Nintedanib: A Review in Fibrotic Interstitial Lung Diseases

Abstract

Progressive fibrosing interstitial lung diseases (ILDs) involve similar pathophysiological processes, indicating the potential for common approaches to treatment. Nintedanib (Ofev ® ), an intracellular tyrosine kinase inhibitor (TKI) with antifibrotic properties, was one of the first drugs approved for use in idiopathic pulmonary fibrosis (IPF) and has more recently been approved for use in other chronic fibrosing ILDs with a progressive phenotype and systemic sclerosis-associated ILD (SSc-ILD). In multinational phase III trials, nintedanib significantly reduced the annual rate of decline in forced vital capacity (FVC) in adults with IPF, other progressive fibrosing ILDs and SSc-ILD. Reductions in FVC decline with nintedanib in patients with IPF and severe gas exchange impairment were comparable to those in patients with milder disease. Real-world experience in patients with IPF supports the effectiveness of nintedanib in slowing ILD progression. Nintedanib had a manageable tolerability profile in patients with fibrotic ILDs in clinical trials and real-world studies. No new safety signals have emerged from global pharmacovigilance data. Nintedanib continues to represent an important therapeutic option in patients with IPF and is the first drug to be approved for use in patients with other chronic fibrosing ILDs with a progressive phenotype or SSc-ILD, with these approvals expanding the range of fibrotic ILDs for which nintedanib can be prescribed. Plain language summaryTreatment options for fibrotic interstitial lung diseases (ILDs) that involve progressive lung function decline have historically been limited. Nintedanib (Ofev ® ) was one of the first antifibrotic drugs to be approved for use in idiopathic pulmonary fibrosis and is now also approved for use in other chronic fibrosing ILDs with a progressive phenotype and systemic sclerosisassociated ILD (SSc-ILD). Nintedanib reduced lung function deterioration in patients with idiopathic pulmonary fibrosis, other chronic fibrosing ILDs with a progressive phenotype and SSc-ILD in well-designed clinical trials. In patients with idiopathic pulmonary fibrosis, the clinical benefit of nintedanib was shown to persist over more than 4 years of treatment. The most common adverse events in nintedanib recipients were diarrhoea and nausea, which were manageable in the majority of patients. Real-world experience supports the effectiveness and acceptable safety of nintedanib. Nintedanib remains an important treatment option for patients with idiopathic pulmonary fibrosis and is the first drug to be approved for use in patients with other chronic fibrosing ILDs with a progressive phenotype and SSc-ILD.

New Insights into Profibrotic Myofibroblast Formation in Systemic Sclerosis: When the Vascular Wall Becomes the Enemy

“…Of note, nintedanib was also shown to ameliorate experimental PAH via inhibition of EndoMT and pulmonary arterial VSMC proliferation, suggesting that this molecule might be used as a therapeutic agent for PAH by preventing fibroproliferative vascular remodeling [ 127 ]. Clinically, treatment with nintedanib was able to reduce the decline in forced vital capacity in SSc patients suffering from ILD [ 128 , 129 , 130 ], even if when considering patients with a background therapy with mycophenolate, such a decline did not significantly differ from placebo-treated patients [ 131 ]. In addition, given its relevant side effects, the effective safety and efficacy of nintedanib for SSc treatment has yet to be fully investigated [ 43 , 117 ].…”

Liver Injury with Nintedanib: A Pharmacovigilance–Pharmacokinetic Appraisal

“…In multinational phase III trials, including open-label extensions, and real-world experience, the drug has demonstrated clinical benefit persisting over long-term treatment, with a manageable tolerability profile [ 1 ]. Nintedanib significantly reduced the annual rate of decline in forced vital capacity in patients with IPF and severe gas exchange impairment as well as in subjects with milder disease.…”

“…Apart from diarrhea, bleeding, and arterial thromboembolism, drug-induced liver injury (DILI), albeit uncommon, emerged as an adverse event (AE) of special interest [ 1 ]. Imbalances were noted in pivotal clinical trials: elevations in alanine aminotransferase, aspartate aminotransferase, or both to levels ≥ 3 times the upper limit of the normal range (ULN) were observed in 13.0% of the subjects with progressive fibrosing ILDs treated with nintedanib (vs. 1.8% in the placebo group), with only one patient in each group meeting criteria for Hy’s law [ 3 ]; the respective proportions were 4.9% vs. 0.7% in SSc-ILD [ 4 ], 4.9% vs. 0.5% in INPULSIS-1, and 5.2% vs. 0.9% in INPULSIS-2 trials [ 5 ], with no individuals meeting criteria for Hy’s law in IPF.…”

Idiopathic pulmonary fibrosis: Current and future treatment

“…These effects on receptor tyrosine kinases lead to decreased fibroblast activity. 5,64,65 INPULSIS phase 3 trials I and II showed a significant decrease in the rate of FVC deterioration in IPF patients although the death rate remained the same. 66 The side effects, primarily diarrhea and nausea, are manageable with medication, but hepatotoxicity may occur in rare cases and the drug is not recommended for those with severe liver disease.…”