Delving into the Latest Updates on Boceprevir with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Boceprevir (INN/USAN), P-03659, SCH-503034

+ [1]

Target

NS3/NS4A

Mechanism

NS3/NS4A inhibitors(Hepatitis C virus serine protease, NS3/NS4A inhibitors)

Therapeutic Areas

Infectious DiseasesDigestive System Disorders

Active Indication

Hepatitis C

Inactive Indication

AnemiaChronic hepatitis C genotype 1Coinfection+ [4]

Originator Organization

Merck & Co., Inc.

Active Organization

Merck GmbH

Inactive Organization

Merck Sharp & Dohme Corp.Merck Sharp & Dohme Ireland Ltd.F. Hoffmann-La Roche Ltd.

+ [1]

Drug Highest PhaseApproved

First Approval Date

US (13 May 2011),

FibrosisHepatitis C, ChronicHepatitis C+ [1]

Regulation-

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Structure

Molecular FormulaC27H45N5O5

InChIKeyLHHCSNFAOIFYRV-DOVBMPENSA-N

CAS Registry394730-60-0

Objectives: 1) To evaluate la proportion of hepatitic C virus (HCV)-monoinfected patients who show sustained virologic response (SVR) to treatment including direct-acting antivirals (DAAs) in the clinical practice in clinical units that treat infectious diseases and 2) to determine the frequency of adverse events, including those that are severe and/or cause treatment interruption, in DAA-based therapy in this setting.
Design: Multicentric, prospective post-authorised cohort study. Setting: Hospitals of the Hepatitis Study Group (GEHEP) of the Spanish Society of Infectious Diseases and Microbiology (SEIMC).
Study population: HCV-monoinfected patients that initiate DAA-based treatment outside clinical trials.
Variables: The primary efficacy outcome variable is the proportion of patients who reach undetectable HCV-RNA 12 weeks after the scheduled end of therapy (SVR12). The primary safety outcome variable is the percentage of subjects who discontinue therapy due to adverse events.
Statistical analysis: A descriptive study will be performed, as well as a double sensibility analysis of the frequency of SVR12 using both an intention-to-treat and an on-treatment approach. Those variables that are associated with SVR12 with a p-value <0.2 will be included in a logistic regression analysis in which SVR12 will be the dependent variable.

Start Date01 Dec 2014

Sponsor / Collaborator

Hospital Universitario de Canarias

[+7]

NCT02118597 / TerminatedNot Applicable

Non-interventional Study to Observe Triple Combination Therapy With Boceprevir or Simeprevir Plus Peginterferon Alfa-2a Plus Ribavirin for Re-treatment of Chronic Hepatitis C in Hungary (IMPERIAL)

This prospective, national, multicenter, non-interventional study examined the use of triple combination therapy with boceprevir, pegylated interferon (peginterferon) alfa-2a and ribavirin in re-treating participants with genotype 1 chronic hepatitis C (CHC) infection. Dosing and treatment duration were at the discretion of the investigator in accordance with local clinical practice and local labeling. Participants were to be observed for the duration of their triple combination therapy and for up to 24 weeks thereafter.

Start Date01 May 2014

Sponsor / Collaborator

Hoffmann-La Roche, Inc.

NCT01641666 / WithdrawnPhase 3

An Open-Label Study to Assess the Safety and Tolerability of Boceprevir in Combination With Peginterferon Alfa-2b Plus Ribavirin for Treatment of Vietnamese Subjects With Chronic Hepatitis C Genotype 1 Who Failed Prior Treatment With Any Interferon Plus Ribavirin in Vietnam

This study is designed to assess the safety and tolerability of boceprevir dosed 800 mg three times daily (TID) orally (PO) in combination with Peginterferon alfa-2b (PEG2b) 1.5 mcg/kg once a week (QW) administered subcutaneously (SC) plus ribavirin (RBV) (800 to 1400 mg/day) PO in Response Guided Therapy (RGT) in adult Vietnamese subjects with Chronic Hepatitis C, Genotype 1 (CHC GT1) who failed prior treatment with any interferon and ribavirin in Vietnam.

Start Date01 May 2014

Sponsor / Collaborator

Merck Sharp & Dohme Corp.

100 Clinical Results associated with Boceprevir

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100 Translational Medicine associated with Boceprevir

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100 Patents (Medical) associated with Boceprevir

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954

Literatures (Medical) associated with Boceprevir

01 Dec 2023·Emerging microbes & infections

Orthogonal dual reporter-based gain-of-signal assay for probing SARS-CoV-2 3CL protease activity in living cells: inhibitor identification and mutation investigation.

Article

Author: Zhao, Liangliang ; Wang, Baogang ; Zhang, Dongna ; Dong, Shuwei ; Bei, Zhu-Chun ; Song, Yabin ; Wang, Hong ; Xu, Likun ; Li, Qingyun ; Yu, Huanhuan

ABSTRACTThe main protease (3-chymotrypsin-like protease, 3CLpro) of SARS-CoV-2 has become a focus of anti-coronavirus research. Despite efforts, drug development targeting 3CLpro has been hampered by limitations in the currently available activity assays. Additionally, the emergence of 3CLpro mutations in circulating SARS-CoV-2 variants has raised concerns about potential resistance. Both emphasize the need for a more reliable, sensitive, and facile 3CLpro assay. Here, we report an orthogonal dual reporter-based gain-of-signal assay for measuring 3CLpro activity in living cells. It builds on the finding that 3CLpro induces cytotoxicity and reporter expression suppression, which can be rescued by its inhibitor or mutation. This assay circumvents most limitations in previously reported assays, especially false positives caused by nonspecific compounds and signal interference from test compounds. It is also convenient and robust for high throughput screening of compounds and comparing the drug susceptibilities of mutants. Using this assay, we screened 1789 compounds, including natural products and protease inhibitors, with 45 compounds that have been reported to inhibit SARS-CoV-2 3CLpro among them. Except for the approved drug PF-07321332, only five of these inhibit 3CLpro in our assays: GC376; PF-00835231; S-217622; Boceprevir; and Z-FA-FMK. The susceptibilities of seven 3CLpro mutants prevalent in circulating variants to PF-07321332, S-217622, and GC376 were also assessed. Three mutants were identified as being less susceptible to PF-07321322 (P132H) and S-217622 (G15S, T21I). This assay should greatly facilitate the development of novel 3CLpro-targeted drugs and the monitoring of the susceptibility of emerging SARS-CoV-2 variants to 3CLpro inhibitors.

16 Nov 2023·The journal of physical chemistry. B

Landscape of In Silico Tools for Modeling Covalent Modification of Proteins: A Review on Computational Covalent Drug Discovery

Review

Author: Ray, Manisha ; Hasan, Md Nazmul ; Saha, Arjun

Covalent drug discovery has been a challenging research area given the struggle of finding a sweet balance between selectivity and reactivity for these drugs, the lack of which often leads to off-target activities and hence undesirable side effects. However, there has been a resurgence in covalent drug design following the success of several covalent drugs such as boceprevir (2011), ibrutinib (2013), neratinib (2017), dacomitinib (2018), zanubrutinib (2019), and many others. Design of covalent drugs includes many crucial factors, where "evaluation of the binding affinity" and "a detailed mechanistic understanding on covalent inhibition" are at the top of the list. Well-defined experimental techniques are available to elucidate these factors; however, often they are expensive and/or time-consuming and hence not suitable for high throughput screens. Recent developments in in silico methods provide promise in this direction. In this report, we review a set of recent publications that focused on developing and/or implementing novel in silico techniques in "Computational Covalent Drug Discovery (CCDD)". We also discuss the advantages and disadvantages of these approaches along with what improvements are required to make it a great tool in medicinal chemistry in the near future.

01 Jun 2024·Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences

Computational Screening Using a Combination of Ligand-Based Machine Learning and Molecular Docking Methods for the Repurposing of Antivirals Targeting the SARS-CoV-2 Main Protease.

Article

Author: Hermawan, Adam ; Yuda, Gusti Putu Wahyunanda Crista ; Hanif, Naufa

BACKGROUND:

COVID-19 is an infectious disease caused by SARS-CoV-2, a close relative of SARS-CoV. Several studies have searched for COVID-19 therapies. The topics of these works ranged from vaccine discovery to natural products targeting the SARS-CoV-2 main protease (M^pro), a potential therapeutic target due to its essential role in replication and conserved sequences. However, published research on this target is limited, presenting an opportunity for drug discovery and development.

METHOD:

This study aims to repurpose 10692 drugs in DrugBank by using ligand-based virtual screening (LBVS) machine learning (ML) with Konstanz Information Miner (KNIME) to seek potential therapeutics based on M^pro inhibitors. The top candidate compounds, the native ligand (GC-376) of the M^pro inhibitor, and the positive control boceprevir were then subjected to absorption, distribution, metabolism, excretion, and toxicity (ADMET) characterization, drug-likeness prediction, and molecular docking (MD). Protein-protein interaction (PPI) network analysis was added to provide accurate information about the M^pro regulatory network.

RESULTS:

This study identified 3,166 compound candidates inhibiting M^pro. The random forest (RF) molecular access system ML model provided the highest confidence score of 0.95 (bromo-7-nitroindazole) and identified the top 22 candidate compounds. Subjecting the 22 candidate compounds, the native ligand GC-376, and boceprevir to further ADMET property characterization and drug-likeness predictions revealed that one compound had two violations of Lipinski's rule. Additional MD results showed that only five compounds had more negative binding energies than the native ligand (- 12.25 kcal/mol). Among these compounds, CCX-140 exhibited the lowest score of - 13.64 kcal/mol. Through literature analysis, six compound classes with potential activity for M^pro were discovered. They included benzopyrazole, azole, pyrazolopyrimidine, carboxylic acids and derivatives, benzene and substituted derivatives, and diazine. Four pathologies were also discovered on the basis of the M^pro PPI network.

CONCLUSION:

Results demonstrated the efficiency of LBVS combined with MD. This combined strategy provided positive evidence showing that the top screened drugs, including CCX-140, which had the lowest MD score, can be reasonably advanced to the in vitro phase. This combined method may accelerate the discovery of therapies for novel or orphan diseases from existing drugs.

2

News (Medical) associated with Boceprevir

08 Feb 2023

·www.biospace.com

Infectious disease specialist Dr. Regis A. Vilchez is appointed CMO of MicuRx Pharmaceuticals, Inc.

SHANGHAI, Feb. 8, 2023 /PRNewswire/ -- Shanghai MicuRx Pharmaceutical Co., Ltd. ("MicuRx," 688373) announced recently that it has appointed Regis A. Vilchez, MD, PhD, an experienced R&D biopharmaceutical executive and infectious disease expert, as Chief Medical Officer of its American subsidiary, MicuRx Pharmaceuticals, Inc. He oversees new drug development programs and clinical activities in the United States, Europe and other regions. Dr. Vilchez earned an M.D. from the Universidad Autónoma de Centro América in Costa Rica and a Ph.D. from Baylor College of Medicine in Houston, Texas, the United States. He completed an internal medicine residency at Robert Wood Johnson Medical School, a clinical infectious diseases fellowship at the University of Pittsburgh, and a molecular virology fellowship at Baylor College of Medicine. Prior to entering the biopharmaceutical industry, Dr. Vilchez was full time faculty in the Departments of Medicine and Molecular Virology & Microbiology at Baylor College of Medicine. Dr. Vilchez has served in multiple R&D roles at Boehringer Ingelheim, Merck, Roche, Abbott/AbbVie, Mallinckrodt Pharmaceuticals and other smaller biotechnology companies. In those roles, Dr. Vilchez has been a key contributor to the global development of new therapies such as Vicriviroc, Victrelis, Viekirax, Technivie, Ocaliva, Terlivaz, and StrataGraft. Dr. Vilchez has co-authored more than 100 peer-reviewed scientific publications in high impact biomedical journals such as the New England Journal of Medicine, The Lancet, and Clinical Microbiology Reviews. The leadership of Dr. Vilchez will enhance MicuRx's global R&D programs and clinical activities. MicuRx is rapidly expanding its business and assembling an international expert team with extensive experience and an innovative spirit to develop a robust global R&D organization. Moving forward, MicuRx will remain focused on advancing its anti-infective product pipeline, and provide more effective and safer treatment options for patients around the world. View original content to download multimedia: SOURCE MicuRx Pharmaceuticals Company Codes: Shanghai:688373, Shanghai:688373.SS

Executive Change

01 Nov 2010

·www.biospace.com

Merck & Co., Inc.'s Investigational Medicine Boceprevir Achieved Significantly Higher SVR Rates In Treatment-Failure and Treatment-Naïve Adult Patients with Chronic Hepatitis C Genotype 1 Compared to Control

BOSTON--(BUSINESS WIRE)--Merck reported today that final results from two pivotal Phase III studies of boceprevir, its investigational oral hepatitis C protease inhibitor, demonstrated significantly higher sustained virologic response (SVR)1 rates in adult patients who previously failed treatment (treatment-failure; HCV RESPOND-2) and in adult patients who were new to treatment (treatment-naïve; HCV SPRINT-2) for chronic hepatitis C virus (HCV) genotype 1 compared to control, the primary objective of the studies. The results for the primary endpoints of these studies, which were first reported in a news release in August 20102, and a broad range of further data analyses from these studies are being presented in oral and poster presentations at the 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD).

100 Deals associated with Boceprevir

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External Link

KEGG	Wiki	ATC	Drug Bank
D08876	Boceprevir	J05AP03	DB08873

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Fibrosis	US	Merck Sharp & Dohme Corp.	13 May 2011
Hepatitis C	US	Merck Sharp & Dohme Corp.	13 May 2011
Hepatitis C, Chronic	US	Merck Sharp & Dohme Corp.	13 May 2011
Liver Diseases	US	Merck Sharp & Dohme Corp.	13 May 2011

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Anemia	Phase 3	-	Merck Sharp & Dohme Corp.	07 Dec 2009
Chronic hepatitis C genotype 1	Phase 3	-	Merck Sharp & Dohme Corp.	01 Aug 2008
Liver Cirrhosis	Phase 2	FR	Merck Sharp & Dohme Corp.	06 Jan 2012
Coinfection	Phase 2	FR	Merck Sharp & Dohme Corp.	01 May 2011
HIV Infections	Phase 2	-	Merck Sharp & Dohme Corp.	01 Nov 2009

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02060058 (CTgov)	Phase 3	-	12	boceprevir+ribavirin (Patients With 32 Week Therapy)	jylgundemr(ppcifpywrz) = bnccshhher fuccyojdqu (cchudfwydp, auiwhugncz - bcmyprqgda) View more	-	13 Mar 2018
				boceprevir+ribavirin (Patients With 48 Weeks Therapy)	utthaxvdwx(nrqhdceirw) = asxkilbmhw pkfrugkuhw (smphykjeem, jqaijbfnfg - mmlqzswbrs) View more
NCT01925183 (CTgov)	Phase 4	HIV Seropositivity \| Hepatitis C, Chronic	6	Pegylated interferon alpha-2a+Boceprevir+Ribavirin (28 Weeks of Treatment Duration)	sujlucbkxh(hbyxicavmd) = hgbepwrzhn ancouxxnrx (ilenpvecjn, lflafqiipm - rmowtryyol) View more	-	09 Feb 2017
				Pegylated interferon alpha-2a+Boceprevir+Ribavirin (48 Weeks of Treatment Duration)	sujlucbkxh(hbyxicavmd) = jxnotnasjp ancouxxnrx (ilenpvecjn, ktolcimweb - jqrmkirnuo) View more
NCT01945294 (3034-107, CTgov)	Phase 3	Chronic hepatitis C genotype 1	257	Boceprevir+Peg-interferon alfa-2b+Ribavirin (Arm 1: 16-week Treatment Arm)	kkusshzafw(vbupacerje) = dprnmmvsdz clupdrmemf (cfxbuegekz, zicysxmjzc - zvexrscowz) View more	-	23 Nov 2016
				Boceprevir+Peg-interferon alfa-2b+Ribavirin (Arm 2: 28-week Treatment Arm)	kkusshzafw(vbupacerje) = mxjgbzouji clupdrmemf (cfxbuegekz, nuzryemfhj - awwghdbdsk) View more
NCT01756079 (3034-105, CTgov)	Phase 4	Chronic hepatitis C genotype 1 \| Fibrosis	58	boceprevir+RBV (Overall Participants)	krqbngiwoi(dsrvykqbtr) = ofipgydjqn klkykmuxwq (ujixuogysd, yuqigtfmad - hbtaaxcjtb) View more	-	21 Nov 2016
				boceprevir+RBV (Overall Participants: Lead-in, Treatment and Follow-up)	eisxlrovgr(lyporqbngr) = tjivhkpsdy qltgtwqlvt (bdttevjpgm, pjwhoywzmi - pejbudgebn) View more
NCT01591460 (TriCo, Pubmed \| Infect Dis Ther) Manual	Phase 4	Hepatitis C	165	Peginterferon Alfa-2a+Ribavirin+Boceprevir	ovxikjksfm(vitthtztsl) = qiuuwugxig lxjhptukng (wjcubxvqtp, 74 - 86)	Positive	01 Jun 2016
NCT01544920 (P07755, CTgov)	Phase 3	Chronic hepatitis C genotype 1	737	peg-Interferon alfa-2a+Boceprevir+Ribavirin (Arm 1: Peg-IFN + RBV)	kesbqctsef(osjyluobri) = oganczpybr yptervcifk (yjophxjvww, syyphqbolz - anlavmytyy) View more	-	30 May 2016
				peg-Interferon alfa-2a+Boceprevir+Ribavirin (Arm 2: BOC + Peg-IFN + RBV)	kesbqctsef(osjyluobri) = jlpbiwoxhx yptervcifk (yjophxjvww, dtuaueapgd - tzdxvcrqhw) View more
NCT01912495 (DAHHS, Pubmed \| J Hepatol) Manual	Phase 2	HIV Infections \| Hepatitis C	127	ribavirin+peginterferon+boceprevir	mhedqfrcng(pztjtispsn) = ibmlxrnuzk xpfifydfbp (srzkmbuuqg ) View more	Positive	01 Apr 2016
				ribavirin+peginterferon	mhedqfrcng(myvvpcgfsz) = fopoicmzqj surcwuowbo (ccjegkwndp )
NCT01912495 (DAHHS, CTgov)	Phase 2	Coinfection \| HIV Infections \| Hepatitis C	65	Peginterferon+Boceprevir+Ribavirin (Boceprevir, Peginterferon and Ribavirin)	hznownmbly(yoevhbpjkt) = tpluhnbjyn evlpwdikgv (dzwnrjmptm, spofarqszs - ynpbovqzcw) View more	-	01 Apr 2016
				Boceprevir Peginterferon+Ribavirin (Boceprevir Peginterferon Ribavirin)	tmwlwbrmpq(xnxxacsgah) = tirfohvgqe fmmabcrxdw (jdlnijhxzo, gbqtsaeiyf - nvsuvzjktf)
NCT01335529 (BocepreVIH, Pubmed) Manual	Phase 2	HIV Infections \| Hepatitis C	64	ribavirin+PEGylated-interferonα2b+boceprevir	tiopcalrjn(hgvxspwlxc) = nihvascudj ccybhxdvtb (shuituzzrm, 43 - 63) View more	Positive	01 Mar 2016
NCT01425203 (P08160, Pubmed) Manual	Phase 3	Hepatitis C, Chronic	238	peginterferon+ribavirin+Boceprevir	mijowezuca(ldwgqimifd) = krivgqrpzf tvxsnmyzlq (wuzozzjfrk )	Positive	28 Feb 2016
				peginterferon+ribavirin+Placebo	mijowezuca(ldwgqimifd) = vegmrlitoh tvxsnmyzlq (wuzozzjfrk )