ChEMBL

The first approval of the last month of 2009 is Ecallantide (trade name Kalbitor), approved on December 1st. Ecallantide, previously known by the research code DX-88, is a human plasma kallikrein (P03952) inhibitor indicated for treatment of acute attacks of Hereditary Angioedema (HAE) in patients 16 years of age or older. HAE is a rare genetic disorder, giving the carrier low levels of C1-esterase inhibitor (C1-INH) activity and inherited as an autosomal dominant trait.

C1-INH is the major endogenous inhibitor of plasma kallikrein, and functions to regulate activation of the complement system and also the intrinsic coagulation (or 'contact system' pathway). One critical aspect of this system is the conversion of High Molecular Weight kininogen (HMWk) to the nona-peptide bradykinin by the trypsin-like serine protease - plasma kallikrein. During HAE attacks, disregulated activity of plasma kallikrein result in excessive bradykinin generation; bradykinin is a potent vasodilator, and this activity is thought to be responsible for the characteristic HAE symptoms of localized swelling, inflammation and pain.

Ecallantide has a block box warning (risk of anaphylaxis).

Ecallantide is a potent, selective, reversible inhibitor of plasma kallikrein (K_i of 25pM), which binds to the active site and blocks further access of substrates. Ecallantide is the first subcutaneous treatment approved in the U.S.A. The other available treatment involves the intravenous administration of C1-INH itself. Ecallantide is a polypeptide of 60 aminoacids (Molecular Weight 7054 Da), with a volume of distribution of 26.4L, a plasma clearance of 153 mL/min and an elimination half-life of ~2 hours. The recommended dose is 30 mg, administered subcutaneously as three 10 mg doses (each in 1 mL) injections (the typical dosage is therefore 0.43umol).

Ecallantide is a synthetic peptide, related to region 20-79 of the natural gene Tissue Factor Pathway Inhibitor (P10646), and contain 3 internal disulphide bonds.

Ecallantide sequence: EAMHSFCAFKADDGPCRAAHPRWFFNIFTRQCEEFIYGGCEGNQNRFESLEECKKMCTRD
Ecallanetide target sequence: GCLTQLYENAFFRGGDVASMYTPNAQYCQMRCTFHPRCLLF 
SFLPASSINDMEKRFGCFLKDSVTGTLPKVHRTGAVSGHSLKQCGHQISACHRDIYKGVD 
MRGVNFNVSKVSSVEECQKRCTNNIRCQFFSYATQTFHKAEYRNNCLLKYSPGGTPTAIK 
VLSNVESGFSLKPCALSEIGCHMNIFQHLAFSDVDVARVLTPDAFVCRTICTYHPNCLFF 
TFYTNVWKIESQRNVCLLKTSESGTPSSSTPQENTISGYSLLTCKRTLPEPCHSKIYPGV 
DFGGEELNVTFVKGVNVCQETCTKMIRCQFFTYSLLPEDCKEEKCKCFLRLSMDGSPTRI 
AYGTQGSSGYSLRLCNTGDNSVCTTKTSTRIVGGTNSSWGEWPWQVSLQVKLTAQRHLCG 
GSLIGHQWVLTAAHCFDGLPLQDVWRIYSGILNLSDITKDTPFSQIKEIIIHQNYKVSEG 
NHDIALIKLQAPLNYTEFQKPICLPSKGDTSTIYTNCWVTGWGFSKEKGEIQNILQKVNI 
PLVTNEECQKRYQDYKITQRMVCAGYKEGGKDACKGDSGGPLVCKHNGMWRLVGITSWGE 
GCARREQPGVYTKVAEYMDWILEKTQSSDGKAQMQSPA 

The full prescribing information can be found here.

The license holder is Dyax Corp. and the product website is www.kalbitor.com.