Pibrentasvir

Lars Maul, Felix Möser, Mariana Müller Nieva and Lea Neumann July 01, 2020

Contents

1 Introduction 1

2 Basic Information 1

3 Structural analysis 2 3.1 Classification ...... 2 3.2 Structural differences between Ombitasvir and Pibrentasvir ...... 2

4 Application as a pharmaceutical 3 4.1 Underlying disease ...... 3 4.2 Combination of the drug and therapy ...... 4 4.3 Effect of Maviret ...... 4 4.4 Properties of Maviret ...... 4 4.5 Side effects and interdependencies with other drugs ...... 5 4.6 Alternatives ...... 5

1 Introduction

The active ingredient Pibrentasvir is used for the treatment of the six genotypes of the Hepatitis-C virus. The antiviral drug belongs to the class of NS5A inhibitors. It is used as a fixed combination with Glecaprevir in the drug Maviret. In the following article, the NS5A inhibitor will be introduced in more detail. First, basic information will be presented leading over to the structural analysis of the molecule. At this point, the focus will be set on the structural comparison to a first-generation NS5A inhibitor and the significance of these changes. Finally, the use of the molecule Pibrentasvir as the drug Maviret will be explained.

2 Basic Information

IUPAC: methylN-[(2S,3R)-1-[(2S)-2-[6-[(2R,5R)-1-[3,5-difluoro-4-[4-(4-fluorophenyl)piperidin-1-yl]phenyl]-5-[6-fluoro- 2-[(2S)-1-[(2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoyl]pyrrolidin-2-yl]-3H-benzimidazol-5-yl]pyrrolidin- 2-yl]-5-fluoro-1H-benzimidazol-2-yl]pyrrolidin-1-yl]-3-methoxy-1-oxobutan-2-yl]carbamate

At standard states of temperature and pressure Pibrentasvir (C57H65F5N10O8, M = 1113.2 g/mol) exists as a white or slightly yellow crystalline powder. It’s an HCV NS5A-Inhibitor which is used for the treatment of the Hepatitis-C virus. The medicine is produced as a fixed combination of the active agents Pibrentasvir and Glecaprevir. The drug is called Maviret and is produced by AbbVie. This fixed combination of the active agents was licensed in 2017 for usage in the EU, Switzerland and theUSA.In the human body, Pibrentasvir is not metabolized and almost exclusively bound to human plasma proteins. When it is

1 absorbed by healthy subjects the mean peak plasma concentration is reached after 5 hours. In non-cirrhotic Hepatitis-C infected subjects the mean peak plasma concentration is about 110 ng/ml. The excretion of the agent is biliary-faecal with an elimination half-life about 13 hours. The agent is not excreted in the urine meaning that the treatment of a patient with renal failure is possible. In combination with Glecaprevir, the bioavailability can be improved compared to a sole administration of Pibrentasvir. Pibrentasvir is not genotoxic according to in vitro or in vivo studies. In rodent studies, it has also been shown that it has no effect on mating, female or male fertility, or early embryonic development.

3 Structural analysis

3.1 Classification This compound belongs to the class of organic compounds known as phenylpiperidines. These are compounds contain- ing a phenylpiperidine skeleton which consists of piperidine bound to a phenyl group. Kingdom: Organic compounds Super class: Organoheterocyclic compounds Class: Piperidines Sub Class: Phenylpiperidines

3.2 Structural differences between Ombitasvir and Pibrentasvir First-generation NS5A inhibitors do not show equivalent efficacy against all genotypes of the HCV virus 1-6 andare prone to drug resistance. Modification of the anchor, symmetric linker and end-cap architecture (figure 2) andalter- ation of the pyrrolidine stereochemistry of Ombitasvir (figure 1), which is a first-generation NS5A inhibitor, results in significant improvements of genotype coverage and resistance-profile while maintaining the strong antiviral properties of Ombitasvir.

First, the linker regions are changed from a phenyl amide linker to a benzimidazole linker and the stereochemical bonds at the pyrrolidine core are changed from 2S,5S to 2R,5R. These changes show strong activity against all tested genotypes and by changing the stereochemistry especially the inhibition of HCV replication of genotypes 1-4 could be improved. On this basis, further structural changes are made to improve the pharmacokinetic profile. The intent is to improve the potencies with comparable activities towards the different HCV genotypes as well as to maintain activity against amino acid substitutions usually selected as resistant variants by first-generation NS5A inhibitors. An exchange of the tert-butyl group with 4-fluorophenyl-substituted piperidine leads to a potency-increasing effect, especially with the doubly fluorinated benzene. An improved oral exposure can be achieved due to the larger and lipophilic anchor. An improvement in plasma exposure is also achieved by fluorinating the benzimidazole linkers. Finally, the moc-Val end-caps are varied to moc-Thr(OMe) groups. This variation shows the best EC50 potencies across all genotypes and the least protein binding attenuation effects. Pibrentasvir also shows a significantly improved resistance profile.

These changes lead to the development of the molecule Pibrentasvir (figure 3) with the properties of a next-generation NS5A inhibitor. Thus Pibrentasvir shows strong activity in genotypes 1-6. The tendency to develop drug resistance in all common genotypes was also greatly reduced. A sufficient plasma exposure upon oral administration to suppress HCV replication exists and Pibrentasvir has the ability to be combined with another mechanistically orthogonal antiviral agent.

2 Figure 1: structure Ombitasvir Figure 2: schematic structure

Figure 3: structure Pibrentasvir

4 Application as a pharmaceutical

4.1 Underlying disease Pibrentasvir is used in pharmaceuticals in combination with Glecaprevir. Glecaprevir / Pibrentasvir (G/P), sold under the brand names Mavyret and Maviret, is a medication used to treat Hepatitis C. It works against all six types of hepatitis C, labelled 1 through 6. There are also subtypes labelled with letters for example genotypes 1a and 1b. Most people are infected by a single, dominant genotype, but it is possible to have more than one at the same time. Hepatitis-C is usually chronic and can lead to severe liver diseases such as cirrhosis and liver cancer. The pathogen is the Hepatitis- C-virus (HCV), which is a single-stranded RNA-virus. The NS5A protein, which stands for non-structural protein 5A, is an important part of the development of the Hepatitis-C-virus. The zinc-binding protein is a large hydrophilic phos- phoprotein that is involved in the RNA-replication. It is also essential for the later stages of the viral life cycle of HCV which includes the assembly of viral particles which leads to infectious virions as well as complex interdependencies

3 with cellular functions. The last point includes the inhibition of apoptosis and the promotion of tumorigenic processes. Both play an important role in the initiation of carcinogenic processes. The proline-rich protein consists of 447 amino acids and is characterized by three domains. Domain I is a zinc-binding domain and Domain II and III are unstructured. All three domains are able to bind the RNA.

4.2 Combination of the drug and therapy Maviret is a combination of Pibrentasvir and Glecaprevir. One pill contains 100 mg Glecaprevir and 40 mg Pibrentasvir. In addition to these main active agents, the drug contains several other active substances like lactose-monohydrates. The usual processing time is about 8 to 12 weeks and is influenced by possible liver issues. The active substances are decomposed by the liver. One treatment costs about 30000 euros.

4.3 Effect of Maviret The drug prevents virus replication as well as the production of new virus components in the cell. Maviret shows a direct antiviral or virostatic effect. Pibrentasvir acts as an NS5A inhibitor which can reduce the HCV RNA blood level. Forthis purpose, Pibrentasvir binds to the NS5A protein which is responsible for the virus’ RNA replication (figure 4). The active substance prevents the virus from reprogramming the cells. It binds directly to the NS5A protein outside and within the cell and thus prevents the direct docking to the individual cell organelles. Furthermore, the transport of the viruses into the cell is prevented by inhibiting a special transport protein, the p-glycoprotein. In addition, glecaprevir acts as an inhibitor of the HCV NS3 / 4A protease, which is also responsible for RNA replication and thus virus replication. The combination of several direct-acting agents with different molecular targets enables sustained virus suppression while avoiding antiviral resistance. In addition to a direct antiviral agent, Maviret also represents a blockade that prevents the viruses from reaching the corresponding host cells in the first place.

Figure 4: NS5A inhibitor’s mechanism of action [18]

4.4 Properties of Maviret Maviret works on all six genotypes of the Hepatitis-C virus and shows a direct antiviral effect. It can be used for patients who suffer from mild to moderate liver cirrhosis and HIV co-infection. Patients with kidney diseases can betreated as well due to the excretion of the active ingredient being biliary-faecal. Furthermore, studies have shown that 99% of patients without cirrhosis tested negative for HCV after 8 weeks of treatment. For patients with cirrhosis, this rate was 97% after 12 weeks of treatment (Exception: Genotype 3 with 95% effectiveness). Serious side effects occurred in approximately 1.7% of the patients during a study. The total number of patients who experienced serious side effects that may have been related to the investigational drug concerned 0.9% of patients with side effects from angioedema.

4 4.5 Side effects and interdependencies with other drugs Interdependencies with drugs that are inductors for the p-glycoprotein could have a decreasing effect on the active substance’s concentration within the cell and thereby the therapeutic effect. Examples for such inductors are Rifampicin, Carbamazepine and St. John’s wort. Alcohol, as well as other liver-toxic substances, might accelerate or even induce potential liver cirrhosis. Headaches, nausea, fatigue and asthenia can be side effects.

4.6 Alternatives Different HCV-protease inhibitors besides Maviret like e.g. Boceprevir and Asunaprevir show antiviral effects against the Hepatitis-C virus. Ombitasvir, Daclatasvir and Elbasvir portray HCV-polymerase-inhibitors, thus showing similar therapeutic effects to Pibrenstasvir and Glecaprevir. There is no vaccine against the hepatitis C virus todate.

References

[1] www.kbv.de/html/32593.php&sa=D&ust=1591441823221000&usg=AFQjCNFRtJ2-iZQVteoenX6jB_ vKPEp1uA (29.04.2020) [2] www.pharmawiki.ch/wiki/index.php?wiki%3DPibrentasvir&sa=D&ust=1591441823222000& usg=AFQjCNGeWOtHykPuC_lhU71uoHDWeruY1A (29.04.2020) [3] pubchem.ncbi.nlm.nih.gov/compound/Pibrentasvir&sa=D&ust=1591441823221000&usg= AFQjCNEreBA54mOWyNc4Eu_FwO-dimXzQg (05.05.2020) [4] www.ema.europa.eu/en/documents/product-information/maviret-epar-product-information_ de.pdf&sa=D&ust=1591441823226000&usg=AFQjCNF5R5i5i1cJKOiPKgN-3eIpFgzp4g (12.05.2020)

[5] flexikon.doccheck.com/de/Pharmakokinetik&sa=D&ust=1591441823227000&usg= AFQjCNFQyxzAcfo0L1BZfHQIvzTqEJGzLw (29.04.2020) [6] flexikon.doccheck.com/de/Pibrentasvir&sa=D&ust=1591441823227000&usg= AFQjCNH0SvS9HdcX2s6aw9\PS_x-qZ9b4RA/ (29.04.2020) [7] pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.8b00082%23&sa=D&ust=1591441823227000& usg=AFQjCNFuXO_EvuUw-FlpJlPU4iaoRXTUkg (21.05.2020) [8] www.sciencedirect.com/science/article/pii/S0168827813002092&sa=D&ust= 1591441823225000&usg=AFQjCNFfN2cgjSx9GniimA4rZSDk2Tb9kQ (07.05.2020) [9] arznei-news.de/glecaprevir/&sa=D&ust=1591441823220000&usg=AFQjCNHzhzI8BNN5Fz3y5D3\ DgTgYtY5ghA (12.05.2020)

[10] www.ncbi.nlm.nih.gov/books/NBK548803/&sa=D&ust=1591441823220000&usg= AFQjCNEXPKXORQLg2bExi1\Umh1Skdrr3Aw (05.05.2020) [11] en.wikipedia.org/wiki/Glecaprevir/pibrentasvir&sa=D&ust=1591441823220000&usg= AFQjCNGWz75BZdjsvD52hGvVTH9HyvDp3Q (05.05.2020) [12] www.abbvie.com/content/dam/abbvie-dotcom/uploads/PDFs/results-summaries/ Clinical_Study_M16-133_German.pdf&sa=D&ust=1591441823229000&usg= AFQjCNGKX51yWka9glRv-Y2HjjVK1ibjSQ (07.05.2020) [13] www.drugbank.ca/drugs/DB13878&sa=D&ust=1591441823228000&usg= AFQjCNGbM1UwZIeC55AhT0FId\GZfq96yUA (29.04.2020) [14] www.pharmazeutische-zeitung.de/arzneistoffe/daten/2017/pibrentasvirmaviretr832017/ &sa=D&ust=1591441823218000&usg=AFQjCNEf5shsw_sjpnxelI8ktUI5IJVk8(12.05.2020)

5 [15] www.ema.europa.eu/en/documents/overview/maviret-epar-medicine-overview_de.pdf (05.05.2020)

[16] flexikon.doccheck.com/de/Glecaprevir (07.05.2020)

[17] www.ema.europa.eu/en/documents/product-information/maviret-epar-product-information_ de.pdf;flexikon.doccheck.com/de/Pharmakokinetik (12.05.2020) [18] https://en.wikipedia.org/wiki/Discovery_and_development_of_NS5A_inhibitors (06.06.2020)

6