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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.


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# Deposited Data Sets:

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Data have been included from the publication: The target landscape of clinical kinase drugs. Klaeger S, Heinzlmeir S and Wilhelm M et al (2017), Science, 358-6367 (

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