The FDA ( Food and Drug Administration ) has approved Ofev ( Nintedanib ) for the treatment of idiopathic pulmonary fibrosis ( IPF ), a debilitating and fatal lung disease, which has a median survival of 2-3 years after diagnosis.
Granted Breakthrough Therapy designation during its review by the FDA, Nintedanib is the first and only tyrosine kinase inhibitor ( TKI ) approved to treat idiopathic pulmonary fibrosis.
In clinical trials, Nintedanib has reduced the annual decline in lung function by approximately 50%. This also included patients with early disease ( forced vital capacity [ FVC ] more than 90% pred ), no honeycombing on a high resolution computed tomography ( HRCT ) and/or concomitant emphysema.
Nintedanib is the first targeted treatment for idiopathic pulmonary fibrosis to consistently meet the primary endpoint in two identically designed phase III clinical trials.
Nintedanib has also significantly reduced the risk of adjudicated acute exacerbations. Idiopathic pulmonary fibrosis exacerbations, events of acute respiratory worsening, can significantly impact the course of the disease. Approximately half of patients hospitalised for an acute IPF exacerbation die during hospitalisation.
The mechanism of action of Nintedanib in idiopathic pulmonary fibrosis is understood. Nintedanib, a TKI, targets growth factor receptors involved in the mechanisms by which pulmonary fibrosis occurs. Most importantly Nintedanib inhibits the platelet-derived growth factor receptor ( PDGFR ), fibroblast growth factor receptor ( FGFR ) and vascular endothelial growth factor receptor ( VEGFR ).
Side effects with Nintedanib can be effectively managed in most patients.
The FDA-approval of Nintedanib is based on the findings from one phase II trial ( TOMORROW ) and two phase III trials ( INPULSIS-1 and INPULSIS-2 ).
The phase II TOMORROW trial was a 12-month, randomised, double-blind, placebo-controlled trial conducted at 92 sites in 25 countries. The trial evaluated the safety and efficacy of oral Nintedanib at four dosage levels in 432 patients diagnosed with idiopathic pulmonary fibrosis, consistent with the criteria published by the American Thoracic Society ( ATS ) and European Respiratory Society ( ERS ).
The primary endpoint for the TOMORROW trial was annual rate of decline in forced vital capacity ( FVC ). Secondary endpoints included acute exacerbations, quality of life measured with the St. Georges Respiratory Questionnaire ( SGRQ ) and total lung capacity.
In patients treated with 150 mg twice daily Nintedanib, FVC declined by 0.06 litres per year as compared with 0.19 litres per year in patients treated with placebo. This dose also resulted in a lower incidence of acute exacerbations versus placebo ( 2.4 versus 15.7 per 100 patient years; p=0.02 ) 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. 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.
The phase III INPULSIS 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 idiopathic pulmonary fibrosis over 52 weeks.
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 ). 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 exacerbation.
Nintedanib reduced the decline in lung function by 50% compared to patients taking placebo. Nintedanib significantly reduced the risk of adjudicated acute exacerbations by 68%.
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 INPULSIS trials, the most common adverse events were gastrointestinal in nature, of mild or moderate intensity, generally manageable and rarely leading to treatment discontinuation. The proportion of patients with serious adverse events was similar in all groups. ( Xagena )
Source: Boehringer-Ingelheim, 2014