestinal nature, of mild to moderate intensity, generally manageable, and only led to treatment discontinuation in 7.6% of the group treated with nintedanib*.^1,2 The most frequent adverse event in the nintedanib* groups was diarrhoea, which was 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. Side effects can be effectively managed in most patients.^1,2 The proportion of patients with serious adverse events was similar in all groups.

Sub-group analysis of the trial results demonstrated the consistency of the effect of nintedanib on FVC decline across a range of IPF patient types** – including patients with minimal lung function impairment (FVC>90% predicted), no honeycombing on HRCT and/or concomitant emphysema. ^1-7

Open-label extension trial (INPULSIS^®–ON)

The effect and safety of nintedanib* long-term
More than 90% of eligible patients who participated in the INPULSIS^® trials opted to continue with nintedanib* treatment as part of an open-label extension trial which is currently ongoing.²² INPULSIS^®-ON is a single arm study. Patients with IPF on placebo in the INPULSIS^® trials initiated treatment with nintedanib* in the extension trial and patients treated with nintedanib* continued to receive treatment.

An interim analysis of INPULSIS^®-ON indicates that the change from baseline in FVC in patients continuing treatment with nintedanib* in the extension trial between baseline and week 48 and between weeks 48 and 96 was comparable to what was observed in patients on active treatment with nintedanib* in the 52 week INPULSIS^® parent trials.²³ The analysis suggests that nintedanib* may have a long-term effect on slowing disease progression. Average total exposure of patients treated with nintedanib* in INPULSIS^® and INPULSIS^®-ON trials was approximately 3 years (35.7 months).²³ Long-term treatment with nintedanib* (up to 51 months) had a manageable safety and tolerability profile, consistent with the findings of the INPULSIS^® studies and with no new safety signals identified. ²³

4. International treatment guidelines for IPF

The 2015 international evidence-based IPF guideline, jointly developed by an international committee including the American Thoracic Society (ATS), the European Respiratory Society (ERS), the Japanese Respiratory Society (JRS) and the Latin American Thoracic Association (ALAT), provides physicians with updated treatment recommendations for patients with IPF.

The guideline gave a conditional recommendation for the use of nintedanib* in patients with IPF. The conditional recommendation means that the majority of individuals in this situation would want the suggested course of action, but many would not.24 Clinicians should recognise that different choices will be appropriate for individual patients and are encouraged to discuss preferences with their patients when making treatment decisions. ²⁴

The committee noted the high value of the potential benefit of nintedanib* on patient-important outcomes such as disease progression as measured by rate of FVC decline and mortality, and a lower value on potentially significant adverse effects and the expected cost of treatment. In comparison to more selective tyrosine kinase inhibitors, the committee noted that nintedanib* appears to have some benefit in terms of patient important outcomes in IPF, though no significant effect on overall mortality was seen.²⁴

*Nintedanib is approved under the brand name OFEV^® in the US, EU, Japan and other territories for use in patients with IPF.

**INPULSIS^® recruited a range of patient types – including patients with early disease (FVC > 90% predicted), no honeycombing on HRCT and/or concomitant emphysema.

                       
Date of preparation: August 2016