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Nintedanib

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Nintedanib
Nintedanib
Nintedanib
Systematic (IUPAC) name
Methyl (3Z)-3-{[(4-{methyl[(4-methylpiperazin-1-yl)acetyl]amino}phenyl)amino](phenyl)methylidene}-2-oxo-2,3-dihydro-1H-indole-6-carboxylate
Clinical data
Trade names Vargatef, Ofev
AHFS/Drugs.com Consumer Drug Information
  • US: D (Evidence of risk)
Oral and intravenous
Identifiers
656247-17-5 7pxN
None
PubChem CID 9809715
ChemSpider 7985471 7pxN
UNII G6HRD2P839 7pxN
ChEBI CHEBI:85164 7pxY
ChEMBL CHEMBL502835
Chemical data
Formula C31H33N5O4
539.6248 g/mol
 14pxN (what is this?)  (verify)

Nintedanib (formerly BIBF 1120) and marketed under the brand names Ofev and Vargatef is used along with other medications to treat some types of non-small-cell lung cancer and for idiopathic pulmonary fibrosis (IPF).

It is a small molecule tyrosine-kinase inhibitor, targeting vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR) and platelet derived growth factor receptor (PDGFR) being developed by Boehringer Ingelheim.

At an assumed cost of 39,300 pounds per year it does not appear to be cost effective for IPF in the United Kingdom.[1]

Medical uses

Idiopathic pulmonary fibrosis

Nintedanib is used for idiopathic pulmonary fibrosis (IPF).[2] Results from randomized controlled trials look promising as of 2014.[3]

Lung cancer

It may also be used along with docetaxel as a second line agent for certain types of non-small-cell lung cancer[4] under the brand name Vargatef; it was approved for this indication by the European Commission in 2014.[5] It is unclear how this combination compares to other second line agents as the comparisons have not been done as of 2014.[4]

Adverse effects

Preclinical studies have shown that nintedanib binds in a highly selective manner to the ATP binding pocket of its three target receptor families, without binding to similarly shaped ATP domains in other proteins, which reduces the potential for undesirable side effects.[6]

The most common side effects observed with nintedanib were reversible elevation in liver enzymes (10-28% of patients) and gastrointestinal disturbance (up to 50%). Side effects observed with nintedanib were worse with the higher 250 mg dose, for this reason subsequent trials have used the equally clinically effective 200 mg dose.[6][7][8][9][10][11][12][13][14]

Nintedanib inhibits the growth and reshaping of blood vessels which is also an essential process in normal wound healing and tissue repair. Therefore a theoretical side effect of nintedanib is reduced wound healing however, unlike other anti-angiogenic agents, this side effect has not been observed in patients receiving nintedanib.[citation needed]

Mechanism of action

Nintedanib is an indolinone-derived drug that inhibits the process of blood vessel formation (angiogenesis). Angiogenesis inhibitors stop the formation and reshaping of blood vessels in and around tumours, which reduces the tumour’s blood supply, starving tumour cells of oxygen and nutrients leading to cell death and tumour shrinkage. Unlike conventional anti-cancer chemotherapy which has a direct cell killing effect on cancer cells, angiogenesis inhibitors starve the tumour cells of oxygen and nutrients which results in tumour cell death. One of the advantages of this method of anti-cancer therapy is that it is more specific than conventional chemotherapy agents, therefore results in fewer and less severe side effects than conventional chemotherapy.[citation needed]

The process of new blood vessel formation (angiogenesis) is essential for the growth and spread of cancers. It is mediated by signaling molecules (growth factors) released from cancer cells in response to low oxygen levels. The growth factors cause the cells of the tumour’s blood vessel to divide and reorganize resulting in the sprouting of new vessels in and around the tumour, improving its blood supply.[citation needed]

Angiogenesis is a process that is essential for the growth and spread of all solid tumours, blocking it prevents the tumour from growing and may result in tumour shrinkage as well as a reduction in the spread of the cancer to other parts of the body. Nintedanib exerts its anti-cancer effect by binding to and blocking the activation of cell receptors involved in blood vessel formation and reshaping (i.e. VEGFR 1-3, FGFR 1-3 AND PDGFRα and β). Inhibition of these receptors in the cells that make up blood vessels (endothelial cells, smooth muscle cells and pericytes) by Nintedanib leads to programmed cell death, destruction of tumor blood vessels and a reduction in blood flow to the tumour. Reduced tumour blood flow inhibits tumor cell proliferation and migration hence slowing the growth and spread of the cancer.[7]

History

Nintedanib was approved for idiopathic pulmonary fibrosis on Oct 15, 2014 by the FDA.[15] This was under the brand name Ofev; in 2014 by the United States Food and Drug Administration and in 2015 by the European Commission.[16]

Society and culture

A review, which assumed the price of nintebanib was 39,300 pounds a year found that it was not cost effective.[1]

Research

Early clinical trials of nintedanib have been carried out in patients with non-small cell lung, colorectal, uterine, endometrial, ovarian and cervical cancer and multiple myeloma.[9][10][12][13][14] These studies reported that the drug is active in patients, safe to administer and is stable in the bloodstream. They identified that the maximum tolerated dose of nintedanib is 20 0 mg when taken once a day.

Clinical studies

In the first human trials, nintedanib halted the growth of tumours in up to 50% of patients with non-small cell lung cancer and 76% of patients with advanced colorectal cancer and other solid tumours.[9][13] A complete response was observed in 1/26 patients with non-small cell lung and 1/7 patients with ovarian cancer treated with nintedanib. A further 2 patients with ovarian cancer had partial responses to nintedanib.[13][14]

Two phase II trials have been carried out assessing the efficacy, dosing and side effects of nintedanib in non-small cell lung and ovarian cancer. These trials found that nintedanib delayed relapse in patients with ovarian cancer by two months[11] and that overall survival of patients with non-small cell lung who received nintedanib was similar to that observed with the FDA approved VEGFR inhibitor sorafenib. These trials also concluded that increasing the dose of the nintedanib has no effect on survival.[8]

Current clinical trials

Nintedanib is being tested in several phase I to III clinical trials for cancer. Angiogenesis inhibitors such as nintedanib may be effective in a range of solid tumour types including; lung, ovarian, metastatic bowel, liver and brain cancer. Patients are also being recruited for three phase III clinical trials that will evaluate the potential benefit of nintedanib when added to existing 1st line treatments in patients with ovarian.[17] and 2nd line treatment in non-small cell lung cancer [18][19] The phase III trials of nintedanib in lung cancer have been named LUME-Lung 1 and LUME-Lung 2.

Current phase II trials are investigating the effect of nintedanib in patients with metastatic bowel cancer, liver cancer and the brain tumour: glioblastoma multiforme.[20]

Phase III trials are investigating the use of nintedanib in combination with the existing chemotherapy agents permexetred and docetaxel in patients with non-small cell lung cancer,[21] and in combination with carboplatin and paclitaxel as a first line treatment for patients with ovarian cancer.[22]

A phase III clinical trial was underway examining the safety and efficacy of nintedanib on patients with the non-cancerous lung condition idiopathic pulmonary fibrosis.[23] Nintedanib, under the brand name Ofev, was approved by the FDA for treatment of idiopathic pulmonary fibrosis on 15 Oct 2014. [24]

References

  1. 1.0 1.1 Loveman, E; Copley, VR; Colquitt, JL; Scott, DA; Clegg, AJ; Jones, J; O'Reilly, KM; Singh, S; Bausewein, C; Wells, A (19 November 2014). "The effectiveness and cost-effectiveness of treatments for idiopathic pulmonary fibrosis: systematic review, network meta-analysis and health economic evaluation.". BMC pharmacology & toxicology 15: 63. PMID 25410822. doi:10.1186/2050-6511-15-63. 
  2. "Nintedanib". drugs.com. Retrieved 12 February 2015. 
  3. Ahluwalia, N; Shea, BS; Tager, AM (15 October 2014). "New therapeutic targets in idiopathic pulmonary fibrosis. Aiming to rein in runaway wound-healing responses.". American journal of respiratory and critical care medicine 190 (8): 867–78. PMID 25090037. doi:10.1164/rccm.201403-0509pp. 
  4. 4.0 4.1 Popat, S; Mellemgaard, A; Fahrbach, K; Martin, A; Rizzo, M; Kaiser, R; Griebsch, I; Reck, M (5 December 2014). "Nintedanib plus docetaxel as second-line therapy in patients with non-small-cell lung cancer: a network meta-analysis.". Future oncology (London, England): 1–12. PMID 25478720. 
  5. "Vargatef (nintedanib*) approved in the EU for lung cancer patients with advanced adenocarcinoma after first-line chemotherapy". Boehringer Ingelheim Press Release Archive. 27 November 2014. Retrieved 13 May 2015. 
  6. 6.0 6.1 Hilberg, F.; U. Tontsch-Grunt, F. Colbatzky, A. Heckel, R. Lotz, J.C.A. van Meel, G.J. Roth (2004). "BIBF1120 a novel, small molecule triple angiokinase inhibitor: profiling as a clinical candidate for cancer therapy". European Journal of Cancer Supplements 2 (50). 
  7. 7.0 7.1 Hilberg, F.; G. J. Roth, M. Krssak, S. Kautschitsch, W. Sommergruber, U. Tontsch-Grunt, P. Garin-Chesa, G. Bader, A. Zoephel, J. Quant, A. Heckel, W. J. Rettig (2008). "BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy". Cancer Res 68 (12): 4774–82. ISSN 1538-7445. PMID 18559524. doi:10.1158/0008-5472.CAN-07-6307. 
  8. 8.0 8.1 Reck, M.; R. Kaiser; C. Eschbach; M. Stefanic; J. Love; U. Gatzemeier; P. Stopfer; J. von Pawel (2011). "A phase II double-blind study to investigate efficacy and safety of two doses of the triple angiokinase inhibitor BIBF 1120 in patients with relapsed advanced non-small-cell lung cancer". Ann Oncol. ISSN 1569-8041. 
  9. 9.0 9.1 9.2 Okamoto, I.; H. Kaneda, T. Satoh, W. Okamoto, M. Miyazaki, R. Morinaga, S. Ueda, M. Terashima, A. Tsuya, A. Sarashina, K. Konishi, T. Arao, K. Nishio, R. Kaiser, K. Nakagawa (2010). "Phase I safety, pharmacokinetic, and biomarker study of BIBF 1120, an oral triple tyrosine kinase inhibitor in patients with advanced solid tumors". Mol Cancer Ther 9 (10): 2825–33. ISSN 1538-8514. PMID 20688946. doi:10.1158/1535-7163.MCT-10-0379. 
  10. 10.0 10.1 Mross, K.; M. Stefanic, D. Gmehling, A. Frost, F. Baas, C. Unger, R. Strecker, J. Henning, B. Gaschler-Markefski, P. Stopfer, L. de Rossi, R. Kaiser (2010). "Phase I study of the angiogenesis inhibitor BIBF 1120 in patients with advanced solid tumors". Clin Cancer Res 16 (1): 311–9. ISSN 1078-0432. PMID 20028771. doi:10.1158/1078-0432.CCR-09-0694. 
  11. 11.0 11.1 Ledermann, J.A. (2009). "A randomised phase II placebo-controlled trial using maintenance therapy to evaluate the vascular targeting agent BIBF 1120 following treatment of relapsed ovarian cancer (OC)". J Clin Oncol 27 (15s): (suppl; abstr 5501). 
  12. 12.0 12.1 Kropff, M.; J. Kienast; G. Bisping; W. E. Berdel; B. Gaschler-Markefski; P. Stopfer; M. Stefanic; G. Munzert (2009). "An open-label dose-escalation study of BIBF 1120 in patients with relapsed or refractory multiple myeloma". Anticancer Res 29 (10): 4233–8. ISSN 1791-7530. PMID 19846979. 
  13. 13.0 13.1 13.2 13.3 Ellis, P. M.; R. Kaiser; Y. Zhao; P. Stopfer; S. Gyorffy; N. Hanna (2010). "Phase I open-label study of continuous treatment with BIBF 1120, a triple angiokinase inhibitor, and pemetrexed in pretreated non-small cell lung cancer patients". Clin Cancer Res 16 (10): 2881–9. ISSN 1078-0432. PMID 20460487. doi:10.1158/1078-0432.CCR-09-2944. 
  14. 14.0 14.1 14.2 du Bois, A.; J. Huober; P. Stopfer; J. Pfisterer; P. Wimberger; S. Loibl; V. L. Reichardt; P. Harter (2010). "A phase I open-label dose-escalation study of oral BIBF 1120 combined with standard paclitaxel and carboplatin in patients with advanced gynecological malignancies". Ann Oncol 21 (2): 370–5. ISSN 1569-8041. PMID 19889612. doi:10.1093/annonc/mdp506. 
  15. "FDA Approves Ofev". drugs.com. Retrieved 12 February 2015. 
  16. "OFEV (nintedanib*) approved in the EU for the treatment of IPF". Boehringer Ingelheim Press Release Archive. 19 January 2015. Retrieved 13 May 2015. 
  17. "Boehringer Ingelheim - AGO-OVAR 12 / LUME-Ovar 1 Trial Information". 2011. 
  18. "Boehringer Ingelheim - LUME-Lung 2 Trial Information". 2011. 
  19. "Boehringer Ingelheim - LUME-Lung 1 Trial Information". 2011. 
  20. http://clinicaltrials.gov/ct2/results?term=++%09+BIBF+1120&phase=1
  21. http://clinicaltrials.gov/ct2/show/NCT00805194 Phase III LUME-Lung 1: BIBF 1120 Plus Docetaxel as Compared to Placebo Plus Docetaxel in 2nd Line Non Small Cell Lung Cancer
  22. http://clinicaltrials.gov/ct2/show/NCT01015118 Phase III BIBF 1120 or Placebo in Combination With Paclitaxel and Carboplatin in First Line Treatment of Ovarian Cancer
  23. http://clinicaltrials.gov/ct2/show/NCT01335477 Safety and Efficacy of BIBF 1120 at High Dose in Idiopathic Pulmonary Fibrosis Patients II
  24. "FDA approves Ofev to treat idiopathic pulmonary fibrosis". 2014.