Drug spotlight- Icatibant, FDA 2011

Icatibant (trade name Firazyr) is a peptidomimetic drug consisting of ten amino acids, which is a selective and specific antagonist of bradykinin B2 receptors. It has been approved by the European Commission for the symptomatic treatment of acute attacks,^[1][2] of hereditary angioedema (HAE) in adults (with C1-esterase-inhibitor deficiency).

Bradykinin is a peptide-based hormone that is formed locally in tissues, very often in response to a trauma. It increases vessel permeability, dilates blood vessels

and causes smooth muscle cells to contract . Bradykinin plays an important role as the mediator of pain. Surplus bradykinin is responsible for the typical symptoms of inflammation, such as swelling, redness, overheating and pain. These symptoms are mediated by activation of bradykinin B2 receptors. Icatibant acts as a bradykinin inhibitor by blocking the binding of native bradykinin to the bradykinin B2 receptor.

Icatibant has received orphan drug status in Australia, EU, Switzerland and US.

In the EU, the approval by the European Commission (July 2008) allows Jerini to market Firazyr in the European Union's 27 member states, as well as Switzerland, Lichtenstein and Iceland, making it the first product to be approved in all EU countries for the treatment of HAE.^[1] In the US, the drug was granted FDA approval on August 25, 2011.^[3]

1.      1 "Jerini Receives European Commission Approval for Firazyr (Icatibant) in the Treatment of HAE" (Press release). Jerini AG. 2008-07-15. Retrieved 2008-07-22.

2.       2 "Jerini Receives Positive CHMP Opinion Recommending European Approval for Icatibant in the Treatment of HAE; FDA Issues Not Approvable Letter" (Press release).Jerini AG. 2008-04-24. Retrieved 2008-07-22.

3.      3 FDA Approves Shire’s FIRAZYR (icatibant injection) for Acute Attacks of Hereditary Angioedema (HAE)" (Press release). Shire. Retrieved 2011-08-28.

On the August 25th 2011, the FDA approved Icatibant (trade name: Firazyr^TM), a bradykinin B2 receptor (B2R) antagonist indicated for the treatment of acute attacks of hereditary angioedema (HAE) in patients aged 18 or older.

HAE is a rare genetic disease and is caused by low levels of C1-esterase inhibitor (C1-INH), the major endogenous inhibitor and regulator of the protease plasma kallikrein and the key regulator of the Factor XII/kallikrein cascade. One component this cascade is the production of bradykinin by plasma kallikrein. During HAE attacks, disregulated activity of plasma kallikrein leads to excessive bradykinin production; bradykinin is a potent vasodilator, which s thought to be responsible for the characteristic HAE symptoms of localised swelling, inflammation and pain.

Icatibant treats the clinical symptoms of HAE attack by selective- and competitively binding, as an antagonist, to the B2 bradykinin receptor (B2R) , with similar affinity to bradykinin (1-10 nM for the B2R, while affinity for the B1R is 100-fold lower). Icatibant is the first in class agent against this target. The -tibant stem covers bradykinin antagonists.

B2R is a Rhodopsin-like receptor, 391 amino acid long, which belongs to the G protein-coupled receptor (GPCR) A3 family and is encoded by the BDKRB2 gene in humans. The amino acid sequence of B2R is:

>B2R

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MFSPWKISMFLSVREDSVPTTASFSADMLNVTLQGPTLNGTFAQSKCPQVEWLGWLNTIQ

PPFLWVLFVLATLENIFVLSVFCLHKSSCTVAEIYLGNLAAADLILACGLPFWAITISNN

FDWLFGETLCRVVNAIISMNLYSSICFLMLVSIDRYLALVKTMSMGRMRGVRWAKLYSLV

IWGCTLLLSSPMLVFRTMKEYSDEGHNVTACVISYPSLIWEVFTNMLLNVVGFLLPLSVI

TFCTMQIMQVLRNNEMQKFKEIQTERRATVLVLVVLLLFIICWLPFQISTFLDTLHRLGI

LSSCQDERIIDVITQIASFMAYSNSCLNPLVYVIVGKRFRKKSWEVYQGVCQKGGCRSEP

IQMENSMGTLRTSISVERQIHKLQDWAGSRQ