Boceprevir

Last updated
Boceprevir
Boceprevir.svg
Clinical data
Trade names Victrelis
AHFS/Drugs.com Consumer Drug Information
MedlinePlus a611039
License data
Routes of
administration 		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding 75% [1]
Elimination half-life 3.4 hours [1]
Identifiers
  • (1R,5S)-N-[3-Amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2(S)-carboxamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
NIAID ChemDB
CompTox Dashboard (EPA)
ECHA InfoCard 100.226.246 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C27H45N5O5
Molar mass 519.687 g·mol−1
3D model (JSmol)
  • O=C(N3[C@H](C(=O)NC(C(=O)C(=O)N)CC1CCC1)[C@H]2C(C)([C@H]2C3)C)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C
  • InChI=1S/C27H45N5O5/c1-25(2,3)20(30-24(37)31-26(4,5)6)23(36)32-13-15-17(27(15,7)8)18(32)22(35)29-16(19(33)21(28)34)12-14-10-9-11-14/h14-18,20H,9-13H2,1-8H3,(H2,28,34)(H,29,35)(H2,30,31,37)/t15-,16?,17-,18-,20+/m0/s1 Yes check.svgY
  • Key:LHHCSNFAOIFYRV-DOVBMPENSA-N Yes check.svgY

Boceprevir (INN, trade name Victrelis) is a protease inhibitor used to treat hepatitis caused by hepatitis C virus (HCV) genotype 1. [2] [3] It binds to the HCV nonstructural protein 3 active site. [4]

Contents

It was initially developed by Schering-Plough, [5] then by Merck after it acquired Schering in 2009. It was approved by the FDA in May 2011. [6] In January 2015, Merck announced that they would be voluntarily withdrawing Victrelis from the market due to the overwhelming superiority of newer direct-acting antiviral agents, such as ledipasvir/sofosbuvir. [7]

Clinical trials

SPRINT-1 trial

The SPRINT-1 trial was a phase-II trial of boceprevir in difficult-to-treat patients with HCV genotype 1. [5] Study results were announced at the 44th annual meeting of the European Association for the Study of the Liver in Copenhagen in April, 2009. When used in combination with peginterferon alfa-2b and ribavirin, boceprevir resulted in significantly higher sustained viral response (SVR) rates in the most difficult-to-treat patients with genotype 1.[ citation needed ]

The phase-II trial compared three different regimens: four weeks of peginterferon alfa-2b (1.5 micrograms/kg once weekly) plus ribavirin (800 to 1400 mg daily based on patient weight) followed by boceprevir (800 mg three times a day in addition to peginterferon and ribavirin) for 24 weeks or 44 weeks; boceprevir in combination with peginterferon alfa-2b plus ribavirin as above for 28 or 48 weeks (triple therapy); and peginterferon alfa-2b plus low-dose ribavirin (400 to 1000 mg/day) and boceprevir for 48 weeks.[ citation needed ]

The patients enrolled in the SPRINT-1 study were among the most difficult to treat, and were exclusively those with genotype 1. (The patients were all treatment naive.) Additionally, many of the patients had other difficult-to-treat indices, including cirrhosis (6–9%), high viral load (90%), and African-American ancestry (14–17%). An SVR after 24 weeks off therapy of 75% was achieved in the group treated for 48 weeks with four weeks of lead-in therapy with peginterferon alfa-2b plus ribavirin followed by the addition of boceprevir. This represents a near doubling of the rate of SVR compared to standard therapy without boceprevir in this group.[ citation needed ]

Anemia was the most common adverse event. It occurred in half of the patients who received boceprevir and by about a third of the patients taking peginterferon alfa-2b plus ribavirin at the standard dose.[ citation needed ]

The lead investigator of the study was Dr. Paul Kwo, associate professor of medicine at the School of Medicine, Indiana University, in Indianapolis, Indiana, USA. [8]

SPRINT-2 trial

The SPRINT-2 trial [9] was a double-blind study which randomly assigned adults with untreated hepatitis C virus, genotype 1, to one of three groups. Each group received a month of peginterferon alfa-2b and ribavirin before being randomized to one of three arms. The first arm received placebo plus peginterferon-ribavirin for 44 weeks, the second arm received boceprevir plus peginterferon-ribavirin for 24 weeks, and those with a detectable HCV RNA level between weeks 8 and 24 received placebo plus peginterferon-ribavirin for an additional 20 weeks, and the third arm received boceprevir plus peginterferon-ribavirin for 44 weeks. Black patients and nonblack patients were enrolled and analyzed separately, since black patients have been shown to respond less well to antiviral therapy with peginterferon plus ribavirin than nonblacks. [10] In all, 938 nonblack and 159 black patients were enrolled in the study.[ citation needed ]

At 44 weeks, among the nonblack cohort, a 40% sustained virologic response (125 of 311 patients) occurred in the placebo group, a 67% response (211 of 316 patients) in the response-guided boceprevir group, and a 68% response (214 of 311 patients) in the fixed-duration therapy group. Important side effects included anemia and dysgeusia (distortion of the sense of taste).[ citation needed ]

RESPOND-2 trial

The RESPOND-2 trial [11] studied patients with chronic hepatitis C genotype 1 who did not have a sustained response to therapy with peginterferon-ribavirin therapy. All patients received a month of peginterferon alfa-2b and ribavirin before being randomized to one of three arms. The first arm received placebo plus peginterferon-ribavirin for 44 weeks. The second group received boceprevir plus peginterferon-ribavirin for 32 weeks, and those with a detectable HCV RNA level at week 8 received peginterferon-ribavirin and placebo for another 12 weeks. The third group received boceprevir and peginterferon-ribavirin for 44 weeks.[ citation needed ]

Four hundred and three people were treated in the trial. At 44 weeks, the control group had a lower sustained virologic response rate (21%) than either of the groups treated with boceprevir—59% sustained viral response for the group with response-guided therapy and 66% response for the group with fixed-duration therapy.[ citation needed ]

See also

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">Ribavirin</span> Antiviral medication

Ribavirin, also known as tribavirin, is an antiviral medication used to treat RSV infection, hepatitis C and some viral hemorrhagic fevers. For hepatitis C, it is used in combination with other medications such as simeprevir, sofosbuvir, peginterferon alfa-2b or peginterferon alfa-2a. Among the viral hemorrhagic fevers it is used for Lassa fever, Crimean–Congo hemorrhagic fever, and Hantavirus infection but should not be used for Ebola or Marburg infections. Ribavirin is taken by mouth or inhaled.

Pegylated interferon alfa-2a, sold under the brand name Pegasys among others, is medication used to treat hepatitis C and hepatitis B. For hepatitis C it is typically used together with ribavirin and cure rates are between 24 and 92%. For hepatitis B it may be used alone. It is given by injection under the skin.

Pegylated interferon alfa-2b is a drug used to treat melanoma, as an adjuvant therapy to surgery. Also used to treat hepatitis C, it is no longer recommended due to poor efficacy and adverse side-effects. Subcutaneous injection is the preferred delivery method.

<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">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">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.

Ombitasvir/paritaprevir/ritonavir, sold under the brand name Technivie among others, is a medication used to treat hepatitis C. It is a fixed-dose combination of ombitasvir, paritaprevir, and ritonavir. Specifically it is used together with dasabuvir or ribavirin for cases caused by hepatitis C virus genotype 1 or 4. Cure rates are around 95%. 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.

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

<span class="mw-page-title-main">Celgosivir</span> Drug for hep-C

Celgosivir, in development by Migenix for the treatment of hepatitis C virus (HCV) infection, is an oral prodrug of the natural product castanospermine that inhibits alpha-glucosidase I, an enzyme that plays a critical role in viral maturation by initiating the processing of the N-linked oligosaccharides of viral envelope glycoproteins. Celgosivir is well absorbed in vitro and in vivo, and is rapidly converted to castanospermine. Celgosivir has a novel mechanism of action, and demonstrates broad antiviral activity in vitro.

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

Mericitabine (RG-7128) is an antiviral drug, a deoxycytidine analog. It was developed as a treatment for hepatitis C, acting as a NS5B RNA polymerase inhibitor, but while it showed a good safety profile in clinical trials, it was not sufficiently effective to be used as a stand-alone agent. However mericitabine has been shown to boost the efficacy of other antiviral drugs when used alongside them, and as most modern treatment regimens for hepatitis C use a combination therapy of several antiviral drugs, clinical trials have continued to see if it can form a part of a clinically useful drug treatment program.

<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.

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.

<span class="mw-page-title-main">Interferon Lambda 4</span> Protein-coding gene in the species Homo sapiens

Interferon lambda 4 is one of the most recently discovered human genes and the newest addition to the interferon lambda protein family. This gene encodes the IFNL4 protein, which is involved in immune response to viral infection.

References

  1. 1 2 Kiser JJ, Burton JR, Anderson PL, Everson GT (May 2012). "Review and management of drug interactions with boceprevir and telaprevir". Hepatology. 55 (5): 1620–1628. doi:10.1002/hep.25653. PMC   3345276 . PMID   22331658.
  2. ↑ Degertekin B, Lok AS (May 2008). "Update on viral hepatitis: 2007". Current Opinion in Gastroenterology. 24 (3): 306–311. doi:10.1097/MOG.0b013e3282f70285. PMID   18408458. S2CID   43762307.
  3. ↑ Njoroge FG, Chen KX, Shih NY, Piwinski JJ (January 2008). "Challenges in modern drug discovery: a case study of boceprevir, an HCV protease inhibitor for the treatment of hepatitis C virus infection". Accounts of Chemical Research. 41 (1): 50–59. doi:10.1021/ar700109k. PMID   18193821. S2CID   2629035.
  4. ↑ "Boceprevir - FDA Antiviral Drugs" (PDF). FDA. FDA. April 2011. Retrieved 1 April 2014.
  5. 1 2 "Interim Results from Boceprevir Phase II Study in Genotype 1 Treatment-Naive Hepatitis C Patients Presented At EASL - Forbes.com". Forbes.com (Press release). Archived from the original on 2011-05-15. Retrieved 2008-05-19.
  6. ↑ "FDA Approves Merck's VICTRELIS™ (boceprevir), First-in-Class Oral Hepatitis C Virus (HCV) Protease Inhibitor" (Press release). Merck & Co. Archived from the original on 2011-05-15. Retrieved 2011-05-14.
  7. ↑ Paul J Bader, RPh (January 2015). "Merck Voluntarily Discontinuing VICTRELIS® (boceprevir) 200 mg Capsules" (PDF). Letter to. Merck & Co., Inc. Retrieved 2016-05-08.
  8. ↑ "UPDATE 2-Schering hepatitis C drug shines, but anemia seen". HCV Advocate EASL 2009 Coverage. 29 April 2009. Archived from the original on 2009-05-11. Retrieved 2009-05-28.
  9. ↑ Poordad F, McCone J, Bacon BR, Bruno S, Manns MP, Sulkowski MS, et al. (March 2011). "Boceprevir for untreated chronic HCV genotype 1 infection". The New England Journal of Medicine. 364 (13): 1195–1206. doi:10.1056/NEJMoa1010494. PMC   3766849 . PMID   21449783.
  10. ↑ Jensen DM (March 2011). "A new era of hepatitis C therapy begins". The New England Journal of Medicine. 364 (13): 1272–1274. doi:10.1056/NEJMe1100829. PMID   21449791. S2CID   9589704.
  11. ↑ Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S, et al. (March 2011). "Boceprevir for previously treated chronic HCV genotype 1 infection". The New England Journal of Medicine. 364 (13): 1207–1217. doi:10.1056/NEJMoa1009482. PMC   3153125 . PMID   21449784.
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.