Skip to main content

New Drug Approvals 2013 - Pt. XX - Simeprevir (OlysioTM)

ATC Code: J05AE14
Wikipedia: Simeprevir

On November 22th 2013, the FDA approved simeprevir (Tradename: Olysio; Research Code(s): TMC-435; TMC435350), a Hepatitis C virus NS3/NS4A protease (HCV NS3/NS4A) inhibitor, for the treatment of chronic hepatitis C virus genotype 1 infection, in combination with peginterferon alfa and ribavirin.

Chronic hepatitis C is a prolonged infection that affects the liver and is caused by a small single-stranded RNA virus, which is transmitted by blood-to-blood contact. Chronic hepatitis C is normally asymptomatic, but may lead to liver fibrosis, and thus liver failure.

Simeprevir is an inhibitor of the hepatitis C virus (HCV) serine protease NS3/NS4A (ChEMBLID:CHEMBL2095231; Uniprot ID:A3EZI9, D2K2A8; Pfam:PF02907), a viral protein complex required for the proteolytic cleavage of the HCV encoded polyprotein (UniProt:P27958) into mature forms of the NS4B, NS5A and NS5B proteins. These proteins are involved in the formation of the virus replication complex, and therefore are vital to its proliferation. In a biochemical assay, simeprevir inhibited the proteolytic activity of recombinant genotype 1a and 1b HCV NS3/4A proteases, with median Ki values of 0.5 nM and 1.4 nM, respectively. However, in patients infected with the genotype 1a hepatitis C virus with an NS3 Q80K polymorphism, the effectiveness of simeprevir is slightly reduced, thus, screening for this polymorphism prior to the beginning of therapy is recommended, and alternative therapies should be considered.

There are several protein structures known for HCV NS3 in complex with inhibitors, a typical entry is PDBe:3rc4, as expected from early genome annotation, the NS3 protease has a fold distantly related to the chymotrypsin-like family of serine proteases, and contains the classic Asp-His-Ser catalytic triad.

The -vir USAN/INN stem covers antiviral agents, and the substem -previr indicates it is a serine protease inhibitor. Simeprevir is the third approved agent to target HCV NS3/NS4A, following the approval of Merck's Boceprevir (q.v.) and Vertex's Telaprevir in 2011. Contrary to its predecessors, simeprevir is a natural derived compound, which requires a substantial lower dose (~16x less) for an effective response. It is also once-daily dosed, offering thus a promising alternative therapy for potential non-complying patients. Other compounds in this class in late stage clinical development/registration or earlier stages of development include Genentech's Danoprevir (RG-7227, ITMN-191), Bristol Myers Squibb's Asunaprevir (BMS-650032), Vaniprevir (MK-7009), Schering's Narlaprevir (SCH-900518), Achillion's Sovaprevir (ACH-0141625), Gilead's Vedroprevir (GS-9451), Ciluprevir (BILN-2061), ABT-450, BI-201335, IDX-320, MK-5172, BIT-225, VX-500, ACH-1625 and GS-9256.

Simeprevir (IUPAC Name: (2R,3aR,10Z,11aS,12aR,14aR)-N-(cyclopropylsulfonyl)-2-({7-methoxy-8-methyl-2-[4-(1-methylethyl)thiazol-2-yl]quinolin-4-yl}oxy)-5-methyl-4,14-dioxo-2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a-tetradecahydrocyclopenta[c]cyclopropa[g][1,6]diazacyclotetradecine-12a(1H)-carboxamide; Canonical smiles: COc1ccc2c(O[C@@H]3C[C@@H]4[C@@H](C3)C(=O)N(C)CCCC\C=C/[C@@H]5C[C@]5(NC4=O)C(=O)NS(=O)(=O)C6CC6)cc(nc2c1C)c7nc(cs7)C(C)C; ChEMBL: CHEMBL501849; PubChem: 24873435; ChemSpider: 23331536; Standard InChI Key: JTZZSQYMACOLNN-VDWJNHBNSA-N) is a a natural product derived compound, with a molecular weight of 749.9 Da, 9 hydrogen bond acceptors, 2 hydrogen bond donors, and has an ALogP of 4.8. The compound is therefore not fully compliant with the rule of five.

Simeprevir is available as an oral capsule and the recommended daily dose is a single capsule of 150 mg. In HCV-infected subjects, the steady-state is reached after 7 days of once daily dosing and the mean steady-state AUC24 is 57469 ng.h/mL (standard deviation: 63571). Simeprevir should be administered with food, since food enhances its bioavailability by up to 69%. In vitro studies indicated that simeprevir is extensively bound to plasma proteins (greater than 99.9%).

The primary enzymatic system involved in the biotransformation of simeprevir in the liver is CYP3A. Therefore, co-administration of simeprevir with inhibitors or inducers of CYP3A may significantly alter the plasma concentration of simeprevir. In vitro studies indicated that simeprevir is a substrate of P-gp, and is transported into the liver by OATP1B1/3. Following a single oral administration of 200mg, the terminal elimination half-life of simeprevir is 10 to 13 hours in HCV-uninfected subjects and 41 hours in HCV-infected subjects. Elimination of simeprevir occurs via biliary excretion, and its metabolites are primarily excreted in feces.

As simeprevir is given as a component of a combination antiviral treatment regime with ribavirin and peginterferon alfa, there is a warning for embryofetal toxicity.

The license holder for OlysioTM is Janssen Pharmaceuticals, and the full prescribing information can be found here.


Popular posts from this blog

A python client for accessing ChEMBL web services

Motivation The CheMBL Web Services provide simple reliable programmatic access to the data stored in ChEMBL database. RESTful API approaches are quite easy to master in most languages but still require writing a few lines of code. Additionally, it can be a challenging task to write a nontrivial application using REST without any examples. These factors were the motivation for us to write a small client library for accessing web services from Python. Why Python? We choose this language because Python has become extremely popular (and still growing in use) in scientific applications; there are several Open Source chemical toolkits available in this language, and so the wealth of ChEMBL resources and functionality of those toolkits can be easily combined. Moreover, Python is a very web-friendly language and we wanted to show how easy complex resource acquisition can be expressed in Python. Reinventing the wheel? There are already some libraries providing access to ChEMBL d

ChEMBL 29 Released

  We are pleased to announce the release of ChEMBL 29. This version of the database, prepared on 01/07/2021 contains: 2,703,543 compound records 2,105,464 compounds (of which 2,084,724 have mol files) 18,635,916 activities 1,383,553 assays 14,554 targets 81,544 documents Data can be downloaded from the ChEMBL FTP site: .  Please see ChEMBL_29 release notes for full details of all changes in this release: New Deposited Datasets EUbOPEN Chemogenomic Library (src_id = 55, ChEMBL Document IDs CHEMBL4649982-CHEMBL4649998): The EUbOPEN consortium is an Innovative Medicines Initiative (IMI) funded project to enable and unlock biology in the open. The aims of the project are to assemble an open access chemogenomic library comprising about 5,000 well annotated compounds covering roughly 1,000 different proteins, to synthesiz

Julia meets RDKit

Julia is a young programming language that is getting some traction in the scientific community. It is a dynamically typed, memory safe and high performance JIT compiled language that was designed to replace languages such as Matlab, R and Python. We've been keeping an an eye on it for a while but we were missing something... yes, RDKit! Fortunately, Greg very recently added the MinimalLib CFFI interface to the RDKit repertoire. This is nothing else than a C API that makes it very easy to call RDKit from almost any programming language. More information about the MinimalLib is available directly from the source . The existence of this MinimalLib CFFI interface meant that we no longer had an excuse to not give it a go! First, we added a BinaryBuilder recipe for building RDKit's MinimalLib into Julia's Yggdrasil repository (thanks Mosè for reviewing!). The recipe builds and automatically uploads the library to Julia's general package registry. The build currently targe

Identifying relevant compounds in patents

  As you may know, patents can be inherently noisy documents which can make it challenging to extract drug discovery information from them, such as the key targets or compounds being claimed. There are many reasons for this, ranging from deliberate obfuscation through to the long and detailed nature of the documents. For example, a typical small molecule patent may contain extensive background information relating to the target biology and disease area, chemical synthesis information, biological assay protocols and pharmacological measurements (which may refer to endogenous substances, existing therapies, reaction intermediates, reagents and reference compounds), in addition to description of the claimed compounds themselves.  The SureChEMBL system extracts this chemical information from patent documents through recognition of chemical names, conversion of images and extraction of attached files, and allows patents to be searched for chemical structures of interest. However, the curren

New Drug Warnings Browser

As mentioned in the announcement post of  ChEMBL 29 , a new Drug Warnings Browser has been created. This is an updated version of the entity browsers in ChEMBL ( Compounds , Targets , Activities , etc). It contains new features that will be tried out with the Drug Warnings and will be applied to the other entities gradually. The new features of the Drug Warnings Browser are described below. More visible buttons to link to other entities This functionality is already available in the old entity browsers, but the button to use it is not easily recognised. In the new version, the buttons are more visible. By using those buttons, users can see the related activities, compounds, drugs, mechanisms of action and drug indications to the drug warnings selected. The page will take users to the corresponding entity browser with the items related to the ones selected, or to all the items in the dataset if the user didn’t select any. Additionally, the process of creating the join query is no