Elbasvir/grazoprevir

Last updated
Elbasvir/grazoprevir
Combination of
Elbasvir NS5A inhibitor
Grazoprevir NS3/4A protease inhibitor
Clinical data
Trade names Zepatier
AHFS/Drugs.com zepatier
License data
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
KEGG

Elbasvir/grazoprevir, sold under the brand name Zepatier, is a fixed-dose combination for the treatment of hepatitis C, containing elbasvir (an inhibitor of hepatitis C virus's NS5A protein) and grazoprevir (an NS3/4A inhibitor). It is used to treat chronic hepatitis C virus (HCV) genotypes 1 or 4 infection in both treatment-naïve and treatment-experienced patients. [2]

Contents

Both elbasvir and grazoprevir were developed by Merck & Co. The US Food and Drug Administration (FDA) approved the drug in January 2016. [4]

Medical uses

Elbasvir/grazoprevir received FDA approval in January 2016. Its indication is for treatment of chronic hepatitis C of the genotypes 1 and 4 for adults. Hepatitis C is a global disease that infects upwards of 150 million people worldwide, especially in older generations. [5] [2] Hepatitis C causes inflammation of the liver that eventually leads to diminished liver function or even failure. [6] Zepatier is indicated for treatment with or without use of ribavirin, as well. [4] Zepatier has shown enough efficacy to be considered a first line of treatment for first-time patients with GT 1a and 1b, with or without cirrhosis. It is recommended for non-naive patients of the same genotypes, in addition to patients of GT4. [7]

Interactions and contraindications

Grazoprevir is transported by the solute carrier proteins SLCO1B1 and SLCO1B3. Drugs that inhibit this proteins, such as rifampicin, ciclosporin, and a number of HIV medications (atazanavir, darunavir, lopinavir, saquinavir, tipranavir, cobicistat), can cause a significant increase in grazoprevir blood plasma levels. Combination of elbasvir/grazoprevir with these drugs is therefore contraindicated. [8] [9]

Both elbasvir and grazoprevir are degraded by the liver enzyme CYP3A4. Combination with drugs that induce this enzyme, such as efavirenz, carbamazepine or St. John's wort, is contraindicated because it can lead to ineffectively low plasma levels of elbasvir and grazoprevir. Combination with CYP3A4 inhibitors may increase plasma levels and is not recommended by the manufacturer. [8]

Side effects

Common side effects during treatment include feeling tired, nausea, reduced appetite, and headache. Low red blood cell count has occurred when co-administered with ribavirin in some cases. [2] [8] The most important risks are Alanine transaminase elevation, hyperbilirubinemia, drug resistance development and drug interactions. [10]

Pharmacology

Mechanism of action

Elbasvir targets the NS5A protein, which effectively prevents the transcription of the HCV RNA and also prevents virion assembly. "Median EC50 values range from 0.2 to 3600 pmol/L, based on genotype." [11] Grazoprevir is an protease inhibitor targeting HCV NS3/4A serine protease. Effectively grazoprevir prevents cleavage of the necessary polyproteins for replication. [11]

Pharmacokinetics

Clinical studies

A C-SALVAGE Phase 2 trial on safety and efficacy was reported in 2015. One randomized, open-label study was done on patients that had previous failure of a ribavirin/peginterferon treatment. SVR24 occurred in 96% of the patients with only 3 individuals relapsing. [12]

Additional phase II trials were examined under the names: C-SWIFT, C-WORTHY, and C-WORTHY Coinfection. [13] The first trial studied shorter dosing periods of 4, 6, or 8 weeks. C-SWIFT showed that the longer the time of treatment, the better the SVR results among patients. [14] The C-WORTHY study combined elbasvir with grazoprevir and additionally ribavirin in cases of cirrhosis. [15] This demographic of patients is the most treatment refractory and the study showed that the ribavirin did not improve effects. [15] The C-WORTHY Coinfection trial studied patients with HCV and HIV. [16] Treatments of monoinfected patients and coinfected patients resulted in better SRV12 for the patients with coinfection and treated with ribrivin, too, at 97%. [16]

Phase III study results of the drug were released in 2016. Results from the C-EDGE IBLD trial show high rates of sustained virological response (SVR) after the completion of the prescribed treatment. This was examined 12-weeks after (SRV12). Safety profiles were consistent with previous studies. This study was a randomized, double-blind and placebo-controlled. 93% of the patients included in these studies showed SVR12 and had been cured of the virus. [17]

The C-EDGE CO-STAR trial showed high SVR after 24-weeks. This study reaffirmed results from studies of the previous year. The study was double-blind and placebo-controlled. Patients had HCV GT1, GT4, or GT6 and were on opioid therapy. Upwards of 96% of the patients achieved SVR24. This study contributed to the knowledge of the incidence of HCV reinfection in patients who receive drug injection of opioid treatments. This is a demographic that the medical community is typically reluctant to treat due to concerns of reinfection and compliance. [17]

Society and culture

Patents

U.S. Patent No. 8871759 was published in 2014 for the specified compounds useful for hepatitis C virus NS5A inhibitors. The patent protects Merck's formulation for the drug and its other associated salt forms, hydrates, solvates, prodrugs and isomers. [18] U.S. Patent No. 7973040 was published in 2011. The patent protects the invention by Merck of the macrocyclic compound within the formula as an inhibitor for NS3 protease. The patent describes the formulation of the compound and its salts, along with its uses and potential implications as an HCV antiviral treatment. [19]

Commercialization

Elbasvir/grazoprevir was FDA approved in the United States, and has been approved for use in the European Union, Canada, Japan, Australia, Saudi Arabia, Israel, and Switzerland. [20] Zepatier is one of a few non-interferon therapies that are market-available. Competing treatments include Gilead's Harvoni (sofosbuvir and ledipasvir) and AbbVie's Viekira Pak (ombitasvir, paritaprevir, and ritonavir). [21] Sale projections for Zepatier are $636 million in 2016 and rising to $1.5 billion by 2020. [22] With Merck's release of Zepatier early in 2016, they saw large bumps in share prices in quarters 1 and 2, but are expected to drop down a bit. Zepatier does not have as strong a market hold as other competitive HCV treatments. [23]

Economics

Estimated costs for a 12-week treatment of elbasvir/grazoprevir are upwards of $54,600. Other treatments that work in a similar manner have effectively more costs. Some treatments for Hepatitis C are on the cheaper side, in some instances as low as $8,400. Additional ribavirin costs can add between $500 and $900. These cheaper prescriptions are however interferon-based treatments and do not target every genotype of the HCV. These regimens were the priority treatment before 2011. Two examples of these treatments are alfa-2a and alfa-2b costing $9250 and $8400, respectively. [24]

Related Research Articles

<span class="mw-page-title-main">Hepatitis C</span> Human viral infection

Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV) that primarily affects the liver; it is a type of viral hepatitis. During the initial infection period, people often have mild or no symptoms. Early symptoms can include fever, dark urine, abdominal pain, and yellow tinged skin. The virus persists in the liver, becoming chronic, in about 70% of those initially infected. Early on, chronic infection typically has no symptoms. Over many years however, it often leads to liver disease and occasionally cirrhosis. In some cases, those with cirrhosis will develop serious complications such as liver failure, liver cancer, or dilated blood vessels in the esophagus and stomach.

<span class="mw-page-title-main">Hepatitis C virus</span> Species of virus

The hepatitis C virus (HCV) is a small, enveloped, positive-sense single-stranded RNA virus of the family Flaviviridae. The hepatitis C virus is the cause of hepatitis C and some cancers such as liver cancer and lymphomas in humans.

<span class="mw-page-title-main">Boceprevir</span> Chemical compound

Boceprevir is a protease inhibitor used to treat hepatitis caused by hepatitis C virus (HCV) genotype 1. It binds to the HCV nonstructural protein 3 active site.

<span class="mw-page-title-main">Telaprevir</span> Chemical compound

Telaprevir (VX-950), marketed under the brand names Incivek and Incivo, is a pharmaceutical drug for the treatment of hepatitis C co-developed by Vertex Pharmaceuticals and Johnson & Johnson. It is a member of a class of antiviral drugs known as protease inhibitors. Specifically, telaprevir inhibits the hepatitis C viral enzyme NS3/4A serine protease. Telaprevir is only indicated for use against hepatitis C genotype 1 viral infections and has not been proven to be safe or effective when used for other genotypes of the virus. The standard therapy of pegylated interferon and ribavirin is less effective than telaprevir in those with genotype 1.

<span class="mw-page-title-main">Hepatitis C virus nonstructural protein 5A</span>

Nonstructural protein 5A (NS5A) is a zinc-binding and proline-rich hydrophilic phosphoprotein that plays a key role in Hepatitis C virus RNA replication. It appears to be a dimeric form without trans-membrane helices.

<span class="mw-page-title-main">Sofosbuvir</span> Chemical compound

Sofosbuvir, sold under the brand name Sovaldi among others, is a medication used to treat hepatitis C. It is taken by mouth.

<span class="mw-page-title-main">Asunaprevir</span> Compound

Asunaprevir is an experimental drug candidate for the treatment of hepatitis C. It was undergoing development by Bristol-Myers Squibb and has completed Phase III clinical trials in 2013.

<span class="mw-page-title-main">Simeprevir</span> Chemical compound

Simeprevir, sold under the brand name Olysio among others, is a medication used in combination with other medications for the treatment of hepatitis C. It is specifically used for hepatitis C genotype 1 and 4. Medications it is used with include sofosbuvir or ribavirin and peginterferon-alfa. Cure rates are in 80s to 90s percent. It may be used in those who also have HIV/AIDS. It is taken by mouth once daily for typically 12 weeks.

<span class="mw-page-title-main">Ledipasvir</span> Hepatitis C drug

Ledipasvir is a drug for the treatment of hepatitis C that was developed by Gilead Sciences. After completing Phase III clinical trials, on February 10, 2014, Gilead filed for U.S. approval of a ledipasvir/sofosbuvir fixed-dose combination tablet for genotype 1 hepatitis C. The ledipasvir/sofosbuvir combination is a direct-acting antiviral agent that interferes with HCV replication and can be used to treat patients with genotypes 1a or 1b without PEG-interferon or ribavirin.

<span class="mw-page-title-main">Deleobuvir</span> Chemical compound

Deleobuvir was an experimental drug for the treatment of hepatitis C. It was being developed by Boehringer Ingelheim. It is a non-nucleoside hepatitis C virus NS5B polymerase inhibitor. Deleobuvir was tested in combination regimens with pegylated interferon and ribavirin, and in interferon-free regimens with other direct-acting antiviral agents including faldaprevir.

<span class="mw-page-title-main">Ombitasvir</span> Chemical compound

Ombitasvir is an antiviral drug for the treatment of hepatitis C virus (HCV) infection by AbbVie. In the United States, it is approved by the Food and Drug Administration for use in combination with paritaprevir, ritonavir and dasabuvir in the product Viekira Pak for the treatment of HCV genotype 1, and with paritaprevir and ritonavir in the product Technivie for the treatment of HCV genotype 4.

<span class="mw-page-title-main">Dasabuvir</span> Chemical compound

Dasabuvir, sold under the brand name Exviera, is an antiviral medication for the treatment of hepatitis C. It is often used together with the combination medication ombitasvir/paritaprevir/ritonavir specifically for hepatitis C virus (HCV) type 1. Ribavirin may also additionally be used. These combinations result in a cure in more than 90% of people. It is taken by mouth.

<span class="mw-page-title-main">Beclabuvir</span> Chemical compound

Beclabuvir is an antiviral drug for the treatment of hepatitis C virus (HCV) infection that has been studied in clinical trials. In February 2017, Bristol-Myers Squibb began sponsoring a post-marketing trial of beclabuvir, in combination with asunaprevir and daclatasvir, to study the combination's safety profile with regard to liver function. From February 2014 to November 2016, a phase II clinical trial was conducted on the combination of asunaprevir/daclatasvir/beclabuvir on patients infected with both HIV and HCV. Furthermore, a recent meta-analysis of six published six clinical trials showed high response rates in HCV genotype 1-infected patients treated with daclatasvir, asunaprevir, and beclabuvir irrespective of ribavirin use, prior interferon-based therapy, or restriction on noncirrhotic patients, IL28B genotype, or baseline resistance-associated variants

<span class="mw-page-title-main">Grazoprevir</span> Drug approved for the treatment of hepatitis C

Grazoprevir is a drug approved for the treatment of hepatitis C. It was developed by Merck and completed Phase III trials, used in combination with the NS5A replication complex inhibitor elbasvir under the trade name Zepatier, either with or without ribavirin.

<span class="mw-page-title-main">Elbasvir</span> Chemical compound

Elbasvir is a drug approved by the FDA in January 2016 for the treatment of hepatitis C. It was developed by Merck and completed Phase III trials, used in combination with the NS3/4A protease inhibitor grazoprevir under the trade name Zepatier, either with or without ribavirin.

<span class="mw-page-title-main">Discovery and development of NS5A inhibitors</span>

Nonstructural protein 5A (NS5A) inhibitors are direct acting antiviral agents (DAAs) that target viral proteins, and their development was a culmination of increased understanding of the viral life cycle combined with advances in drug discovery technology. However, their mechanism of action is complex and not fully understood. NS5A inhibitors were the focus of much attention when they emerged as a part of the first curative treatment for hepatitis C virus (HCV) infections in 2014. Favorable characteristics have been introduced through varied structural changes, and structural similarities between NS5A inhibitors that are clinically approved are readily apparent. Despite the recent introduction of numerous new antiviral drugs, resistance is still a concern and these inhibitors are therefore always used in combination with other drugs.

<span class="mw-page-title-main">Narlaprevir</span> Chemical compound

Narlaprevir, is an inhibitor of NS3/4A serine protease, intended for the treatment of chronic hepatitis C caused by genotype 1 virus in combination with other antiviral drugs.

<span class="mw-page-title-main">Glecaprevir</span> Chemical compound

Glecaprevir (INN,) is a hepatitis C virus (HCV) nonstructural (NS) protein 3/4A protease inhibitor that was identified jointly by AbbVie and Enanta Pharmaceuticals. It is being developed as a treatment of chronic hepatitis C infection in co-formulation with an HCV NS5A inhibitor pibrentasvir. Together they demonstrated potent antiviral activity against major HCV genotypes and high barriers to resistance in vitro.

Sofosbuvir/velpatasvir, sold under the brand name Epclusa among others, is a fixed-dose combination medication for the treatment of hepatitis C in adults. It combines sofosbuvir and velpatasvir. It is more than 90% effective for hepatitis C genotypes one through six. It also works for hepatitis C in those who also have cirrhosis or HIV/AIDS. It is taken by mouth.

Glecaprevir/pibrentasvir (G/P), sold under the brand names Mavyret and Maviret, is a fixed-dose combination medication used to treat hepatitis C. It contains glecaprevir and pibrentasvir. It works against all six types of hepatitis C. At twelve weeks following treatment between 81% and 100% of people have no evidence of hepatitis C. It is taken once a day by mouth with food.

References

  1. ↑ "Prescription medicines: registration of new chemical entities in Australia, 2016". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 10 April 2023.
  2. 1 2 3 4 "Zepatier- elbasvir and grazoprevir tablet, film coated". DailyMed. 25 May 2022. Retrieved 20 May 2023.
  3. ↑ "Zepatier EPAR". European Medicines Agency. 17 September 2018. Archived from the original on 8 July 2022. Retrieved 8 July 2022.
  4. 1 2 "FDA approves Zepatier for treatment of chronic hepatitis C genotypes 1 and 4". U.S. Food and Drug Administration (FDA) (Press release). 28 January 2016. Archived from the original on 23 April 2019. Retrieved 31 January 2016.
  5. ↑ "WHO Factsheet". World Health Organization. 2016. Archived from the original on May 2, 2004.
  6. ↑ Bell AM, Wagner JL, Barber KE, Stover KR (2016). "Elbasvir/Grazoprevir: A Review of the Latest Agent in the Fight against Hepatitis C". International Journal of Hepatology. 2016: 3852126. doi: 10.1155/2016/3852126 . PMC   4925941 . PMID   27403342.
  7. ↑ AASLD-IDSA (2016). "Recommendations for testing, managing, and treating hepatitis C". HCV Guidelines. Archived from the original on 25 July 2017. Retrieved 20 November 2016.
  8. 1 2 3 Haberfeld H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.
  9. ↑ FDA Professional Drug Information on Zepatier.
  10. ↑ "European Public Assessment Report" (PDF). European Medicines Agency. Archived (PDF) from the original on 18 December 2017. Retrieved 16 December 2017.
  11. 1 2 Keating GM (April 2016). "Elbasvir/Grazoprevir: First Global Approval". Drugs. 76 (5): 617–24. doi:10.1007/s40265-016-0558-3. PMID   26943930. S2CID   772093.
  12. ↑ Buti M, Gordon SC, Zuckerman E, Lawitz E, Calleja JL, Hofer H, et al. (January 2016). "Grazoprevir, Elbasvir, and Ribavirin for Chronic Hepatitis C Virus Genotype 1 Infection After Failure of Pegylated Interferon and Ribavirin With an Earlier-Generation Protease Inhibitor: Final 24-Week Results From C-SALVAGE". Clinical Infectious Diseases. 62 (1): 32–6. doi: 10.1093/cid/civ722 . PMID   26371152.
  13. ↑ "Elbasvir-Grazoprevir Zepatier - Clinical Trials". Hepatitis C Online. 1 April 2022. Retrieved 20 May 2023.
  14. ↑ Zeuzem S, Ghalib R, Reddy KR, Pockros PJ, Ben Ari Z, Zhao Y, et al. (July 2015). "Grazoprevir-Elbasvir Combination Therapy for Treatment-Naive Cirrhotic and Noncirrhotic Patients With Chronic Hepatitis C Virus Genotype 1, 4, or 6 Infection: A Randomized Trial". Annals of Internal Medicine. 163 (1): 1–13. doi:10.7326/M15-0785. PMID   25909356. S2CID   7893871.
  15. 1 2 Lawitz E, Gane E, Pearlman B, Tam E, Ghesquiere W, Guyader D, et al. (March 2015). "Efficacy and safety of 12 weeks versus 18 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin for hepatitis C virus genotype 1 infection in previously untreated patients with cirrhosis and patients with previous null response with or without cirrhosis (C-WORTHY): a randomised, open-label phase 2 trial". Lancet. 385 (9973): 1075–86. doi:10.1016/S0140-6736(14)61795-5. PMID   25467591.
  16. 1 2 Sulkowski M, Hezode C, Gerstoft J, Vierling JM, Mallolas J, Pol S, et al. (March 2015). "Efficacy and safety of 8 weeks versus 12 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin in patients with hepatitis C virus genotype 1 mono-infection and HIV/hepatitis C virus co-infection (C-WORTHY): a randomised, open-label phase 2 trial". Lancet. 385 (9973): 1087–97. doi:10.1016/S0140-6736(14)61793-1. PMID   25467560.
  17. 1 2 "Merck Announces Results From Phase 3 Studies of Zepatier (Elbasvir and Grazoprevir) in Chronic Hepatitis C Patient Populations at The International Liver Congress" (Press release). Merck. 2016-04-16. Archived from the original on 2016-12-26. Retrieved 2016-11-19– via Business Wire.
  18. ↑ USpatent 8871759,Craig A. Coburn,"Inhibitors of hepatitis C virus replication",published 2014-10-28, assigned to Merck Sharp & Dohme Corp.
  19. ↑ USpatent 7973040,Steven Harper, Vincenzo Summa, Nigel J. Liverton, John A. McCauley,"Macrocyclic quinoxaline compounds as HCV NS3 protease inhibitors",published 2011-07-05, assigned to Merck Sharp & Dohme Corp.
  20. ↑ "Merck Announces Presentation Of New Findings For Zepatier (Elbasvir And Grazoprevir) In Patients With Chronic Hepatitis C At The Liver Meeting" (Press release). Merck. 12 November 2016. Archived from the original on 21 November 2016. Retrieved 20 November 2016– via Business Wire.
  21. ↑ Van Arnum P. "Blockbuster Watch: Key Market Entrants for 2016". DCAT Connect. Archived from the original on 21 November 2016. Retrieved 19 November 2016.
  22. ↑ Beasley D (2016-01-29). "FDA approves Merck's new hepatitis C pill". Reuters. Thomas Reuters. Archived from the original on 2016-11-21. Retrieved 19 November 2016.
  23. ↑ "Merck puts up strong Q2 numbers, but choppy waters ahead". Modern Healthcare. Associated Press. July 29, 2016. Archived from the original on July 9, 2022. Retrieved November 21, 2016.
  24. ↑ Spach DH, Kim HN. "Medications to treat HCV". Archived from the original on 2016-11-28. Retrieved 2016-11-20.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.