HCV: The Journey from Discovery to a Cure: Volume II (Topics in Medicinal Chemistry, 32)

Preface
Contents
Part I: HCV NS5A Inhibitors
NS5A as a Target for HCV Drug Discovery
	1 General Properties of NS5A
	2 NS5A as a Target for HCV Drug Discovery
	3 Discovery Challenges
	4 Anti-HCV Effects In Vitro and In Vivo
	5 Resistance
	6 Mode of Action
	7 Conclusion
	References
The Discovery and Development of Daclatasvir: An Inhibitor of the Hepatitis C Virus NS5A Replication Complex
	1 Introduction
	2 Optimization of Dimeric NS5A Replication Complex Inhibitors to Daclatasvir
	3 Mode of Action Studies with Daclatasvir
	4 Clinical Trials with Daclatasvir
	5 Conclusion
	References
The Discovery of Ledipasvir (GS-5885): The Potent Once-Daily Oral HCV NS5A Inhibitor in the Single-Tablet Regimen Harvoni
	1 Introduction
	2 Discovery Work Leading to Ledipasvir
	3 Ledipasvir (1, LDV, GS-5885)
	4 Translation of Ledipasvir´s Preclinical Potency and PK Properties in Phase 1 Clinical Trials
	5 LDV/SOF Approval and Real-World Data
	6 Conclusion
	References
The Discovery of Velpatasvir (GS-5816): The Potent Pan-Genotypic Once-Daily Oral HCV NS5A Inhibitor in the Single-Tablet Regim...
	1 Introduction
	2 Genetic Variability of the HCV Genome
	3 Fused-Tetracyclic Core Inhibitors
	4 Fused-Pentacyclic Inhibitors and the Discovery of Velpatasvir (VEL)
	5 Velpatasvir Synthesis
	6 Velpatasvir Nonclinical Data and Clinical Antiviral Activity
	7 Approval of Epclusa (SOF/VEL) and Vosevi(SOF/VEL/VOX)
	8 Epclusa (Sofosbuvir/Velpatasvir) Real-World Effectiveness
	9 Conclusion
	References
Discovery of Elbasvir
	1 Background
	2 Lead Identification
	3 Lead Optimization
	4 Pharmacological Activity
	5 Second-Generation Analogues of MK-4882
	6 Pharmacokinetics and Metabolism Studies
	7 Preclinical Safety Assessment Studies
	8 Synthesis
	9 Early Phase Clinical Trials
	10 Summary
	References
HCV NS5A as an Antiviral Therapeutic Target: From Validation to the Discovery and Development of Ombitasvir and Pibrentasvir a...
	1 Introduction
	2 Discovery of AbbVie´s First-Generation HCV NS5A Inhibitors
		2.1 Screening Hit and the Establishment of NS5A Inhibitors as a Viable HCV Drug Discovery Approach
		2.2 Identification of the E-Ring Pharmacophore and the Move to C-2 Symmetrical Compounds
		2.3 N-Phenylpyrrolidine Series Discovery
		2.4 Phenyl-Amino Pyrrolidine Series
		2.5 Phenyl Imidazole Pyrrolidine Series
		2.6 Phenyl Imidazole Pyrrole Series
		2.7 Advanced Characterization and Selection of Ombitasvir (ABT-267)
	3 Discovery of a Next-Generation NS5A Inhibitor [13]
	4 Clinical Studies
	References
Part II: HCV NS4B Inhibitors
Evolution of HCV NS4B Inhibitors
	1 HCV NS4B Protein and Related Biochemical Assays to Discover New Binders
		1.1 Structure and Function of NS4B
		1.2 Screening Assays to Discover NS4B Ligands
	2 HCV NS4B Inhibitors
		2.1 Clemizole
		2.2 Anguizole and Structurally Related Compounds
		2.3 6-(Indol-2-yl)pyridine-3-sulfonamides and Related Compounds
		2.4 Piperazinone Derivatives
		2.5 2-Oxadiazoloquinoline Derivatives
		2.6 Other NS4B Binders
	3 Final Overview and Future Directions
	References
Part III: Clinical Trials and Combination Therapy
The Evolution of Clinical Trials for Hepatitis C
	1 Introduction
	2 Early Days: Interferon
	3 Interferon and Ribavirin Combination Therapy
	4 Pegylated Interferon and Ribavirin
	5 The Era of Direct-Acting Antiviral (DAA) Therapy
	6 Interferon-Based DAA Regimens
	7 A Historic Proof of Concept: Curability of HCV Without Interferon
	8 Further Early Studies of DAA Combination Therapy
	9 The Era of Approved Interferon-Free Therapy Begins
	10 The Issue of NS5A Inhibitor Resistance
	11 The Advent of Pangenotypic DAA Regimens
	12 Special Populations
		12.1 Decompensated Cirrhosis and Pre-liver Transplant (LT)
		12.2 Post-liver Transplant
		12.3 Renal Failure
		12.4 HIV Coinfection
		12.5 DAA Failures
	13 Conclusion
	References
The Clinical Development of Ledipasvir/Sofosbuvir (LDV/SOF, Harvoni)
	1 Introduction
	2 Clinical Pharmacology of Sofosbuvir, Ledipasvir, and Ledipasvir/Sofosbuvir
		2.1 Clinical Pharmacology of Sofosbuvir
		2.2 Clinical Pharmacology of Ledipasvir/Sofosbuvir
			2.2.1 Clinical Pharmacology of LDV/SOF in Adults
			2.2.2 Clinical Pharmacology of LDV/SOF in Adolescent Patients
	3 Dose Selection of Sofosbuvir, Ledipasvir, and Ledipasvir/Sofosbuvir
		3.1 Dose Selection of Sofosbuvir
		3.2 LDV/SOF Dose Selection
	4 Safety and Efficacy of Ledipasvir/Sofosbuvir in Phase 2 Trials
		4.1 Study P7977-0523 (ELECTRON)
		4.2 Study GS-US-337-0118 (LONESTAR)
		4.3 Study GS-US-337-012 (ELECTRON-2)
		4.4 Safety of Ledipasvir/Sofosbuvir in Phase 2 Trials
	5 Safety and Efficacy of Ledipasvir/Sofosbuvir in Phase 3 Registrational Trials
		5.1 Efficacy of Ledipasvir/Sofosbuvir in Treatment-Naive Genotype 1 Patients
			5.1.1 ION-1 (Study GS-US-337-0102)
			5.1.2 ION-3 (Study GS-US-337-0109)
		5.2 Efficacy of Ledipasvir/Sofosbuvir in Treatment-Experienced Genotype 1 Patients
			5.2.1 ION-2 (Study GS-US-337-0108)
		5.3 Safety of Ledipasvir/Sofosbuvir in Phase 3 Registrational Trials
		5.4 Summary of Phase 3 Data Supporting Initial Registration of Ledipasvir/Sofosbuvir
	6 Safety and Efficacy of Ledipasvir/Sofosbuvir in Other Patient Populations
		6.1 LDV/SOF in Patients with Compensated Cirrhosis Who Failed Prior IFN-Based Treatment
			6.1.1 GS-US-337-0121 (SIRIUS)
		6.2 LDV/SOF in Patients with Non-genotype 1 Infection
			6.2.1 Efficacy of LDV/SOF in Patients with Genotype 2 HCV Infection
				GS-US-337-1468 (LEPTON)
				GS-US-337-1903
			6.2.2 LDV/SOF in Patients with Genotype 3 HCV Infection
				Study GS-US-337-0122 (ELECTRON-2)
				Study GS-US-337-1701
			6.2.3 LDV/SOF in Patients with Genotype 4 HCV Infection
				SYNERGY Trial
				Study GS-US-337-1119
			6.2.4 LDV/SOF in Genotype 5 HCV Infection
				Study GS-US-337-1119
			6.2.5 LDV/SOF in Genotype 6 HCV Infection
				GS-US-337-0122 (ELECTRON-2)
			6.2.6 Safety of LDV/SOF in Patients with Non-genotype 1 Infection
		6.3 LDV/SOF in Patients with HCV/HIV Coinfection
			6.3.1 Study CO-US-337-0115 (ERADICATE)
			6.3.2 Study GS-US-337-0115 (ION-4)
			6.3.3 Safety of LDV/SOF in Patients with HIV/HCV Coinfection
		6.4 LDV/SOF in Patients Who Are Posttransplant or with Decompensated Liver Disease
			6.4.1 Studies GS-US-337-0123 (SOLAR-1) and GS-US-337-0124 (SOLAR-2)
			6.4.2 Safety of LDV/SOF in Patients Who Are Posttransplant or with Decompensated Liver Disease
		6.5 LDV/SOF in Adolescent Patients
			6.5.1 Study GS-US-337-1116
			6.5.2 Safety of LDV/SOF in Adolescent Patients
		6.6 LDV/SOF in Retreatment of Patients Who Failed Prior SOF Regimens
		6.7 LDV/SOF in Other Key Populations
	7 Conclusion
	References
The Clinical Development of Sofosbuvir/Velpatasvir (SOF/VEL, Epclusa)
	1 Introduction
	2 Phase 1 Studies
	3 Phase 1b Study
	4 Phase 2 Studies
		4.1 Study GS-US-342-0102
		4.2 Study GS-US-337-0122
		4.3 Study GS-US-342-0109
	5 Phase 3 Studies
		5.1 ASTRAL-1
		5.2 ASTRAL-2
		5.3 ASTRAL-3
		5.4 ASTRAL-4
		5.5 Summary of Phase 3 Data Supporting Initial Registration of SOF/VEL
		5.6 ASTRAL-5
	6 Conclusion
	References
The Clinical Development of Sofosbuvir/Velpatasvir/Voxilaprevir (SOF/VEL/VOX, Vosevi)
	1 Introduction
	2 Phase 1 Studies
	3 Phase 1b Study
	4 Phase 2 Studies
		4.1 Study GS-US-337-1468 (LEPTON)
		4.2 Studies GS-US-367-1168 and GS-US-367-1169
		4.3 Study GS-US-367-1871 (TRILOGY-3)
	5 Phase 3 Studies
		5.1 Efficacy in DAA-Experienced Patients
			5.1.1 GS-US-367-1171 (POLARIS-1)
			5.1.2 GS-US-367-1170 (POLARIS-4)
		5.2 Efficacy in DAA-Naive Patients
			5.2.1 GS-US-367-1172 (POLARIS-2)
			5.2.2 GS-US-367-1173 (POLARIS-3)
		5.3 Safety of SOF/VEL/VOX
		5.4 Summary of Phase 3 Data Supporting the Initial Registration of SOF/VEL/VOX
	6 Conclusion
	References
Clinical Development of Viekira Pak to Mavyret
	1 Introduction
	2 Hepatitis C Therapy in 2003-2008
	3 Sea Change: 2009-2010
		3.1 The Perelson Paper
		3.2 INFORM-1
	4 The Shift to Interferon-Free Therapy
		4.1 Two Programs
		4.2 Pilot and Co-Pilot
	5 The AVIATOR Study
	6 The Phase 3 Program and Regulatory Approval
		6.1 2 DAAs
	7 The Next-Generation Development Program: From ABT-493/ABT-530 to Mavyret
		7.1 The Case for a Next Generation
		7.2 Closing the Gaps
		7.3 Learning from the First Generation
	8 The Future of HCV Therapy
	References
Development of ZEPATIER
	1 Overview
	2 Phase 1 Trials
		2.1 Elbasvir Monotherapy Proof of Concept Study
		2.2 Grazoprevir Monotherapy Proof of Concept Study
	3 Phase 2 Trials
		3.1 Phase 2 Dose-Ranging Trials of Grazoprevir in Combination with Pegylated Interferon and Ribavirin
		3.2 C-WORTHY: Elbasvir and Grazoprevir Among a Broad Population of HCV GT1–Infected Participants
		3.3 C-SCAPE: Elbasvir plus Grazoprevir, with or Without Ribavirin, Among Participants with HCV GT2, GT4, GT5, or GT6 Infection
		3.4 C-SALVAGE: Elbasvir/Grazoprevir with Ribavirin Among GT1-Infected Participants Who Failed Prior Treatment with Boceprevir,...
		3.5 C-SWIFT: Short-Duration Treatment with Elbasvir plus Grazoprevir and Sofosbuvir Among GT1- or GT3-Infected Treatment-Naive...
	4 Phase 3 Trials
		4.1 C-EDGE Treatment-Naive: Elbasvir/Grazoprevir in Treatment-Naive Participants with HCV Infection, with or Without Cirrhosis
		4.2 C-EDGE Treatment-Experienced: Elbasvir/Grazoprevir in Participants with HCV Infection Who Experienced Virologic Failure Af...
		4.3 C-SURFER: Elbasvir/Grazoprevir in HCV GT1-Infected Participants with Advanced Chronic Kidney Disease
		4.4 C-EDGE CO-INFECTION: Elbasvir/Grazoprevir in Treatment-Naive, HCV-/HIV-Coinfected Participants with or Without Cirrhosis
		4.5 C-EDGE CO-STAR: Elbasvir and Grazoprevir in HCV-Infected Participants Receiving Opioid Agonist Therapy
		4.6 C-EDGE IBLD: Elbasvir/Grazoprevir in Participants with HCV Infection and Inherited Blood Disorders
		4.7 C-EDGE Head-2-Head: Elbasvir/Grazoprevir Versus Sofosbuvir plus Pegylated Interferon and Ribavirin in Participants with HC...
		4.8 C-CORAL: Elbasvir/Grazoprevir in HCV GT1-, GT4-, or GT6-Infected People from the Asia-Pacific Region and Russia
		4.9 Japanese Phase 2/3 Study: Elbasvir/Grazoprevir in Japanese Participants with HCV GT1 Infection
		4.10 C-ISLE: Elbasvir/Grazoprevir and Sofosbuvir in Participants with HCV GT3 Infection and Cirrhosis
	5 Integrated Analyses
		5.1 Patients with Compensated Cirrhosis
		5.2 HCV GT1a-Infected Patients
		5.3 HCV GT1b-Infected Patients
		5.4 HCV GT4-Infected Patients
		5.5 Integrated Safety Analysis
	6 Summary
	References
Part IV: Impact of Curative Therapies
Real-World Evidence and Hepatitis C
	1 Introduction
	2 Identifying and Filling Knowledge Gaps for Approved HCV Therapies
	3 FDA Commitment to Real-World Evidence
	4 Sources of Real-World Evidence
	5 HCV-TARGET and Other Real-World Cohorts
	6 Real-World Evidence Finds an Important Safety Signal in Patients with Cirrhosis
	7 RWE Contributes to the Approval of the First All-Oral DAA Regimen Commonly Prescribed
	8 RWE Confirms Safety and Effectiveness of DAA Regimens
	9 RWE Reassures and Refines Criteria for Shortened Treatment Duration
	10 RWE Characterizes Impact of Proton Pump Inhibitors on Outcomes
	11 RWE Contributes to Safety and Efficacy Profile of DAAs in Unique Populations
	12 Summary
	References
The Benefit of Direct-Acting Antiviral HCV Cure Therapies
	1 Introduction
	2 Methods
	3 Results
	4 Discussion
	References
Cure and Control: What Will It Take to Eliminate HCV?
	1 Introduction
	2 Global HCV Epidemiology
		2.1 HCV Prevalence
		2.2 HCV Incidence and Risk Factors for Acquisition
	3 Infectious Diseases Control, Elimination and Eradication
		3.1 Definitions
		3.2 Treatment as Prevention
		3.3 Micro-elimination
		3.4 Lessons Learnt from Other Infectious Diseases
	4 Feasibility of HCV Elimination: What Is Required to Achieve the WHO 2030 Targets?
		4.1 Direct-Acting Antiviral Therapy: Facilitating ``Access for All´´
			4.1.1 Reducing HCV Incidence and HCV-Related Mortality: Insights from Mathematical Modelling Studies
			4.1.2 Broad Unrestricted Access to DAA Treatment
			4.1.3 Reduce Prices for DAA Treatment
		4.2 Screening, Diagnosis and Linkage to Care
			4.2.1 Increase HCV Testing, Diagnosis and Linkage to Care
			4.2.2 Develop Low Price, Simple HCV Diagnostics
			4.2.3 Optimise HCV Screening Strategies
		4.3 Prevention of HCV Infection and Reinfection
			4.3.1 Facilitate Access to Harm Reduction for PWID
			4.3.2 Behavioural Risk Reduction Among Gay and Bisexual Men
			4.3.3 Pre-exposure or Post-exposure Prophylaxis?
			4.3.4 Address HCV Reinfection
			4.3.5 Prevent Health-Care-Associated HCV Transmission
		4.4 Monitoring and Evaluation
		4.5 Economic Considerations
			4.5.1 Cost-Effectiveness of Direct-Acting Antiviral Treatment for HCV
			4.5.2 Cost-Effectiveness of HCV Diagnostics
		4.6 Social and Political Will
			4.6.1 Social and Political Support for HCV Elimination
			4.6.2 Adequate Health Service Provision
			4.6.3 Deliver HCV Education and Training to Health-Care Providers
			4.6.4 Reduce Stigma and Discrimination
	5 National HCV Elimination Strategies
		5.1 Australia
		5.2 Georgia
		5.3 Egypt
	6 Conclusion
	References
Perspectives on HCV Cure
	References
Index