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   Table of Contents      
LETTER TO THE EDITOR
Year : 2015  |  Volume : 1  |  Issue : 3  |  Page : 172-173

Nintedanib: A novel therapeutic agent for pulmonary fibrosis


1 Department of Pharmacology, GSVM Medical College, Kanpur, Uttar Pradesh, India
2 Department of Pulmonary Medicine, King George's Medical University, Lucknow, Uttar Pradesh, India

Date of Web Publication30-Sep-2015

Correspondence Address:
Surya Kant
Department of Pulmonary Medicine, King George's Medical University, Lucknow, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2394-7438.166312

Rights and Permissions

How to cite this article:
Singh A, Verma AK, Bajpai J, Prakash V, Kant S, Bhatia A. Nintedanib: A novel therapeutic agent for pulmonary fibrosis . MAMC J Med Sci 2015;1:172-3

How to cite this URL:
Singh A, Verma AK, Bajpai J, Prakash V, Kant S, Bhatia A. Nintedanib: A novel therapeutic agent for pulmonary fibrosis . MAMC J Med Sci [serial online] 2015 [cited 2019 Aug 22];1:172-3. Available from: http://www.mamcjms.in/text.asp?2015/1/3/172/166312




  Introduction Top


Idiopathic pulmonary fibrosis (IPF) is a chronic form of fibrosing interstitial pneumonia which is confined to the lung and is associated with the histological appearance of usual interstitial pneumonia on surgical (thoracoscopic or open) lung biopsy.[1] Possible risk factors are smoking and environmental toxin exposures. It is a diagnosis of exclusion and is more commonly reported in patients aged between 40 and 70 years.[2]

In spite of best therapy and care, a mean survival of 2–3 years has been reported in the literature.[3],[4] Male gender, advanced age, increased grade of breathlessness at baseline, and worse baseline pulmonary function are considered as poor prognostic factors.[5] Current treatment options include oxygen therapy, pulmonary rehabilitation, and lung transplantation in selected cases. Pharmacological therapeutic options have been more or less disappointing. However, some medicines such as prednisolone, pirfenidone, and N-acetyl cysteine have shown variable benefit.


  Lung Fibrosis in Idiopathic Pulmonary Fibrosis Top


Various cytokines that influence fibrosis in experimental models which include transforming growth factor-α (TGF-α), vascular endothelial growth factor (VEGF), keratinocyte growth factor, insulin-like growth factor-1, fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF) have been shown to be raised in patients of IPF.[6]

Many of these growth factors have been demonstrated to activate tyrosine kinase signaling pathways that promote fibroblast proliferation and matrix production. For this reason, tyrosine kinase inhibition has the potential to become a potent mode of therapy in IPF leading to attenuation of lung fibrosis.

Nintedanib - a novel therapy

Nintedanib is a novel molecule of the angiokinase inhibitor class, which inhibits fibroblast growth factor receptor (FGFR), vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR).[7] The drug is undergoing a number of clinical trials in evaluation for the management of IPF and few cancers as well.

Phase 1 studies

Initial trials in rat models by Chaudhary et al. demonstrated that in bleomycin-induced lung fibrosis, nintedanib (BIBF 1000) attenuated lung fibrosis in vivo and inhibited the differentiation of fibroblasts to myofibroblasts. Both the rates of collagen deposition and expression of pro-fibrotic genes were reduced when compared to similar imatinib without adverse effects of TGF inhibition.[8],[9] Nintedanib also demonstrated anticancer properties by inhibiting the process of angiogenesis.[10]


  Adverse Effects Top


The most common adverse effects observed in the earlier studies with nintedanib were: Raised liver enzymes levels that were reversible and gastrointestinal disorders usually observed with higher 250 mg dose. This drug inhibits the growth and remodeling of the blood vessels, which is an important process in normal wound healing process and tissue repair. An adverse event of nintedanib is thought to be reduced wound healing; however, this side-effect has not been seen in patients receiving nintedenib. The most common side-effects of nintedanib observed in clinical studies are diarrhea, nausea, abdominal pain, vomiting, liver enzyme elevation, decreased appetite, headache, decreased weight, and high blood pressure.

Phase 2/3 trials

Tomorrow

A phase 2 study tested the safety and efficacy of nintedenib in four different doses in 432 patients with IPF.[11] Patients were randomized to receive one of four doses of drug (50 mg once a day, 50 mg twice a day, 100 mg twice a day, or 150 mg twice a day) or placebo for 12 months. The primary end point in the study, annual decline in forced vital capacity (FVC) was significantly 68.4% lower in the group receiving 150 mg of drug twice daily (0.06 L/year vs. 0.19 L/year).


  Inplusis Top


INPULSIS-1 and INPULSIS-2 were phase 3 randomized trials designed to evaluate the efficacy and safety of 150 mg of nintedanib twice daily in patients with idiopathic pulmonary fibrosis.[12] The primary end point was similar to tomorrow trial with additional secondary end points being the time to the first acute exacerbation and the change from baseline in the total score on the St. George's Respiratory Questionnaire, both assessed over a 52-week period. In the 1066 patients enrolled, the primary end point was significantly lower in both INPULSIS-1 (−114.7 ml vs. −239.9 ml; CI: 77.7–172.8; P < 0.001) and INPULSIS-2 (−113.6 ml vs. −207.3 ml; 95% CI: 44.8–142.7; P < 0.001).

In INPULSIS-1, there was no significant difference between the nintedanib and placebo groups in the time to the first acute exacerbation; but in INPULSIS-2, there was a significant benefit with nintedanib versus placebo (hazard ratio: 0.38; 95% CI: 0.19–0.77; P = 0.005). The most frequent adverse event in the nintedanib groups was diarrhea (61.5% vs. 18.6% in INPULSIS-1 and 63.2% vs. 18.3% in INPULSIS-2). The study concluded that in patients with IPF, nintedanib reduced the annual decline in FVC, which is consistent with a slowing of disease progression.

Current role

Nintedanib was recently approved by US Food and Drug administration for use in IPF. The recommendation comes from observation of phase2/3 trials, which showed a significant decline in FVC reduction in patients receiving Nintedanib compared to placebo.[12] It is contraindicated in moderate to severe liver diseases and pregnancy.

Summary

Nintedanib is a novel tyrosine kinase inhibitor, primarily developed as an antitumor agent. Two randomized studies have shown consistent and significant reduction in annual FVC decline in IPF patients with 150 mg twice daily dose. In addition, a reduction in acute exacerbations and improved quality of life-score were additional benefits vis-à-vis placebo. Gastrointestinal side-effects like diarrhea and elevated aminotransferase levels need to be watched for.

Nintedanib marks the birth of a new class of agents, which target lung fibrosis. By slowing the rate of lung function decline and simultaneously preventing acute exacerbations, this drug provides dual benefit in IPF. The drug definitely is a new hope in the management of pulmonary fibrosis.

 
  References Top

1.
American Thoracic Society; European Respiratory Society. Idiopathic pulmonary fibrosis: Diagnosis and treatment: International consensus statement. Am J Respir Crit Care Med 2000;161:646-64.  Back to cited text no. 1
    
2.
Hubbard R, Lewis S, Richards K, Johnston I, Britton J. Occupational exposure to metal or wood dust and aetiology of cryptogenic fibrosing alveolitis. Lancet 1996;347:284-9.  Back to cited text no. 2
    
3.
Nicholson AG, Colby TV, du Bois RM, Hansell DM, Wells AU. The prognostic significance of the histologic pattern of interstitial pneumonia in patients presenting with the clinical entity of cryptogenic fibrosing alveolitis. Am J Respir Crit Care Med 2000;162:2213-7.  Back to cited text no. 3
    
4.
King TE Jr, Schwarz MI, Brown K, Tooze JA, Colby TV, Waldron JA Jr, et al. Idiopathic pulmonary fibrosis: Relationship between histopathologic features and mortality. Am J Respir Crit Care Med 2001;164:1025-32.  Back to cited text no. 4
    
5.
Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, et al. An official ATS/ERS/JRS/ALAT statement: Idiopathic pulmonary fibrosis: Evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011;183:788-824.  Back to cited text no. 5
    
6.
Allen JT, Spiteri MA. Growth factors in idiopathic pulmonary fibrosis: Relative roles. Respir Res 2002;3:13.  Back to cited text no. 6
    
7.
Chaudhary NI, Roth GJ, Hilberg F, Müller-Quernheim J, Prasse A, Zissel G, et al. Inhibition of PDGF, VEGF and FGF signalling attenuates fibrosis. Eur Respir J 2007;29:976-85.  Back to cited text no. 7
    
8.
Hilberg F, Roth GJ, Krssak M, Kautschitsch S, Sommergruber W, Tontsch-Grunt U, et al. BIBF 1120: Triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res 2008;68:4774-82.  Back to cited text no. 8
    
9.
Wollin L, Maillet I, Quesniaux V, Holweg A, Ryffel B. Antifibrotic and anti-inflammatory activity of the tyrosine kinase inhibitor nintedanib in experimental models of lung fibrosis. J Pharmacol Exp Ther 2014;349:209-20.  Back to cited text no. 9
    
10.
Hamada N, Kuwano K, Yamada M, Hagimoto N, Hiasa K, Egashira K, et al. Anti-vascular endothelial growth factor gene therapy attenuates lung injury and fibrosis in mice. J Immunol 2005;175:1224-31.  Back to cited text no. 10
    
11.
Richeldi L, Costabel U, Selman M, Kim DS, Hansell DM, Nicholson AG, et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med 2011;365:1079-87.  Back to cited text no. 11
    
12.
Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 2014;370:2071-82.  Back to cited text no. 12
    




 

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Lung Fibrosis in...
Adverse Effects
Inplusis
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