Discovery and Development of the Next-Generation HCV NS3 Protease Inhibitor Glecaprevir
The early collaboration between Enanta and Abbott/AbbVie on HCV NS3 protease inhibitor program led to the discovery of ABT-450 (paritaprevir), which is a component of two FDA-approved IFN-free DAA combination therapies (Viekira Pak™ and Technivie™) with approval to treat genotypes 1 and 4, respectively. However, its activity against some key resistant mutants and other HCV genotypes was limited. This chapter reviews our further effort to identify a next-generation HCV protease inhibitor with pan-genotypic activity, excellent activity against resistant mutants, and favorable pharmacokinetic (PK) properties, which included the identification of the first proof-of-concept (PoC) compound in P2-P4 macrocyclic series by evaluation of different core structures and the discovery of the candidate compound ABT-493 through extensive SAR studies at P*, P1, and P1’ positions and particularly on the linker. In combination with the HCV NS5A inhibitor pibrentasvir, ABT-493 (glecaprevir) was approved by the FDA in August 2017 for treatment of hepatitis C and is marketed by AbbVie as Mavyret™/Maviret™ in multiple countries.
KeywordsABT-493 DAA combination therapy Glecaprevir HCV protease inhibitor P2-P4 macrocyclic Pan-genotypic
Authors want to thank Dale J. Kempf and other Abbott medicinal chemistry team members for editing and reviewing this chapter and helpful discussion/idea exchanges during collaboration. Also thanks to Abbott’s virology and DMPK teams for the characterizations of all compounds, which were essential for identification of the candidate ABT-493. Authors also want to thank all Joint Steering Committee members from both Enanta and Abbott for their support.
Compliance with Ethical Standards
Funding The study was supported by Enanta Pharmaceuticals, Inc. and AbbVie.
Conflict of Interest
G.W., J.M., L.-J.J., J.L., B.W., and Y.S.O. are current Enanta employees who hold Enanta stock options, and all of them and Y.G. may hold Enanta stock. K.F.M. is a current AbbVie employee and may hold AbbVie stock or options. The chemistry research and the preclinical characterization were conducted by Enanta and AbbVie, respectively. The design and conduct of the clinical studies of glecaprevir were provided by AbbVie. AbbVie and Enanta participated in the interpretation of the data and review and approval of the publication.
AbbVie is committed to responsible data sharing regarding the clinical trials it sponsors. This includes access to anonymized, individual and trial-level data (analysis data sets), as well as other information (e.g., protocols and Clinical Study Reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications.
This clinical trial data can be requested of AbbVie by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). Data requests can be submitted at any time and the data will be accessible for 12 months, with possible extensions considered. For more information on the process, or to submit a request, visit the following link: https://www.abbvie.com/our-science/clinicaltrials/clinical-trials-data-and-information-sharing/data-and-information-sharing-with-qualifiedresearchers.html.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed in the preclinical research conducted at Enanta and at AbbVie. All procedures performed by AbbVie in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
The authors would like to thank the patients and their families as well as the study site staff who participated in the clinical trials of glecaprevir.
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