Elbasvir/grazoprevir

Elbasvir/grazoprevir
Combination of
Elbasvir NS5A inhibitor
Grazoprevir NS3/4A protease inhibitor
Clinical data
Trade names Zepatier
AHFS/Drugs.com zepatier
Routes of
administration		 Oral (tablets)
ATC code J05AX68 (WHO) (temporary)
Legal status
Legal status
Identifiers

Elbasvir/grazoprevir (trade name Zepatier ZEP-ah-teer) is a fixed-dose two drug combination for the treatment of hepatitis C, containing 50 mg elbasvir (a hepatitis C virus NS5A inhibitor) and 100 mg grazoprevir (an NS3/4A protease inhibitor). It is used to treat chronic HCV genotypes 1 or 4 infection in both treatment-naïve and treatment-experienced patients.[1]

Both elbasvir and grazoprevir were developed by Merck & Co. The drug was approved on January 28, 2016.[2]

Indications

Elbasvir/Grazoprevir received FDA approval in January 2016. Its indication is for treatment of chronic Hepatitis C Virus (HCV) of the genotypes (GT) 1 and 4 for adults. HCV is a global disease that infects upwards of 150 million people worldwide, most especially in older generations.[3][1] Hepatitis C causes inflammation of the liver that eventually leads to diminished liver function or even failure. The treatment of this virus with zepatier is now another approved treatment of the virus without requiring interferon use.[4] Zepatier is indicated for treatment with or without use of ribavirin, as well.[2] 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.[5]

Dosing

There is one FDA approved dosing regimen of the Zepatier. It comes in 50 mg of elbasvir and 100 mg of grazoprevir. Genetic testing for patients of GT1 is recommended to determine if the patient is NS5A resistant before the initial treatment. This resistance results in a likely decrease in SRV12. [1] Dosage is taken once daily over the most common span of 12-weeks. Elbasvir/grazoprevir is often times prescribed with ribavirin for patients with renal impairment. "ZEPATIER is available as a beige-colored, oval-shaped, film-coated tablet debossed with “770” on one side and plain on the other."[1]

Patient Population Treatment Duration
Genotype 1a: Treatment-naïve or PegIFN/RBV-experienced without baseline NS5A polymorphisms ZEPATIER 12 Weeks
Genotype 1a: Treatment-naïve or PegIFN/RBV-experienced with baseline NS5A polymorphisms ZEPATIER + RBV 16 Weeks
Genotype 1b: Treatment-naïve or PegIFN/RBV-experienced ZEPATIER 12 Weeks
Genotype 1a§ or 1b: PegIFN/RBV/PI-experienced ZEPATIER + RBV 12 Weeks
Genotype 4: Treatment-Naïve ZEPATIER 12 Weeks
Genotype 4: PegIFN/RBV-experienced ZEPATIER + RBV 16 Weeks

Side Effects

General side effects during treatment with Zepatier include feeling tired, nausea, and headache. Low red blood cell count has occurred when co-administered with ribavirin in some cases. Any lasting side effects should be brought up to a health care professional.[1]

Mechanism of Action

Elbasvir is a protease inhibitor. It targets NS5A 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.”[6] Grazoprevir is another protease inhibitor targeting HCV NS3/4A. Effectively Grazoprevir prevents cleavage of the necessary polyproteins for replication.[6]

Research

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.[7] 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. [8]

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.[9]

Additional Phase 2 trials were examined under the names: C-SWIFT, C-WORTHY, and C-WORTHY Coinfection. 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.[10] C-WORTHY study combined elbasvir with grazoprevir and additionally ribavirin in cases of cirrhosis. This demographic of patients is the most treatment refractory and the study showed that the ribavirin did not improve effects.[11] C-WORTHY Coinfection studied patients with HCV and HIV. Treatments of monoinfected patients and coinfected patients resulted in better SRV12 for the patients with coinfection and treated with ribrivin, too, at 97%.[12]

Phase 3 study results of the drug were released in 2016. Results from C-EDGE IBLD 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.[13]

C-EDGE CO-STAR showed high SVR after 24-weeks. This studied 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.[13]

Commercialization

Zepatier (elbasvir/grazoprevir) was FDA approved in the United States, but has also been approved for use in the European Union, Canada, Japan, Australia, Saudi Arabia, Israel and Switzerland.[14] 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).[15] Sale projections for Zepatier are $636 million in 2016 and rising to $1.5 billion by 2020.[16] 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.[17] Current shares are at 61.87 NYSE for Merck and Co.

Cost

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.[18]

References

  1. 1 2 3 4 5 "ZEPATIER™ (elbasvir and grazoprevir) Tablets, for Oral Use. Full Prescribing Information" (PDF). Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. Retrieved 31 January 2016.
  2. 1 2 "FDA approves Zepatier for treatment of chronic hepatitis C genotypes 1 and 4". U.S. Food and Drug Administration. Retrieved 31 January 2016.
  3. ↑ "WHO Factsheet". World Health Organization. 2016.
  4. ↑ Allison M. Bell, Jamie L. Wagner, Katie E. Barber, and Kayla R. Stover (2016). "Elbasvir/Grazoprevir: A Review of the Latest Agent in the Fight against Hepatitis C". International Journal of Hematology.
  5. ↑ AASLD-IDSA (2016). "Recommendations for testing, managing, and treating hepatitis C". HCV Guidelines. Retrieved 20 November 2016.
  6. 1 2 Keating, G. M. (2016). "Elbasvir/Grazoprevir: first global approval.". Drugs. 76 (5): 617. doi:10.1007/s40265-016-0558-3. Retrieved 19 November 2016.
  7. ↑ US patent 8871759, Craig A. Coburn, "Inhibitors of hepatitis C virus replication", published 2014-10-28, assigned to Merck Sharp & Dohme Corp.
  8. ↑ US patent 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.
  9. ↑ Buti M, Gordon SC, Zuckerman E, Lawitz E, Calleja JL, Hofer H, Gilbert C, Palcza J, Howe AY, DiNubile MJ, Robertson MN, Wahl J, Barr E, Forns X (2015). "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 (32-6).
  10. ↑ Poordad F, Lawitz E, Gutierrez J et al. (2015). "Grazoprevir/elbasvir + sofosbuvir in cirrhotic and noncirrhotic, treatment-naive patients with hepatitis C virus genotype 1 infection, for durations of 4, 6, or 8 weeks and genotype 3 infection for durations of 8 or 12 weeks.". European Association for the Study of the Liver.
  11. ↑ Lawitz E, Gane E, Pearlman B et al. (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 (1075-86).
  12. ↑ Sulkowski M, Hezode C, Gerstoft J et al. (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 (1087-97).
  13. 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". Business Wire. Berkshire Hathaway. 2016-04-16. Retrieved 2016-11-19.
  14. ↑ "Merck Announces Presentation Of New Findings For ZEPATIER™ (Elbasvir And Grazoprevir) In Patients With Chronic Hepatitis C At The Liver Meeting". Business Wire. The Street. Retrieved 20 November 2016.
  15. ↑ Van Arnum, Patricia. "Blockbuster Watch: Key Market Entrants for 2016". DCAT Connect. Retrieved 19 November 2016.
  16. ↑ Beasley, Deena. "FDA approves Merck's new hepatitis C pill". Reuters. Thomas Reuters. Retrieved 19 November 2016.
  17. ↑ "Merck puts up strong Q2 numbers, but choppy waters ahead". Modern Healthcare. Associated Press. July 29, 2016.
  18. ↑ Spach, D. H.; Kim, H. N. "Medications to treat HCV.".
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