Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.
Ofev® (nintedanib) is a kinase inhibitor indicated for the treatment of idiopathic pulmonary fibrosis (IPF) and other chronic fibrosing interstitial lung diseases (ILDs) that present with a progressive phenotype. Ofev is also useful for slowing down the decline in pulmonary function in patients with systemic-sclerosis-associated interstitial lung disease (SSc-ILD).1
IPF is a rare progressive ILD that severely affects lung function.2 This disease is characterized by an uncontrolled proliferation of lung fibroblasts and the deposition of extracellular matrix (ECM) components by myofibroblasts, resulting in a decline in forced vital capacity (FVC) and worsening dyspnea.3,4 The origin of IPF is unknown, however, this is a fatal disease with a median survival of 3 to 4 years after diagnosis when no therapy is administered.2
There are 2 drugs currently approved for the treatment of IPF, pirfenidone and nintedanib. Nintedanib is commercialized as Ofev and was approved for IPF treatment by the US Food and Drug Administration (FDA) in October 2014 and by the European Medicines Agency (EMA) in January 2015.5 Nintedanib is available as a soft gelatine capsule in 100 mg and 150 mg formulations. The recommended dosage is 150 mg twice daily.1,5 Maximum plasma concentrations for nintedanib are reached 2 to 4 hours after administration, and the terminal elimination half-life is about 10 to 15 hours. Drug metabolization occurs mainly via hydrolytic cleavage, glucuronidation, and excretion through the liver.5
Read more about IPF therapies
The most common side effects observed for nintedanib are gastrointestinal, such as diarrhea, vomiting, and nausea.1,6 Management of these side effects can be performed with antidiarrheal and anti-emetic medications while ensuring the patient is hydrated. Liver enzymes should be periodically monitored, as liver injury may occur.1
Mechanism of Action of Nintedanib
Nintedanib is an small molecule intracellular inhibitor of several tyrosine kinases, including fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR), and vascular endothelial growth factor receptor (VEGFR).4 The blocking of kinase activity results from a competitive and irreversible inhibition of the intracellular adenosine triphosphate (ATP)-binding pocket of the tyrosine kinase target.3 By occupying the ATP-binding site of multiple kinases, nintedanib affects signaling pathways associated with the proliferation, migration, and transformation of lung fibroblasts and therefore interferes with the pathogenesis of lung fibrosis.3,5,6
Nintedanib also targets the non-receptor Src family kinase lymphocyte-specific tyrosine-protein kinase (LcK) and colony-stimulating factor 1 receptor.7 The Src family kinases are involved in the pathogenesis of pulmonary fibrosis.5
Nintedanib in Clinical Trials
Both the efficacy and safety of nintedanib were evaluated in 3 clinical trials. Eligibility criteria required that participants had been diagnosed in the previous 5 years.1 The most frequent severe side effects reported in patients with IPF during these trials were bronchitis and myocardial infarction.
The TOMORROW trial (NCT00514683) was a phase 2 randomized study that included 428 patients with IPF. This was a placebo-controlled, dose-finding trial performed over 52 weeks.8 Four nintedanib doses were included in the study. The primary endpoint was the annual rate of decline in FVC. The secondary endpoints were the time to the first acute exacerbation and the change from baseline in St. George’s Respiratory Questionnaire (SGRQ) total score over the course of the 52 weeks. When compared to the placebo, 150 mg of nintedanib decreased the annual rate of decline in FVC, which was associated with a slowing of the disease progression. Patients experienced 68% less decline in lung function. Nintedanib also reduced the incidence of acute exacerbations. Both the safety and tolerability profiles were acceptable.
Get detailed prescribing information on the Ofev monograph page at MPR.
After the TOMORROW trial, nintedanib was evaluated in 2 phase 3 clinical trials, INPULSIS-1 (NCT01335464) and INPULSIS-2 (NCT01335477).9 The INPULSIS trials were also 52-week studies that were randomized and placebo-controlled, and they included a total of 1066 patients from 24 countries. The primary endpoint for these trials was the annual rate decline in FVC, similar to the first TOMORROW trial, and in both trials with nintedanib, the rate of decline was significantly decreased. In INPULSIS-2, the time to the first acute exacerbation was impacted, with participants having 80% less risk of experiencing acute exacerbation with nintedanib usage.
About 90% of eligible patients who were part of the INPULSIS trials continued their treatment with nintedanib in an open-label extension of the INPULSIS trials, INPULSIS-ON (NCT01619085).10 In this trial, nintedanib showed manageable safety and tolerability profiles and no additional safety issues.
Evidence gathered from these trials may suggest a potential benefit in starting IPF treatment in newly diagnosed patients, even when reduced functional impairment is found. The duration of the treatment is under discussion since evidence is still needed that nintedanib maintains its efficacy for periods longer than 2 years.6
1- Ofev® (nintedanib) capsules, for oral use. Boehringer Ingelheim. Accessed August 9, 2021.
2- Quinn C, Wisse A, Manns ST. Clinical course and management of idiopathic pulmonary fibrosis. Multidiscip Respir Med. 2019;14:35. doi:10.1186/s40248-019-0197-0
3- Wollin L, Wex E, Pautsch A, et al. Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis. Eur Respir J. 2015;45(5):1434-1445. doi:10.1183/09031936.00174914
4- Richeldi L, Cottin V, du Bois RM, et al. Nintedanib in patients with idiopathic pulmonary fibrosis: combined evidence from the TOMORROW and INPULSIS(®) trials. Respir Med. 2016;113:74-79. doi:10.1016/j.rmed.2016.02.001
5- Wind S, Schmid U, Freiwald M, et al. Clinical pharmacokinetics and pharmacodynamics of nintedanib. Clin Pharmacokinet. 2019;58(9):1131-1147. doi:10.1007/s40262-019-00766-0
6- Sgalla G, Iovene B, Calvello M, Ori M, Varone F, Richeldi L. Idiopathic pulmonary fibrosis: pathogenesis and management. Respir Res. 2018;19(1):32. doi:10.1186/s12931-018-0730-2
7- Cottin V, Wollin L, Fischer A, Quaresma M, Stowasser S, Harari S. Fibrosing interstitial lung diseases: knowns and unknowns. Eur Respir Rev. 2019;28(151):180100. doi:10.1183/16000617.0100-2018
8- Richeldi L, Costabel U, Selman M, et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med. 2011;365(12):1079-1087. doi:10.1056/NEJMoa1103690
9- Richeldi L, du Bois RM, Raghu G, et al.; INPULSIS Trial Investigators. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2071-2082. doi:10.1056/NEJMoa140258410- Crestani B, Huggins JT, Kaye M, et al. Long-term safety and tolerability of nintedanib in patients with idiopathic pulmonary fibrosis: results from the open-label extension study, INPULSIS-ON.Lancet Respir Med. 2019;7(1):60-68. doi:10.1016/S2213-2600(18)30339-4
Reviewed by Harshi Dhingra, MD, on 8/12/2021.