Nintedanib: From Discovery to the Clinic

Abstract

Nintedanib (BIBF1120) is a potent, oral, small-molecule tyrosine kinase inhibitor, also known as a triple angiokinase inhibitor, inhibiting three major signaling pathways involved in angiogenesis. Nintedanib targets proangiogenic and pro-fibrotic pathways mediated by the VEGFR family, the fibroblast growth factor receptor (FGFR) family, the platelet-derived growth factor receptor (PDGFR) family, as well as Src and Flt-3 kinases. The compound was identified during a lead optimization program for small-molecule inhibitors of angiogenesis and has since undergone extensive clinical investigation for the treatment of various solid tumors, and in patients with the debilitating lung disease idiopathic pulmonary fibrosis (IPF). Recent clinical evidence from phase III studies has shown that nintedanib has significant efficacy in the treatment of NSCLC, ovarian cancer, and IPF. This review article provides a comprehensive summary of the preclinical and clinical research and development of nintedanib from the initial drug discovery process to the latest available clinical trial data.

Relaxing Effect of TSU-68, an Antiangiogenic Agent, on Mouse Airway Smooth Muscle

“…Due to similar pathophysiological processes (inflammation, extracellular matrix proliferation, and angiogenesis) involved in both cancer and chronic disease, an increasing number of anti-cancer agents are being tested for treating chronic respiratory disease and particularly pulmonary disease [25]. For example, the antitumor drugs BIBF1120, SCH-527123, and gefinitib play new roles in the clinical treatment of chronic respiratory disease [27, 31, 56]. …”

“…Recently, several bioavailable small-molecule agents have been evaluated for their efficacy in a series of respiratory diseases and their complications, including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and asthma, etc [25]. For example, recent pharmaceutical and clinical research has demonstrated that BIBF1120, a potent triple blocker of PDGFR, VEGFR, and VEGFR, has significant antitumor efficacy in the treatment of non-small cell lung cancer (NSCLC) [26, 27] and reduces the loss of lung function in IPF [12, 28-30]. Gefinitib, which is also an effective small-molecule agent in NSCLC therapy, plays a new role in asthma treatment via inhibiting airway remodeling and inflammation [31].…”

Discovery and Development of Nintedanib: A Novel Antiangiogenic and Antifibrotic Agent

“…Inhibition of VEGFR2 was a potential mode of action to suppress neoangiogenesis in tumour tissue. Consequently, a lead optimisation programme aimed at the identification of a new chemical entity displaying potent and selective inhibition of VEGFR2 was initiated [1,[4][5][6]. An important target characteristic was selective inhibition of VEGFR2 over other kinases, based on work showing that VEGFR2 is a principal mediator of the physiological and pathological effects of the key endothelial cell mitogen, VEGFA [7].…”

“…Nonclinical pharmacokinetics studies of nintedanib were conducted in CD1 mice, Wistar rats, and cynomolgus and rhesus monkeys (Table 11.6) [6]. Nintedanib exposure was significant in all animals, with moderate variability.…”

Idiopathic pulmonary fibrosis: from clinical trials to real-life experiences

“…Both of these receptors are pro-angiogenic receptor tyrosine kinases and nintedanib was designed as an anti-angiogenic drug for cancer indications [14,15]. Two phase III, international, placebo-controlled, double-blind clinical studies with identical designs (INPULSIS-1 and INPULSIS-2) [9] investigated the efficacy and safety of nintedanib in patients with IPF, after a phase II proof-of-concept study [16].…”