New Drug Approvals - Pt. XXIII - Ecallantide (Kalbitor)

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.

Comments

Improvements in SureChEMBL's chemistry search and adoption of RDKit

Dear SureChEMBL users, If you frequently rely on our "chemistry search" feature, today brings great news! We’ve recently implemented a major update that makes your search experience faster than ever. What's New? Last week, we upgraded our structure search engine by aligning it with the core code base used in ChEMBL . This update allows SureChEMBL to leverage our FPSim2 Python package , returning results in approximately one second. The similarity search relies on 256-bit RDKit -calculated ECFP4 fingerprints, and a single instance requires approximately 1 GB of RAM to run. SureChEMBL’s FPSim2 file is not currently available for download, but we are considering generating it periodicaly and have created it once for you to try in Google Colab ! For substructure searches, we now also use an RDKit -based solution via SubstructLibrary , which returns results several times faster than our previous implementation. Additionally, structure search results are now sorted by

Improved querying for SureChEMBL

Dear SureChEMBL users, Earlier this year we ran a survey to identify what you, the users, would like to see next in SureChEMBL. Thank you for offering your feedback! This gave us the opportunity to have some interesting discussions both internally and externally. While we can't publicly reveal precisely our plans for the coming months (everything will be delivered at the right time), we can at least say that improving the compound structure extraction quality is a priority. Unfortunately, the change won't happen overnight as reprocessing 167 millions patents takes a while. However, the good news is that the new generation of optical chemical structure recognition shows good performance, even for patent images! We hope we can share our results with you soon. So in the meantime, what are we doing? You may have noticed a few changes on the SureChEMBL main page. No more "Beta" flag since we consider the system to be stable enough (it does not mean that you will never

ChEMBL brings drug bioactivity data to the Protein Data Bank in Europe

In the quest to develop new drugs, understanding the 3D structure of molecules is crucial. Resources like the Protein Data Bank in Europe (PDBe) and the Cambridge Structural Database (CSD) provide these 3D blueprints for many biological molecules. However, researchers also need to know how these molecules interact with their biological target – their bioactivity. ChEMBL is a treasure trove of bioactivity data for countless drug-like molecules. It tells us how strongly a molecule binds to a target, how it affects a biological process, and even how it might be metabolized. But here's the catch: while ChEMBL provides extensive information on a molecule's activity and cross references to other data sources, it doesn't always tell us if a 3D structure is available for a specific drug-target complex. This can be a roadblock for researchers who need that structural information to design effective drugs. Therefore, connecting ChEMBL data with resources like PDBe and CSD is essen

ChEMBL 34 is out!

We are delighted to announce the release of ChEMBL 34, which includes a full update to drug and clinical candidate drug data. This version of the database, prepared on 28/03/2024 contains: 2,431,025 compounds (of which 2,409,270 have mol files) 3,106,257 compound records (non-unique compounds) 20,772,701 activities 1,644,390 assays 15,598 targets 89,892 documents Data can be downloaded from the ChEMBL FTP site: https://ftp.ebi.ac.uk/pub/databases/chembl/ChEMBLdb/releases/chembl_34/ Please see ChEMBL_34 release notes for full details of all changes in this release: https://ftp.ebi.ac.uk/pub/databases/chembl/ChEMBLdb/releases/chembl_34/chembl_34_release_notes.txt New Data Sources European Medicines Agency (src_id = 66): European Medicines Agency's data correspond to EMA drugs prior to 20 January 2023 (excluding vaccines). 71 out of the 882 newly added EMA drugs are only authorised by EMA, rather than from other regulatory bodies e.g.

In search of the perfect assay description

Credit: Science biotech, CC BY-SA 4.0 Assays des cribe the experimental set-up when testing the activity of drug-like compounds against biological targets; they provide useful context for researchers interested in drug-target relationships. Ver sion 33 of ChEMBL contains 1.6 million diverse assays spanning ADMET, physicochemical, binding, functional and toxicity experiments. A set of well-defined and structured assay descriptions would be valuable for the drug discovery community, particularly for text mining and NLP projects. These would also support ChEMBL's ongoing efforts towards an in vitro assay classification. This Blog post will consider the features of the 'perfect' assay description and provide a guide for depositors on the submission of high quality data. ChEMBL's assays are typically structured with the overall aim, target, and method . The ideal assay description is succinct but contains all the necessary information for easy interpretation by database u

The ChEMBL-og

Search This Blog