Ibrutinib

Structural formula
General
Non-proprietary name	Ibrutinib
other names	PCI-32765; 1 - [(3 R ) -3- [4-Amino-3- (4-phenoxyphenyl) pyrazolo [3,4- d ] pyrimidin-1-yl] piperidin-1-yl] prop-2-en-1- on ( IUPAC );
Molecular formula	C 25 H 24 N 6 O 2
External identifiers / databases
EC number	805-642-2
ECHA InfoCard	100.232.543
PubChem	24821094
DrugBank	DB09053
Wikidata	Q5984881
Drug information
Drug class	Cytostatic
Mechanism of action	Tyrosine kinase inhibitor
properties
Molar mass	440.50 g mol −1
safety instructions
H and P phrases	H: 302-315-319-335-360
	P: ?
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Ibrutinib (manufacturer: AbbVie ; marketed by Janssen in the EU ) is a drug from the group of tyrosine kinase inhibitors sold under the trade name Imbruvica u. a. used to treat chronic lymphocytic leukemia (CLL) and mantle cell lymphoma .

Development and clinical studies

Ibrutinib is an orally administered tyrosine kinase inhibitor - originally developed by Pharmacyclics - that inhibits Bruton's tyrosine kinase ( BTK ). This plays a central role in the intracellular signal transmission in B lymphocytes . Ibrutinib is therefore clinically used in malignant B-cell diseases, in the narrower sense B-cell non-Hodgkin lymphomas , but also autoimmune diseases in which B cells play a role, such as rheumatoid arthritis .

Pharmacyclics was bought by Abbvie in 2015.

Ibrutinib (then still under the name PCI-32765) was first synthesized in 2007 as a designer drug to inhibit BTK . The substance showed a high in vitro effectiveness against lymphoma cells and was finally used in clinical testing. In two large therapy studies that were published in the New England Journal of Medicine , ibrutinib was shown to be effective in intensively pretreated patients with treatment-resistant chronic lymphocytic leukemia (CLL) or with mantle cell lymphoma . On the basis of these study results, the US Food and Drug Administration (FDA) rated the drug as breakthrough , which has resulted in an accelerated approval process (see also Break Through Therapy ). Ibrutinib was approved by the FDA on November 13, 2013 for the treatment of mantle cell lymphoma. The trade name in the United States is Imbruvica. Ibrutinib was approved by the FDA for the treatment of CLL in February 2014.

According to the results of the RESONATE-2 study published in December 2015, ibrutinib was also superior to chlorambucil (based on overall survival, progression-free survival) in the first-line therapy of CLL (ie in previously untreated patients ).

A study published in April 2015 showed a very good effect of ibrutinib in patients with Waldenström's macroglobulinemia . The study included 73 patients who had received at least one previous treatment and who had relapsed. The treatment was effective in more than 90% of patients and very effective in 73%.

Admission status

In the USA

In August 2017, the FDA granted the sixth approval for ibrutinib: graft-versus-host reaction . This means that the following indications are approved in the USA:

Chronic lymphocytic leukemia (CLL),
small lymphocytic lymphoma (SLL),
Waldenström's disease (WM),
pretreated mantle cell lymphoma (MCL) as a single substance,
pretreated marginal zone lymphoma (MZL) and
pretreated chronic graft-versus-host reaction (cGVHD).

In the EU

In July 2014 the Committee for Medicinal Products for Human Use of the European Medicines Agency (EMA) recommended ibrutinib for approval for the indication Chronic Lymphatic Leukemia (CLL). Ibrutinib also received a recommendation for approval for the indication of mantle cell lymphoma .

The following indications are approved in the EU:

Chronic lymphocytic leukemia (CLL) in first-line therapy as a single substance,
pretreated mantle cell lymphoma (MCL) as a single substance and
pretreated Waldenström's disease as a single substance (WM)

literature

Vinay Prasad, Sham Mailankody: Research and Development Spending to Bring a Single Cancer Drug to Market and Revenues After Approval. In: JAMA Internal Medicine . 2017 September, doi : 10.1001 / jamainternmed.2017.3601 .

Individual evidence

↑ Template: CL Inventory / not harmonized There is not yet a harmonized classification for this substance . A label for 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] piperidine is shown, which is derived from a self-classification by the distributor -1-yl] prop-2-en-1-one in the Classification and Labeling Inventory of the European Chemicals Agency (ECHA), accessed on July 29, 2019.

^ European public assessment report (EPAR) , EMA, accessed on May 9, 2017

↑ ^a ^b Summary of the EPAR for the public , EMA, accessed on September 18, 2017

↑ Summary of the risk management plan (RMP) for Imbruvica (ibrutinib) , EMA, accessed on May 9, 2017

↑ AbbVie Completes Acquisition of Pharmacyclics , AbbVie PM, May 26, 2015, accessed on September 18, 2017

↑ Ibrutinib: Kinase inhibitor active against B-cell malignancies. Deutsches Ärzteblatt, June 20, 2013, accessed on July 23, 2013 .

^ Ibrutinib Receives Two Oncology Breakthrough Therapy Designations from US Food and Drug Administration. prnewswire.com, February 12, 2013, accessed July 29, 2013 .

↑ FDA approves Imbruvica for rare blood cancer. US Department of Health and Human Services, November 13, 2013, accessed November 13, 2013 .

↑ FDA approves Zydelig for three types of blood cancers. US Department of Health and Human Services, July 23, 2014, accessed July 29, 2014 .

↑ Burger JA1, Tedeschi A, Barr PM, Robak T, Owen C, Ghia P, Bairey O, Hillmen P, Bartlett NL, Li J, Simpson D, Grosicki S, Devereux S, McCarthy H, Coutre S, Quach H, Gaidano G, Maslyak Z, Stevens DA, Janssens A, Offner F, Mayer J, O'Dwyer M, Hellmann A, Schuh A, Siddiqi T, Polliack A, Tam CS, Suri D, Cheng M, Clow F, Styles L, James DF, Kipps TJ; RESONATE-2 Investigators: Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. N Engl J Med. 2015; 373 (25): 2425-37. PMID 26639149 .

↑ Treon SP, Tripsas CK, Meid K, Warren D, Varma G, Green R, Argyropoulos KV, Yang G, Cao Y, Xu L, Patterson CJ, Rodig S, Zehnder JL, Aster JC, Harris NL, Kanan S, Ghobrial I, Castillo JJ, Laubach JP, Hunter ZR, Salman Z, Li J, Cheng M, Clow F, Graef T, Palomba ML, Advani RH: Ibrutinib in previously treated Waldenström's macroglobulinemia. N Engl J Med. 2015 Apr 9; 372 (15): 1430-40. doi : 10.1056 / NEJMoa1501548 PMID 25853747 .

↑ US FDA Approves IMBRUVICA® (ibrutinib) as First Approved Treatment Specifically for Adults with Chronic Graft-Versus-Host-Disease (cGVHD) , PM AbbVie of August 2, 2017, accessed on September 18, 2017.

↑ European Medicines Agency recommends approval of two new treatment options for rare cancers. European Medicines Agency's (EMA), July 25, 2014, accessed July 29, 2014 .

[1] Template: CL Inventory / not harmonized There is not yet a harmonized classification for this substance . A label for 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] piperidine is shown, which is derived from a self-classification by the distributor -1-yl] prop-2-en-1-one in the Classification and Labeling Inventory of the European Chemicals Agency (ECHA), accessed on July 29, 2019.

[2] European public assessment report (EPAR) , EMA, accessed on May 9, 2017

[EPAR_dt-3] Summary of the EPAR for the public , EMA, accessed on September 18, 2017

[4] Summary of the risk management plan (RMP) for Imbruvica (ibrutinib) , EMA, accessed on May 9, 2017

[5] AbbVie Completes Acquisition of Pharmacyclics , AbbVie PM, May 26, 2015, accessed on September 18, 2017

[6] Ibrutinib: Kinase inhibitor active against B-cell malignancies. Deutsches Ärzteblatt, June 20, 2013, accessed on July 23, 2013 .

[7] Ibrutinib Receives Two Oncology Breakthrough Therapy Designations from US Food and Drug Administration. prnewswire.com, February 12, 2013, accessed July 29, 2013 .

[mzl-8] FDA approves Imbruvica for rare blood cancer. US Department of Health and Human Services, November 13, 2013, accessed November 13, 2013 .

[FDA_Idelalisib_Approval-9] FDA approves Zydelig for three types of blood cancers. US Department of Health and Human Services, July 23, 2014, accessed July 29, 2014 .

[10] Burger JA1, Tedeschi A, Barr PM, Robak T, Owen C, Ghia P, Bairey O, Hillmen P, Bartlett NL, Li J, Simpson D, Grosicki S, Devereux S, McCarthy H, Coutre S, Quach H, Gaidano G, Maslyak Z, Stevens DA, Janssens A, Offner F, Mayer J, O'Dwyer M, Hellmann A, Schuh A, Siddiqi T, Polliack A, Tam CS, Suri D, Cheng M, Clow F, Styles L, James DF, Kipps TJ; RESONATE-2 Investigators: Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. N Engl J Med. 2015; 373 (25): 2425-37. PMID 26639149 .

[11] Treon SP, Tripsas CK, Meid K, Warren D, Varma G, Green R, Argyropoulos KV, Yang G, Cao Y, Xu L, Patterson CJ, Rodig S, Zehnder JL, Aster JC, Harris NL, Kanan S, Ghobrial I, Castillo JJ, Laubach JP, Hunter ZR, Salman Z, Li J, Cheng M, Clow F, Graef T, Palomba ML, Advani RH: Ibrutinib in previously treated Waldenström's macroglobulinemia. N Engl J Med. 2015 Apr 9; 372 (15): 1430-40. doi : 10.1056 / NEJMoa1501548 PMID 25853747 .

[12] US FDA Approves IMBRUVICA® (ibrutinib) as First Approved Treatment Specifically for Adults with Chronic Graft-Versus-Host-Disease (cGVHD) , PM AbbVie of August 2, 2017, accessed on September 18, 2017.

[CHMP-13] European Medicines Agency recommends approval of two new treatment options for rare cancers. European Medicines Agency's (EMA), July 25, 2014, accessed July 29, 2014 .