A Phase 2, Open-label Study to Assess the Safety and Efficacy of Bemnifosbuvir (BEM) and Ruzasvir (RZR) in Subjects With Chronic Hepatitis C Virus (HCV) Infection
Phase: PHASE2
Conditions: Chronic Hepatitis C Virus, Hepatitis C, Chronic, Hepatitis C, Hepatic Cirrhosis, HCV
Sponsor: Atea Pharmaceuticals, Inc.

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A PHASE 2, OPEN-LABEL STUDY TO ASSESS THE SAFETY AND EFFICACY OF 
BEMNIFOSBUVIR (BEM) AND RUZASVIR (RZR) IN SUBJECTS WITH CHRONIC 
HEPATITIS C VIRUS (HCV) INFECTION 
 
Sponsor Protocol Number: 
AT-01B-004 
EU CT Number: 
2023-504566-28-00 
Investigational Products: 
Bemnifosbuvir Hemisulfate (BEM; AT-527) and Ruzasvir 
(RZR; AT-038) 
Sponsor 
Atea Pharmaceuticals, Inc. 
225 Franklin Street, Suite 2100  
Boston, MA 02110 
 +1 (857) 284-8891 
 
COMPLIANCE 
The study will be conducted in accordance with this protocol, European Regulation 536/2014, 
the ethical principles in the latest version of the Declaration of Helsinki, standards of Good 
Clinical Practice, as defined by the International Conference on Harmonisation and all applicable 
federal and local regulations.   
Protocol Version 
 
Date 
Amendment 3 
FINAL 
29Mar2024 
Amendment 2 
FINAL 
15Aug2023 
Amendment 1 
FINAL 
09Jan2023 
Original 
FINAL 
06Dec2022 
 
CONFIDENTIALITY STATEMENT 
The information provided in this document is strictly confidential and is available for review 
to investigator(s) and to the appropriate Independent Ethics Committee (IEC) or Institutional 
Review Board (IRB). It may not be used, divulged, published, or otherwise disclosed without 
the written authorization from the Sponsor. 

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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................2 
STUDY SYNOPSIS ........................................................................................................................6 
LIST OF ABBREVIATIONS ........................................................................................................14 
1. 
INTRODUCTION ......................................................................................................17 
1.1. 
Background .................................................................................................................17 
1.2. 
Rationale for the Dose Selection ................................................................................19 
1.2.1. 
BEM ............................................................................................................................19 
1.2.2. 
RZR .............................................................................................................................20 
1.3. 
Study Rationale ...........................................................................................................21 
1.4. 
Risk/Benefit Assessment ............................................................................................21 
2. 
STUDY OBJECTIVES ..............................................................................................23 
2.1. 
Primary Objectives .....................................................................................................23 
2.2. 
Secondary Objectives .................................................................................................23 
2.3. 
Exploratory Objectives ...............................................................................................23 
3. 
STUDY DESIGN .......................................................................................................24 
3.1. 
General Study Design .................................................................................................24 
3.2. 
Number of Subjects ....................................................................................................25 
4. 
SUBJECT SELECTION .............................................................................................27 
4.1. 
Study Population .........................................................................................................27 
4.2. 
Inclusion Criteria ........................................................................................................27 
4.3. 
Exclusion Criteria .......................................................................................................28 
5. 
STUDY TREATMENTS............................................................................................31 
5.1. 
Description and Handling of Study Treatments .........................................................31 
5.1.1. 
Test Products ..............................................................................................................31 
5.1.2. 
Control Product(s) ......................................................................................................31 
5.1.3. 
Packaging and Labeling ..............................................................................................31 
5.1.4. 
Storage and Handling .................................................................................................31 
5.2. 
Method of Assigning Subjects to Treatment ..............................................................31 
5.3. 
Blinding ......................................................................................................................31 
5.4. 
Dosing and Administration .........................................................................................31 

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5.4.1. 
Dispensing ..................................................................................................................31 
5.4.2. 
Administration Instructions ........................................................................................31 
5.4.3. 
Dosing for Optional PK-only Substudy and PK-VK Substudy ..................................32 
5.4.4. 
Treatment Compliance ................................................................................................32 
5.5. 
Study Drug Accountability .........................................................................................32 
5.6. 
Stopping Rules ............................................................................................................32 
5.6.1. 
Individual Virologic Stopping Rules ..........................................................................32 
5.6.2. 
Individual Safety Stopping Rules ...............................................................................33 
5.6.3. 
Study Stopping Rules .................................................................................................33 
5.7. 
Premature Discontinuation .........................................................................................34 
5.8. 
Prior Therapy, Concomitant Therapy, Permitted Therapy, Cautionary 
Therapy, and Prohibited Therapy ...............................................................................35 
5.8.1. 
Prior Medication .........................................................................................................35 
5.8.2. 
Concomitant Medication ............................................................................................35 
5.8.3. 
Permitted Therapy ......................................................................................................35 
5.8.4. 
Cautionary Therapy ....................................................................................................35 
5.8.5. 
Prohibited Therapy .....................................................................................................36 
5.9. 
Contraception Requirements ......................................................................................37 
6. 
STUDY PROCEDURES AND GUIDELINES..........................................................38 
6.1. 
Medical History and Demographics ...........................................................................41 
6.2. 
Physical Examination and Body Weight ....................................................................41 
6.3. 
Vital Signs ..................................................................................................................42 
6.4. 
12-Lead Electrocardiogram ........................................................................................42 
6.5. 
Liver Staging ..............................................................................................................42 
6.6. 
Laboratory Evaluations ...............................................................................................42 
6.7. 
Pharmacodynamics and Pharmacokinetics .................................................................43 
6.7.1. 
Hepatitis C Virus Genotyping, RNA Levels, and Mutation Analysis ........................43 
6.7.2. 
Pharmacokinetic Sampling for All Subjects ...............................................................43 
6.7.3. 
Optional Substudies ....................................................................................................43 
6.7.4. 
Sample Processing, Storage, and Shipping .................................................................44 
6.7.5. 
Bioanalytical Methods for Pharmacokinetic Samples ................................................44 
7. 
ADVERSE EVENTS..................................................................................................45 

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7.1. 
Definitions ..................................................................................................................45 
7.1.1. 
Severity Assessment ...................................................................................................46 
7.1.2. 
Causality Assessment .................................................................................................46 
7.2. 
Routine Reporting .......................................................................................................47 
7.3. 
Serious Adverse Event Reporting ...............................................................................47 
7.4. 
Pregnancy Reporting ..................................................................................................49 
8. 
STATISTICAL ANALYSES .....................................................................................50 
8.1. 
Analysis Populations ..................................................................................................50 
8.1.1. 
Screened Patients ........................................................................................................50 
8.1.2. 
Safety Population ........................................................................................................50 
8.1.3. 
Per Protocol Population ..............................................................................................50 
8.1.4. 
PK Compliant Per-Protocol (PK-PP) Population .......................................................50 
8.1.5. 
Pharmacokinetic Populations......................................................................................51 
8.2. 
Endpoints ....................................................................................................................51 
8.2.1. 
Primary Endpoint ........................................................................................................51 
8.2.2. 
Secondary Endpoints ..................................................................................................51 
8.2.3. 
Exploratory Endpoints ................................................................................................51 
8.2.4. 
Safety Endpoints .........................................................................................................52 
8.3. 
Demographics and Baseline Characteristics ...............................................................52 
8.4. 
Efficacy Analyses .......................................................................................................52 
8.4.1. 
Primary Analyses ........................................................................................................52 
8.4.2. 
Secondary Analyses ....................................................................................................52 
8.5. 
Safety Analyses ..........................................................................................................53 
8.6. 
Pharmacokinetic Analyses ..........................................................................................53 
8.7. 
Interim Analyses .........................................................................................................53 
8.8. 
Sample Size ................................................................................................................54 
9. 
ETHICS ......................................................................................................................55 
9.1. 
Institutional Review Board (IRB)/ Independent Ethics Committee (IEC) .................55 
9.2. 
Ethical Conduct of the Study ......................................................................................55 
9.3. 
Participant Information and Consent ..........................................................................55 
9.4. 
Subject Confidentiality and Personal Data Protection ................................................55 

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10. 
DATA COLLECTION, RETENTION, AND MONITORING .................................57 
10.1. 
Case Report Forms .....................................................................................................57 
10.2. 
Data Management and Processing ..............................................................................57 
10.3. 
Quality Assurance .......................................................................................................57 
10.4. 
Record Retention ........................................................................................................57 
10.5. 
Monitoring of the Study..............................................................................................58 
11. 
ADMINISTRATIVE PROCEDURES .......................................................................59 
11.1. 
Adherence to Protocol ................................................................................................59 
11.2. 
Investigator Responsibilities and Delegation of Investigator Duties .........................59 
11.3. 
Premature Termination or Suspension of a Study ......................................................59 
11.4. 
Publications .................................................................................................................59 
12. 
REFERENCES ...........................................................................................................60 
 
LIST OF TABLES 
Table 1: 
Planned Study Enrollment ..........................................................................................26 
Table 2: 
Schedule of Assessments ............................................................................................39 
Table 3: 
Optional PK-only and PK-VK Substudies:  Sampling Schedule ...............................41 
Table 4: 
Adverse Event Relationship to Study Drug ................................................................47 
Table 5: 
Lower One-sided 95% Confidence Bounds Associated with Observed 
Outcomes ....................................................................................................................54 
 
LIST OF FIGURES 
Figure 1: 
Exposure-Response Analysis (Study AT-01B-001) ...................................................20 
Figure 2: 
Study Design ...............................................................................................................24 
 
 

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STUDY SYNOPSIS 
Name of Sponsor/Company:  Atea Pharmaceuticals, Inc. 
Name of Investigational Products: bemnifosbuvir hemisulfate (BEM; AT-527) and ruzasvir 
(RZR; AT-038) 
Protocol Number: AT-01B-004 
Phase: 2 
Country: Multiple 
Title of Study: A Phase 2, Open-Label Study to Assess the Safety and Efficacy of 
Bemnifosbuvir (BEM) and Ruzasvir (RZR) in Subjects with Chronic Hepatitis C Virus (HCV) 
Infection 
Objectives:  
 
Primary: 
• To evaluate the safety and tolerability of BEM + RZR  
• To evaluate the efficacy of BEM + RZR as assessed by the proportion of subjects 
achieving sustained virologic response at 12 weeks post-treatment (SVR12)  
 
Secondary: 
• To evaluate the efficacy of BEM + RZR, as assessed by the proportion of subjects 
experiencing virologic failure (either on-treatment or post-treatment relapse [by 12 
weeks post-treatment])  
• To evaluate the efficacy of BEM + RZR as assessed by the proportion of subjects 
achieving sustained virologic response at 24 weeks post-treatment (SVR24)  
 
Exploratory: 
• To evaluate the effect of baseline resistance-associated variants (RAVs) in 
nonstructural protein (NS) 5A and/or NS5B on the efficacy of BEM + RZR  
• To evaluate the emergence of NS5A and NS5B RAVs in subjects who experience 
virologic failure 
• To evaluate antiviral activity/viral kinetics (VK) of BEM + RZR  
• To evaluate the pharmacokinetics (PK) and VK of BEM + RZR in the subgroup of 
subjects who agree to additional serial PK and VK sampling 

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Study Design: 
This is an open-label trial to evaluate 8 weeks of treatment with BEM + RZR in subjects with 
chronic HCV infection. Approximately 280 treatment-naïve subjects with genotype (GT) 1, 2, 
3, 4, 5, 6 or 7, either without cirrhosis or with compensated cirrhosis, will be enrolled.  
A lead-in group of 60 non-cirrhotic subjects will initially be enrolled.  At 4 weeks 
posttreatment, this lead-in group will be evaluated for safety, sustained virologic response at 
4 weeks posttreatment (SVR4) and virologic relapse; enrollment will open to the remaining 
220 subjects provided that ≤ 
 in the lead-in group experience virologic failure that 
was not due to poor compliance and no study stopping rules (Section 5.6.3) are met.  
Subjects will be screened for up to 4 weeks, although this can be extended for up to 6 weeks 
for extenuating circumstances with Sponsor approval. Re-screens may be approved on a 
case-by-case basis by the Sponsor (re-screened subjects will be assigned a new subject 
number). 
Eligible subjects will enter the treatment period and receive BEM + RZR for 8 weeks. After 
Day 1, during the treatment period, subjects may self-administer study drugs (ie, 
investigational medicinal product [IMP]) at home, with the exception of subjects who agree to 
additional blood sampling as part of up to 2 substudies.  These subjects will be required to take 
their study drug in the clinic on certain days (see Table 3). 
Subjects will return to the clinic for evaluations at Weeks 1, 2, 4, 6 and 8 (End of Treatment 
[EOT]) during the treatment period.  
Following their last visit of the treatment period (including subjects who prematurely 
discontinue treatment), subjects will enter the Follow-up period and return to the clinic for 
evaluations at Follow-up Weeks 4, 12, and 24. End-of-Study (EOS) is defined as the visit at 24 
weeks posttreatment. 
Adverse events (AEs) and concomitant medications will be reviewed during visits throughout 
the treatment and follow-up periods. Subjects may also be contacted between visits to assess 
their compliance with the dosing regimen (during the treatment period) and to discuss AEs and 
concomitant medications.  
The primary endpoint is SVR12. Secondary endpoints include virologic failure and SVR24. 
Exploratory endpoints are resistance to either study drug (BEM or RZR), SVR12 in subgroups 
defined by demographics and/or baseline characteristics, HCV RNA changes from baseline 
and exposure-response relationships. Safety endpoints are the incidence of AEs, serious 
adverse events (SAEs), and AEs resulting in treatment discontinuation; clinical laboratory 
abnormalities; vital sign measurements; and electrocardiogram (ECG) parameters. 
At clinical sites that agree to participate, there will be two optional substudies (PK only; PK-
VK), each requiring separate consent; up to 100 subjects can consent to either or both. 
Subjects who consent to the PK-only substudy will provide additional blood samples at any 
planned treatment visit as early as Week 2 based on convenience for subject and investigator. 
Subjects who consent to the PK-VK substudy will provide additional blood samples a) on Day 
CCI

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1; and b) on Days 2 and 3 (24 and 48 hours after the first dose; ± 2 hours). Study drug will be 
administered at the clinic on these days (see Table 3).  
Number of Subjects Planned: 
Approximately 280 subjects will be enrolled, with targets based on GT and compensated 
cirrhosis status as described in the table below. A blood sample for genotyping will be 
collected at screening. Genotype results at screening are generally not required to initiate 
dosing.  However, as the study progresses, the Sponsor may use results to help manage these 
enrollment targets. 
A lead-in group of 60 non-cirrhotic subjects will be enrolled and evaluated for SVR4; 
enrollment will open to the remaining 220 subjects provided that 
 in the lead-in 
group experience virologic failure that was not due to poor compliance, and no study stopping 
rules are met (Section 5.6.3).  Of the 60 subjects in the lead-in group, a target of 15 GT3-
infected subjects will be enrolled; the remainder will be of any GT.  
Total Number 
Genotype 
Enrollment Targets 
Fibrosis Stage 
N = 280 
1a 
n = 75 
F0-F4 
(Target: 20% with 
compensated cirrhosis) 
1b 
n = 40 
2 
n = 40 
3 
n = 75  
4 
n = 25 
5, 6, or 7 
n = 25 
F0-F4  
(No specified target for 
compensated cirrhosis) 
Estimated Duration of Participation: 
Subjects will participate in the trial for a maximum of approximately 38 weeks from the time 
the subject signs the Informed Consent Form (ICF) through the final contact. The Screening 
phase is 4 weeks and may be extended to 6 weeks for extenuating circumstances. After 
Screening, subjects receive treatment for 8 weeks, and are then followed for 24 weeks.  
Diagnosis and Main Criteria for Inclusion: 
Inclusion Criteria: 
1. Willing and able to provide written informed consent 
2. Male or female subjects between ≥ 18 years of age (or the legal age of consent per 
local regulations) and ≤ 85 years of age 
3. Fridericia-corrected QT (QTcF) interval ≤ 440 ms for males and ≤ 460 ms for females 
at Screening  
Note: The mean of the triplicate readings, rounded to the nearest whole number, 
should be used to assess the QTcF. 
CCI

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4. Female subjects of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or to the use of an acceptable effective contraception, as 
described in Section 5.9   
5. Females of childbearing potential must have a negative pregnancy test at Screening and 
at Day 1 prior to dosing 
6. Subjects must be direct-acting antiviral (DAA)-treatment-naïve, defined as never 
exposed to an approved or experimental DAA for HCV  
Note: Prior exposure to (peg)interferon with or without ribavirin is acceptable, as long 
as it/they were not administered with a DAA. 
7. Willingness to provide a blood sample at Screening for genotyping. 
8. Documented medical history compatible with chronic HCV, including any one of the 
following:  
• positive for anti-HCV antibody, HCV RNA, or an HCV GT at least 6 months prior 
to Day 1, or  
• positive for anti-HCV antibody at Screening with clinical or laboratory evidence of 
chronic HCV disease, such as the presence of fibrosis by biopsy or noninvasive 
tests 
9. HCV RNA ≥ 1,000 IU/mL at Screening. 
10. Liver disease staging assessment as follows: 
• Absence of cirrhosis (F0 to F3) defined as any one of the following: 
− Liver biopsy within 24 months of Day 1 showing absence of cirrhosis 
− Fibroscan® within 12 months of Day 1 with a result of ≤ 12.5 kPa 
− Fibrosure® (Fibrotest®) performed during screening with a score of ≤ 0.48 and 
an aspartate aminotransferase (AST)-to-platelet ratio index (APRI) of ≤ 1 
• Compensated cirrhosis (F4) defined as any one of the following: 
− Liver biopsy performed prior to Day 1 showing cirrhosis (Metavir stage 4 or 
equivalent) 
− Fibroscan® within 12 months of Day 1 showing cirrhosis with result 
> 12.5 kPa  
− Fibrosure® (Fibrotest®) performed during screening with a score of > 0.75 and 
an APRI of > 2 
APRI formula:  AST ÷ lab upper limit of normal (ULN) for AST × 100 ÷ 
(platelet  count ÷ 100). 
NOTE: In the absence of a definitive diagnosis of presence or absence of 
cirrhosis by the above criteria, a liver biopsy or Fibroscan® is required. Liver 
biopsy results supersede the results obtained by Fibroscan® or Fibrosure®. 

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NOTE: Subjects in the lead-in group must not have F4 cirrhosis. 
11. Subject is, in the opinion of the investigator, willing and able to comply with the study 
drug regimen and all other study requirements 
Exclusion Criteria: 
1. Female subject is pregnant or breastfeeding 
2. Co-infected with hepatitis B virus (HBV; positive for hepatitis B surface antigen 
[HBsAg]) and/or human immunodeficiency virus (HIV) 
3. Abuse of alcohol and/or illicit drug use that could interfere with adherence to study 
requirements as judged by the investigator 
4. Prior exposure to any HCV DAA 
5. Requirement of any prohibited medications, as described in Section 5.8   
6. Use of other investigational drugs within 30 days of dosing or plans to enroll in another 
clinical trial of an investigational agent while participating in the present study 
7. Subject with known allergy to the study medications or any of their components 
8. History or signs of decompensated liver disease:  ascites, variceal bleeding, hepatic 
encephalopathy, spontaneous bacterial peritonitis, or other clinical signs of portal 
hypertension or hepatic insufficiency 
9. Cirrhotic and has a Child-Pugh score >6, corresponding to a Child-Pugh Class B or C  
Note: To calculate the Child-Pugh score, refer to the following website:   
https://www.mdcalc.com/calc/340/child-pugh-score-cirrhosis-mortality 
10. History of hepatocellular carcinoma (HCC) or findings suggestive of possible HCC 
11. Active clinically significant diseases including:   
• Evidence of history of chronic hepatitis not caused by HCV, including drug-
induced hepatitis, hemochromatosis, Wilson’s disease, alpha-1-antitrypsin 
deficiency, alcoholic liver disease, and autoimmune hepatitis 
• Cardiac abnormalities/dysfunction that may interfere with subject treatment, 
assessment, or compliance with the protocol, including unstable angina, unstable 
congestive heart failure, and unstable arrhythmia 
• Malignant disease or suspicion or history of malignant disease within previous 
5 years (except for adequately treated basal or basosquamous cell carcinoma) 
• Any medical condition requiring chronic use of immunosuppressive drugs (e.g., for 
organ transplantation).  
 
• Subject with intestinal malabsorption (e.g., structural defects, digestive failure, or 
enzyme deficiencies, with the exception of lactose intolerance) 

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• Any other clinically significant medical condition that, in the opinion of the 
investigator, would jeopardize the safety of the subject or impact the validity of the 
study results 
12. Clinically significant abnormal ECG at Screening, as determined by the investigator. 
13. Any of the following laboratory parameters at Screening: 
• Alanine aminotransferase (ALT) or AST > 10 x ULN 
• Total bilirubin > 3 mg/dL (> 51.3 μmol/L) 
• Albumin < 2.8 g/dL (< 28 g/L) 
• International Normalized Ratio (INR) > 2.2 unless subject has a stable INR on an 
anticoagulant 
• Hemoglobin < 10 g/dL 
• Hemoglobin A1c (HbA1c) > 8.5% 
• Platelet count < 50 x 109/L 
• Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 as estimated by 
the Modification of Diet in Renal Disease (MDRD) formula 
• Concomitant grade ≥2 toxicity of both lipase and amylase per Division of AIDS 
criteria (https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf). 
Note: Retests of Screening laboratory parameters or assessments may be permitted 
once in certain scenarios with medical monitor approval. Such scenarios may 
include lab processing error, results inconsistent with subject’s historical 
values/medical history, or other extenuating circumstances such as a recent or 
intercurrent illness potentially affecting Screening laboratory results. 
Investigational Product, Dosage, and Mode of Administration: 
• BEM (manufactured by 
 or 
.) 
will be provided as 275-mg tablets (A2-275 mg tablets) 
• RZR (manufactured by 
) will be provided as 90-mg 
capsules 
• Subjects will take 550 mg BEM (as 2 x 275-mg tablets) and 180 mg RZR (as 2 x 
90-mg capsules) once daily for 8 weeks 
• Study drugs will be taken together orally 
• Subjects will be instructed to take the study drugs in the morning at approximately 
the same time each day. Study drugs can be taken with water and with or without 
food. 
Duration of Treatment: 
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The duration of treatment will be 8 weeks.  
Reference Therapy, Dosage, and Mode of Administration: 
Not applicable 
Criteria for Efficacy 
SVR12 and SVR24 are defined as HCV ribonucleic acid [RNA] < lower limit of quantification 
[LLOQ] at 12 weeks and 24 weeks respectively post-treatment. 
Statistical Methods: 
Results of all efficacy analyses will be presented by genotype and cirrhotic status.  
All efficacy analyses will be performed on the PP population(s) consisting of all subjects who: 
• Meet all inclusion/exclusion criteria 
• Do not receive concomitant medications that are prohibited due to their potential 
impact on HCV viral load or the pharmacokinetic concentration of either agent (BEM 
or RZR). 
• Have a collected or imputed posttreatment viral load assessment at posttreatment Week 
12 (posttreatment Week 4 for lead-in subjects) unless the subject discontinues early for 
virologic failure or AE, in which case the ET visit may be used 
• Complete treatment (≥90% compliance with the study drug regimen), discontinue 
treatment early due to virological failure or discontinue treatment early due to a drug-
related AE 
Note:  Compliance will be calculated using drug compliance data collected on the 
eCRF. 
The Sponsor expects approximately 95% of the enrolled subjects to meet these criteria. 
An interim analysis will be performed on data from the lead-in group using the PP 
population(s). The proportion of subjects achieving SVR4, defined as HCV RNA < LLOQ at 4 
weeks posttreatment, will be presented with 2-sided 95% confidence intervals (CIs) using the 
Wilson score method. Virologic failure, defined as either on-treatment failure or posttreatment 
relapse by 4 weeks posttreatment, will also be estimated and presented with 95% CIs. A 
virologic failure rate of >10% that is not due to poor compliance (> 
 in the lead-in 
group) will close the study to further enrollment. Safety will also be evaluated, including AEs 
and clinical laboratory evaluations.  
The primary efficacy endpoint is SVR12. The proportion of subjects achieving SVR12 with 
two-sided 95% CIs using the Wilson score method will be presented. Reasons for failure to 
achieve SVR12 will be summarized. 
Secondary efficacy endpoints and corresponding analyses include: 
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• The proportion of subjects in the PP population(s) experiencing virological failure 
(either on-treatment or post-treatment relapse by 12 weeks post treatment) will be 
estimated and presented with 95% CIs.  
• The proportion of subjects in the PP population(s) achieving SVR24 will be analyzed 
using the same method as SVR12.  
All subjects who receive at least one dose of either study drug will be included in the safety 
analyses.  
Study treatment exposure (such as treatment duration and total dose received) will be 
summarized with descriptive statistics.  
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The incidence and frequency of subjects with treatment-emergent adverse events 
will be tabulated by primary System Organ Class and Preferred Term. The tabulation of the 
number of subjects with treatment-emergent adverse events also will be provided by grade and 
relationship to study drug.  
Changes from baseline in laboratory tests and vital signs will be summarized. Laboratory 
abnormalities will be graded in accordance with the Division of AIDS (DAIDS) severity scale, 
where applicable. Shift tables for treatment-emergent laboratory abnormalities will be 
presented.  
The PK population will include all subjects who received at least one dose of both study drugs 
taken together and for whom evaluable plasma concentration data are available.  Plasma 
concentrations of the study drugs and metabolites will be listed by time point and summarized 
using descriptive statistics, as applicable.  
The PK-only substudy population will include all subjects who received at least one dose of 
both study drugs taken together and for whom evaluable drug concentration data are available 
for the visit when serial samples were collected. The serial PK/VK substudy population will 
include all subjects who received at least one dose of both study drugs taken together and for 
whom evaluable drug concentration and VK (HCV RNA) data are available for the visit when 
serial blood samples were collected. Derived PK parameters (e.g., maximum observed plasma 
concentration [Cmax] and area under the plasma concentration-time curve [AUC]) will be 
summarized descriptively. 
 

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LIST OF ABBREVIATIONS 
Term 
Definition 
AE(s) 
Adverse event(s) 
ALT 
Alanine aminotransferase 
APRI 
Aspartate aminotransferase-to-platelet ratio index 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration-time curve 
AUCt 
area under the plasma concentration-time curve from time 0 to the last time point (ie, 
corresponding to a quantifiable concentration) 
BEM 
Bemnifosbuvir 
BMI 
Body mass index 
CI(s) 
Confidence interval(s) 
Cmax 
Maximum observed plasma concentration 
COVID-19 
Coronavirus Disease 2019 
CRO 
Contract research organization 
DAA(s) 
Direct acting antiviral(a) 
DAIDS 
Division of AIDS 
DDI 
Drug-drug interaction 
EC50/95 
50% effective concentration 
ECG 
Electrocardiogram(s) 
eCRF 
Electronic case report form 
EDC 
Electronic Data Capture 
Emax 
Maximal effect 
EOS 
End of Study, defined as the day in which the subject completes their last assessment; the 
planned EOS is study Week 32 (i.e., 24 weeks posttreatment) 
EOT 
End of Treatment, defined as the last day study drug is administered; the planned EOT is 
at the end of Week 8 
ET 
Early termination 
EU 
European Union 
FDC 
Fixed-dose combination 
GCP 
Good Clinical Practices 
(e)GFR 
(Estimated) Glomerular filtration rate 
GT 
Genotype 
HbA1c 
Hemoglobin A1c 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCC 
Hepatocellular carcinoma 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 

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ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
LLOQ 
(Lower) Limit of quantitation 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical dictionary for regulatory activities 
NS 
Nonstructural 
NS5A 
Nonstructural protein 5A 
NS5B 
Nonstructural protein 5B 
PD 
Pharmacodynamic 
P-gp 
P-glycoprotein 
PK 
Pharmacokinetic(s) 
PP 
Per protocol 
PT 
Preferred term / Prothrombin time 
QTcF 
Fridericia-corrected QT interval  
RAV(s) 
Resistance-associated variant(s) 
RBC 
Red blood cell 
RZR 
Ruzasvir 
SAE(s) 
Serious adverse event(s) 
SAP 
Statistical analysis plan 
SVR4/12/24 
Sustained virologic response at 4/12/24 weeks posttreatment  
ULN 
Upper limit normal 
UPR 
uprifosbuvir 
VK 
Viral kinetics 
 
 

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PRINCIPAL INVESTIGATOR PROTOCOL APPROVAL 
Protocol Number: AT-01B-004 
 
TITLE:  A Phase 2, Open-Label Study to Assess the Safety and Efficacy of Bemnifosbuvir 
(BEM) and Ruzasvir (RZR) in Subjects with Chronic Hepatitis C Virus (HCV) Infection  
I have read this study protocol and agree that it contains all necessary information required to 
conduct this study. I agree to conduct the study according to this protocol and in accordance with 
Good Clinical Practices and the applicable regulatory requirements: 
 
 
 
 
_____________________________  
 
 
 
 
 
 
____________________ 
Signature  
 
 
 
 
 
 
 
 
 
 
 
 
 
Date (dd-mmm-yyyy) 
Principal Investigator 
 
 
 
 
_____________________________  
Printed Name  
Principal Investigator 

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1. 
INTRODUCTION 
1.1. 
Background 
There are approximately 58 million people globally who are chronically infected with hepatitis C 
virus (HCV), with about 1.5 million new infections occurring per year. A significant number of 
those with chronic infection will go on to develop cirrhosis, hepatocellular carcinoma, or liver 
failure, resulting in approximately 290,000 deaths each year 1. Despite the significant advances 
in treatment, HCV remains a global health burden largely owing to the epidemic of injection 
drug use, and a lack of diagnosis of many of those who have been infected.  The number of acute 
HCV cases reported in the US has increased every year during 2012–2019, with the highest rates 
in persons aged 20–39 years, consistent with age groups most impacted by the nation’s opioid 
crisis2.  Similar trends have been observed in the European Union (EU). Although improving, 
global access to HCV treatments also remains limited. Of the 58 million living with HCV 
infection globally in 2019, an estimated 9.4 million (16%) persons had been treated with direct-
acting antivirals (DAAs) by the end of 2019 1. 
Oral DAAs have drastically improved efficacy outcomes, with much improved safety profiles 
compared to the interferon-containing regimens of the past. Sustained virologic response (SVR) 
rates with oral DAA regimens (e.g., EPCLUSA®, HARVONI®, MAVYRET™), are generally 
greater than 95%, with treatment durations of 8-12 weeks for most patients, depending on the 
regimen and patient population 3,4,5.  The more difficult-to-treat patient populations include those 
with HCV genotype (GT) 3 infection, prior DAA treatment failure, or cirrhosis.  Depending on 
regimen (e.g., EPCLUSA/HARVONI), some of these populations require at least 12 weeks of 
treatment and still with adjunctive ribavirin dosing (for patients with decompensated cirrhosis). 
Furthermore, none of the approved HCV protease inhibitor-containing regimens 
(eg, MAVYRET) are indicated in patients with decompensated cirrhosis. An ideal novel regimen 
would have high efficacy with a simple 8-week or shorter treatment duration in broad patient 
populations, with improved safety (compared to protease inhibitor and ribavirin-containing 
regimens), and less drug-drug interaction potential compared to currently approved regimens. 
Atea Pharmaceuticals, Inc. is developing a novel, oral two-drug combination regimen for the 
treatment of chronic HCV infection. The two drugs in the regimen are bemnifosbuvir 
hemisulfate (referred to as bemnifosbuvir, BEM) and ruzasvir (referred to as RZR or AT-038, 
formerly known as MK-8408). BEM is a unique 6-modified purine nucleotide prodrug and RZR 
is a small molecule nonstructural protein 5A (NS5A) inhibitor of HCV.  
BEM is a hemisulfate salt of AT-511, a phosphoramidate protide that is converted after multi-
step activation to the active 5’-triphosphate metabolite (AT-9010).  AT-9010 is a potent inhibitor 
of the HCV nonstructural protein 5B (NS5B) RNA-dependent RNA polymerase after 
incorporation into HCV RNA, causing termination of chain elongation. AT-511 exhibited potent 
pan-genotypic anti-HCV activity in replicons containing NS5B sequences derived from 
laboratory reference strains of GT1a-5a, with 50% effective concentration (EC50) values ranging 
from 9 to 28 nM and having 6- to 11-fold greater intra-assay potency than sofosbuvir. Similarly, 
AT-511 showed potent pan-genotypic anti-HCV activity in replicons containing NS5B 
sequences from clinical isolates (GT1a-4d), with EC50 and 95% effective concentration values 

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ranging from 6 to 14 nM and 33 to 80 nM, respectively, which were 4- to 14-fold more potent 
than sofosbuvir. A comprehensive nonclinical development program has fully characterized the 
nonclinical pharmacology, pharmacokinetics and metabolism, and nonclinical toxicology of 
BEM. BEM has a clean nonclinical safety profile, with no target organs of toxicity identified in 
toxicology studies up to 13 weeks in duration, no evidence for genetic toxicity, no concerning 
findings in developmental and reproductive toxicology studies, and no test-article related 
findings in safety pharmacology studies. In the Phase 1 clinical study AT-01B-001 (N=88), 
healthy or HCV-infected subjects received either single or multiple doses (seven daily doses) up 
to 600 mg BEM (equivalent to 553 mg AT-511 free base). Rapid and potent pan-genotypic 
antiviral activity was observed with BEM, regardless of cirrhosis status. Mean maximum HCV 
RNA reductions of 4.4 log10 IU/mL after 7 days of dosing with BEM (553 mg free base) were 
observed in non-cirrhotic GT1 HCV-infected subjects. Similar potent antiviral activity was also 
observed in both non-cirrhotic GT3 and Child-Pugh A cirrhotic HCV-infected subjects, with 
mean maximum HCV RNA reductions of 4.5 log10 IU/mL and 4.6 log10 IU/mL, respectively, 
after 7 days of dosing with BEM (553 mg free base). Pharmacokinetic-pharmacodynamic (PK-
PD) analysis indicated that antiviral activity closely correlated with plasma exposure of AT-273. 
Maximal effect (Emax) modeling demonstrated that BEM doses of 550 mg free base will result in 
maximal viral load reduction. In the Phase 2 study AT-01B-002 (N=10), daily treatment with 
550 mg BEM and 60 mg daclatasvir was evaluated for durations of 8 to 12 weeks. Despite the 
use of a less potent first-generation HCV NS5A inhibitor, viral load decreased rapidly, with 70% 
of subjects achieving plasma HCV RNA < lower limit of quantitation (LLOQ) by Week 2 (and 
50% achieving target not detected by Week 2). Eight of the 9 subjects who received 8 weeks of 
treatment went on to achieve sustained virologic response at 12 weeks posttreatment (SVR12), 
and the single subject who received 12 weeks of treatment also achieved SVR12.  The very rapid 
early clearance of HCV RNA observed in this study supports continued evaluation of BEM with 
a more potent, next-generation HCV NS5A inhibitor. In addition, this study provided proof-of-
concept that a drug combination including BEM (albeit with a first-generation NS5A inhibitor) 
could result in SVR12 with 8 weeks of treatment. In the HCV program, BEM doses up to 550 
mg daily have been well tolerated for durations up to 8-12 weeks. Adverse events (AEs) were 
generally mild or moderate in intensity, with no clinically relevant patterns in laboratory, 
electrocardiogram (ECG), or vital signs parameters.  Additional details on the clinical and non-
clinical studies are described in the BEM Investigator’s Brochure.  
RZR was initially developed for HCV by Merck and has since been licensed by Atea after 
 
 
 with 292 subjects who received doses of RZR as a single-drug formulation, 
225 subjects who received RZR as part of a fixed-dose combination in Phase 1 studies, and 1269 
HCV GT1-6-infected subjects who had received daily RZR doses of 60 or 180 mg for 8 to 24 
weeks in Phase 2 studies as part of 2-drug and 3-drug regimens.  RZR has broad, potent pan-
genotypic activity with an EC50 ≤10 pM against subgenomic replicons from GT1-6. RZR retains 
its potent activity in full-length infectious viruses from GT1a (H77Sv3) and GT2a (JFH-1) as 
well as against GT1a resistance-associated variants (RAVs) selected by previous NS5A 
inhibitors in the clinic. Its potency is also not affected by signature RAVs from other HCV DAA 
classes. In combination with other DAAs, additive to synergistic antiviral effects were observed 
in vitro. Synergy experiments conducted in vitro by Atea in HCV GT1b replicon (Huh-luc/neo-
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ET) cells demonstrate a synergistic antiviral effect between RZR and BEM. Results of the 
nonclinical safety program have demonstrated an acceptable safety profile that compares 
favorably to other HCV NS5A protein inhibitors and supports the continued clinical 
development of RZR. Collectively, the battery of in vitro and in vivo genetic toxicity studies, 
safety pharmacology and phototoxicity studies, pivotal Good Laboratory Practice repeat-dose 
oral toxicity studies in rats up to 6 months, including a 1-month combination toxicity study in 
rats with uprifosbuvir (UPR; a nucleoside prodrug inhibitor of HCV NS5B previously developed 
by Merck) and dogs up to 9 months revealed minimal non-adverse findings.  A 13-week 
combination toxicity study in rats with BEM has also been conducted, and preliminary results 
indicate that the combination of RZR at 500 mg/kg/day and BEM at 500 mg/kg/day is well 
tolerated. Pharmacodynamic data from a Phase 1b proof-of-concept study in HCV-infected 
patients (MK-8408-003) demonstrated RZR monotherapy for 5 days achieved viral load 
reduction (> 3 log10 reductions) in HCV GT1-, 2- and 3-infected patients, supporting evaluation 
of RZR at a dose equal or greater than 10 mg in combination with other antiviral agents. Prior 
Phase 2 studies conducted by Merck evaluated the 2-drug combination regimen of RZR (60 mg 
and 180 mg) + UPR (450 mg) once daily for 12 weeks in cirrhotic or non-cirrhotic subjects 
infected with HCV GT1-6. While high SVR12 rates (>90%) were observed at both doses of RZR 
in GT1-6-infected subjects overall and who were noncirrhotic, 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Additional details on the clinical and non-clinical studies are described in the RZR Investigator’s 
Brochure. 
1.2. 
Rationale for the Dose Selection 
1.2.1. 
BEM 
A 550 mg daily dose of BEM was selected as the optimal dose for evaluation in this study. As 
described in the BEM Investigator’s Brochure, a standard Emax model was used to support this 
dose selection. As presented in Figure 1, the fitted curve indicates that Emax is achieved with 
AT-273 (guanosine nucleoside metabolite representing intracellular active triphosphate) area 
under the plasma concentration-time curve from time 0 to the last time point (AUC) greater than 
2000 ng/mL*h. Only the 600 mg/day dose of BEM (553 mg AT-511 free base equivalent) 
produced AT-273 AUC values that are consistently above the threshold of 2000 ng/mL*h. 
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Figure 1: 
Exposure-Response Analysis (Study AT-01B-001) 
 
In addition, as summarized in the BEM Investigator’s Brochure, the steady-state exposures of 
BEM and its metabolites achieved at the no-observed-adverse-effect level doses in the 13-week 
toxicology studies exceeded the steady-state exposures observed in humans, providing adequate 
exposure multiples for a daily dose of 550 mg. BEM doses at 550 mg daily have been well 
tolerated at durations of up to 8-12 weeks.   
1.2.2. 
RZR 
A daily dose of 180 mg RZR was selected as the optimal dose for evaluation in this study. As 
described in Section 1.1, prior Phase 2 studies conducted by Merck evaluated both 60 mg and 
180 mg daily doses of RZR as part of a 2-drug combination regimen with UPR. 
 
 
 
 
 
 
  
At the 180-mg dose of RZR, the target area under the concentration time curve over 24 hours 
(AUC0-24h) is 233 uM•h. Based on the animal-to-human AUC0-24h, the safety exposure multiples 
in rats at the end of 1 and 6 months of daily dosing, and in dogs at the end of 9 months of daily 
dosing, were 6-fold and 50-fold respectively, relative to this target. These data support the safety 
of RZR.  
Furthermore, RZR has been generally well-tolerated in HCV-infected patients when 
administered as once daily doses of 180 mg (282 subjects) for up to 12 weeks combined with 
UPR alone or at a daily dose of 60 mg (936 subjects) for 8 to 24 weeks in combination with UPR 
and grazoprevir.  There were no observed cardiac or renal safety signals. Drug-related serious 
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adverse events (SAEs) and drug-related discontinuations due to AEs were rare. There were no 
consistent treatment-related changes in labs, vital signs, or ECG safety parameter values. 
1.3. 
Study Rationale 
A combination of BEM and RZR has the potential to provide a convenient, protease-sparing, 
pan-genotypic treatment regimen for HCV-infected patients with or without cirrhosis. This Phase 
2 study is designed to compare the efficacy and safety of this combination therapy after 8 weeks 
of treatment. The results of this study will support future later phase studies of BEM and RZR. 
1.4. 
Risk/Benefit Assessment 
The non-clinical and clinical data summarized in the respective Investigator’s Brochures indicate 
an encouraging risk-benefit profile for BEM and RZR, supporting advancement of the 
combination to Phase 2 clinical trials with an expectation of clinical safety and marked anti-HCV 
efficacy.  
Over 750 human subjects have been exposed to BEM across both Coronavirus Disease 2019 
(COVID-19) and HCV development programs.  There have been no deaths in subjects receiving 
BEM, and none of the reported SAEs in the BEM program have been related to study drug (ie, 
investigational medicinal product [IMP]; SAEs have only been reported in the COVID-19 
program). Gastrointestinal-related AEs, specifically mild to moderate nausea and vomiting, have 
been observed more frequently at BEM doses > 550 mg twice daily (reported in the COVID-19 
program), however, tolerability at lower doses including the HCV dose of 550 mg daily has been 
comparable to placebo. In the AT-01B-002 Phase 2 study, BEM was evaluated in combination 
with a first-generation NS5A inhibitor (daclatasvir) in HCV-infected subjects for durations of up 
to 8 weeks (9 subjects) and 12 weeks (1 subject) with no safety issues. This study also provided 
proof-of-concept that a drug combination including BEM (albeit with a less potent NS5A 
inhibitor) could result in SVR12 with 8 weeks of treatment. There have been no clinically 
significant patterns in laboratory parameters or ECGs in the BEM program.  
Similarly, RZR has been evaluated in over 1800 human subjects, including 1269 HCV-infected 
subjects where RZR was administered as part of 2 and 3 drug combination regimens (including a 
nucleoside analog and protease inhibitor). In a prior Phase 2 study in 282 HCV-infected subjects, 
a daily dose of 180 mg combined with UPR was well tolerated for 12 weeks.  
For both compounds, there has been no evidence for genetic toxicity, no concerning findings in 
developmental and reproductive toxicology studies, and no test-article related findings in safety 
pharmacology studies.  Although there is substantial precedent for drug combinations including 
nucleoside analogs and NS5A inhibitors for the treatment of HCV, a 13-week combination 
toxicity study in rats with BEM and RZR has also been conducted, and preliminary results 
indicate that the combination is well tolerated.  
The present protocol mandates thorough clinical and laboratory safety monitoring, with routine 
testing. Standard serum chemistries, complete blood counts with differentials, urinalyses and 
clinical AEs will also be monitored. In addition, safety-related stopping rules for individuals 
(Section 5.6.2) and the study (Section 5.6.3) have been incorporated into the protocol to further 
reduce subject risk.  

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Subjects in clinical trials generally cannot expect to receive direct benefit from treatment during 
participation.  However, the potential benefit to subjects is that the combination regimen is 
reasonably anticipated to be a curative regimen for their HCV infection.  The likelihood of rapid 
HCV RNA clearance to non-detectable levels which can potentially result in SVR achievement 
is supported by the potent pan-genotypic anti-HCV activity observed in non-clinical virology 
studies and the clinical studies conducted to date (summarized in Section 1.1). Both compounds 
have potent pan-genotypic activity and have demonstrated SVR in the clinic in differing 
combination regimens. For BEM, SVR12 has been observed in HCV-infected subjects after 
8 weeks of treatment with a less potent, first-generation NS5A inhibitor (daclatasvir). 
Furthermore, antiviral activity of BEM after monotherapy was not diminished in GT3-infected 
subjects or those with compensated cirrhosis, populations which are generally more difficult to 
treat.  Combining BEM with a more potent NS5A inhibitor such a RZR is anticipated to result 
high rates of SVR12 after 8 weeks of treatment. Therapy with any DAA has the potential to 
select for the emergence of drug-resistant viral mutants. However, consistent with its high pan-
genotypic potency in vitro, and its retained activity against prototype nucleoside-resistant 
mutants, BEM is expected to have a high resistance barrier in HCV-infected patients. RZR 
retains its potent activity against GT1a RAVs selected by previous NS5A inhibitors in the clinic. 
Its potency is also not affected by signature RAVs from other HCV DAA classes. The 
emergence of resistance will be evaluated in this study.  
As study AT-01B-004 is designed to explore 8 weeks of treatment, a lead-in group of 60 subjects 
(non-cirrhotic male and female) will be initially enrolled and treated.  Atea will evaluate safety 
and the rate of sustained virologic response at 4 weeks posttreatment (SVR4) in the lead-in group 
before enrollment is fully opened. To mitigate the risk of treatment failures, enrollment will only 
open to the remaining 220 subjects provided that 
 in the lead-in group experience 
virologic failure that  was not due to poor compliance, and that no study stopping rules are met 
(Section 5.6.3). Additional protocol-defined virologic stopping rules (Section 5.6.1) are also 
incorporated to immediately discontinue subjects not responding to treatment. For those subjects 
who generally comply with the study protocol and experience lack of efficacy (failure to achieve 
SVR12 or sustained virologic response at 24 weeks posttreatment [SVR24]) with the 
investigational regimen, the Sponsor may reimburse the investigator for the cost of a course of 
post-study medication depending on local drug access and reimbursement policies. 
These considerations support a favorable risk/benefit profile for evaluation of BEM and RZR in 
this study. 
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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objectives 
The primary objectives of this study are:  
• To evaluate the safety and tolerability of BEM + RZR  
• To evaluate the efficacy of BEM + RZR as assessed by the proportion of subjects 
achieving SVR12  
2.2. 
Secondary Objectives 
The secondary objectives of this study are: 
• To evaluate the efficacy of BEM + RZR, as assessed by the proportion of subjects 
experiencing virologic failure (either on-treatment or post-treatment relapse [by 
12 weeks post-treatment])  
• To evaluate the efficacy of BEM + RZR as assessed by the proportion of subjects 
achieving SVR24 
2.3. 
Exploratory Objectives 
• To evaluate the effect of baseline RAVs in NS5A and/or NS5B on the efficacy of 
BEM + RZR 
• To evaluate the emergence of NS5A and NS5B RAVs in subjects who experience 
virologic failure 
• To evaluate antiviral activity/viral kinetics (VK) of BEM + RZR  
• To evaluate the PK and VK of BEM + RZR in the subgroup of subjects who agree to 
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3. 
STUDY DESIGN 
3.1. 
General Study Design 
This is an open-label trial to evaluate 8 weeks of treatment with BEM + RZR in subjects with 
chronic HCV infection (Figure 2). Approximately 280 treatment-naïve subjects with genotype 
(GT) 1, 2, 3, 4, 5, 6, or 7, either without cirrhosis or with compensated cirrhosis, will be enrolled. 
A lead-in group of 60 non-cirrhotic subjects will initially be enrolled. At 4 weeks posttreatment, 
this lead-in group will be evaluated for safety, SVR4, and virologic relapse; enrollment will open 
to the remaining 220 subjects provided that 
 in the lead-in group  experience 
virologic failure that was not due to poor compliance and no study stopping rules are met 
(Section 5.6.3). 
 
Figure 2: 
Study Design 
 
 
 
 
Subjects will be screened for up to 4 weeks, although this can be extended for up to 6 weeks for 
extenuating circumstances with Sponsor approval. Such circumstances may include awaiting 
reporting of laboratory results or scheduling assessment of cirrhosis (eg, FibroScan®) if needed. 
Re-screens may be approved on a case-by-case basis by the Sponsor (re-screened subjects will be 
assigned a new subject number). 
At the end of the screening period (Baseline; Day 1), eligible subjects will enter the treatment 
period and receive BEM + RZR for 8 weeks. After Day 1 during the treatment period, subjects 
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may self-administer study drugs (ie, IMP) at home, with the exception of subjects who agree to 
additional PK and/or PK-VK blood sampling as part of up to two substudies. These subjects will 
be required to take their study drug in the clinic on certain days (see Table 3).  
Subjects will return to the clinic for evaluations at Weeks 1, 2, 4, 6, and 8 (End of Treatment 
[EOT]) during the treatment period. 
Following their last visit of the treatment period (including subjects who prematurely discontinue 
treatment) subjects will enter the Follow-up period and return to the clinic for evaluations at 
Follow-up Weeks 4, 12, and 24.  End-of-Study (EOS) is defined as the visit at 24 weeks 
posttreatment. 
Adverse events and concomitant medications will be reviewed during visits throughout the 
treatment and follow-up periods. Subjects may also be contacted between visits to assess their 
compliance with the dosing regimen (during the treatment period) and to discuss AEs and 
concomitant medications.  
The primary endpoint is SVR12. Secondary endpoints include virologic failure and SVR24. 
Exploratory endpoints are resistance to either study drug (BEM or RZR), SVR12 in subgroups 
defined by demographics and/or baseline characteristics, HCV RNA changes from baseline and 
exposure-response relationships. Safety endpoints are the incidence of AEs, SAEs, and AEs 
resulting in treatment discontinuation; clinical laboratory abnormalities; vital sign measurements; 
and ECG parameters.  
At clinical sites that agree to participate, there will be two optional substudies (PK only; PK-
VK), each requiring separate consent; up to 100 subjects can consent to either or both. Subjects 
who consent to the PK-only substudy will provide additional blood samples at any planned 
treatment visit as early as Week 2 based on convenience for subject and investigator. Subjects 
who consent to the PK-VK substudy will provide additional blood samples a) on Day 1; and b) 
on Days 2 and 3 (24 and 48 hours after the first dose; ± 2 hours). Study drug will be administered 
at the clinic on these days (see Table 3). 
Patients with HCV or HCV patient groups were not consulted. The study conforms to many 
aspects of canonical HCV study design and patient care, as described in both health authority 
guidance 6 and clinical practice guidelines 7. 
This is a global clinical trial that complies with the European Union Clinical Trial Regulations.  
Results will be released to a publicly accessible web site (eg, Clinical Trial Information System 
[CTIS]) after the last European subject’s completion of the study. However, if the study is 
ongoing outside the EU as of that date, results will be released after the last subject’s completion 
date. 
3.2. 
Number of Subjects 
Approximately 280 subjects will be enrolled, with targets based on GT and compensated 
cirrhosis status (Table 1).  A blood sample for genotyping will be collected at screening. 
Genotype results at screening are generally not required to initiate dosing.  However, as the study 
progresses, the Sponsor may use results to help manage these enrollment targets. 

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A lead-in group of 60 non-cirrhotic subjects will be enrolled and evaluated for SVR4; enrollment 
will open to the remaining 220 subjects provided that 
 in the lead-in group  
experience virologic failure that was not due to poor compliance, and no study stopping rules are 
met (Section 5.6.3). Of the 60 subjects in the lead-in group, a target of 15 GT3-infected subjects 
will be enrolled; the remainder will be of any GT. 
Table 1: 
Planned Study Enrollment 
Total Number 
Genotype 
Enrollment Targets 
Fibrosis Stage 
N = 280 
1a 
n = 75 
F0-F4 
(Target: 20% with 
compensated cirrhosis) 
1b 
n = 40 
2 
n = 40 
3 
n = 75 
4 
n = 25 
5, 6, or 7 
n = 25 
F0-F4 
(No specified target for 
compensated cirrhosis) 
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4. 
SUBJECT SELECTION 
4.1. 
Study Population 
Subjects must meet all the inclusion criteria and none of the exclusion criteria to be eligible for 
participation in this study. A signed copy of the informed consent form will be provided to each 
subject. 
Both eligible males and females between 18 and 85 (inclusive) years of age will be enrolled in 
the study. HCV disproportionately affects more men than women, and prevalence is higher in 
people over 50 years. However, in people who inject drugs or engage in behaviors that increase 
the risk of transmitting bloodborne diseases, the risk for acquiring HCV is elevated regardless of 
sex or age. As such, including both males and females across the adult lifespan ensures that 
enrolled subjects represent the diversity of the patient population. In addition, current nonclinical 
data supports enrolling females of childbearing potential and male subjects with childbearing-
potential partners provided acceptable effective contraception is used, as specified in Section 5.9. 
4.2. 
Inclusion Criteria 
1. Willing and able to provide written informed consent 
2. Male or female subjects between ≥ 18 years of age (or the legal age of consent per local 
regulations) and ≤ 85 years of age 
3. Fridericia-corrected QT (QTcF) interval ≤ 440 ms for males and ≤ 460 ms for females at 
Screening  
Note: The mean of the triplicate readings, rounded to the nearest whole number, should 
be used to assess the QTcF. 
4. Female subjects of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or to the use of an acceptable effective contraception, as 
described in Section 5.9  
5. Females of childbearing potential must have a negative pregnancy test at Screening and 
at Day 1 prior to dosing 
6. Subjects must be DAA-treatment-naïve, defined as never exposed to an approved or 
experimental DAA for HCV  
Note: Prior exposure to (peg)interferon with or without ribavirin is acceptable, as long 
as it/they were not administered with a DAA. 
7. Willingness to provide a blood sample at Screening for genotyping. 
8. Documented medical history compatible with chronic HCV, including any one of the 
following:  
a. positive for anti-HCV antibody, HCV RNA, or an HCV GT at least 6 months prior to 
Day 1, or  
b. positive for anti-HCV antibody at Screening with clinical or laboratory evidence of 
chronic HCV disease, such as the presence of fibrosis by biopsy or noninvasive tests 

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9. HCV RNA ≥ 1,000 IU/mL at Screening. 
10. Liver disease staging assessment as follows: 
• Absence of cirrhosis (F0 to F3) defined as any one of the following: 
− Liver biopsy within 24 months of Day 1 showing absence of cirrhosis 
− Fibroscan® within 12 months of Day 1 with a result of ≤ 12.5 kPa 
− Fibrosure® (Fibrotest®) performed during screening with a score of ≤ 0.48 and 
an aspartate aminotransferase (AST)-to-platelet ratio index (APRI) of ≤ 1 
• Compensated cirrhosis (F4) defined as any one of the following: 
− Liver biopsy performed prior to Day 1 showing cirrhosis (Metavir stage 4 or 
equivalent) 
− Fibroscan® within 12 months of Day 1 showing cirrhosis with result > 12.5 kPa  
− Fibrosure® (Fibrotest®) performed during screening with a score of > 0.75 and 
an APRI) of > 2 
NOTE: Subjects in the lead-in group must not have F4 cirrhosis 
APRI formula:  AST ÷ lab upper limit of normal (ULN) for AST × 100 ÷ (platelet 
count ÷ 100). 
NOTE:  In the absence of a definitive diagnosis of presence or absence of 
cirrhosis by the above criteria, a liver biopsy or Fibroscan® is required. Liver 
biopsy results supersede the results obtained by Fibroscan® or Fibrosure®. 
11. Subject is, in the opinion of the investigator, willing and able to comply with the study 
drug regimen and all other study requirements 
4.3. 
Exclusion Criteria 
1. Female subject is pregnant or breastfeeding 
2. Co-infected with hepatitis B virus (HBV, positive for hepatitis B surface antigen 
[HBsAg]) and/or human immunodeficiency virus (HIV) 
3. Abuse of alcohol and/or illicit drug use that could interfere with adherence to study 
requirements as judged by the investigator 
4. Prior exposure to any HCV DAA 
5. Requirement of any prohibited medications, as described in Section 5.8  
6. Use of other investigational drugs within 30 days of dosing or plans to enroll in another 
clinical trial of an investigational agent while participating in the present study 
7. Subject with known allergy to the study medication(s) or any of their components 

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8. History or signs of decompensated liver disease:  ascites, variceal bleeding, hepatic 
encephalopathy, spontaneous bacterial peritonitis, or other clinical signs of portal 
hypertension or hepatic insufficiency 
9. Cirrhotic and has a Child-Pugh score >6, corresponding to a Child-Pugh Class B or C.  
Note: To calculate the Child-Pugh score, refer to the following website:  
https://www.mdcalc.com/calc/340/child-pugh-score-cirrhosis-mortality 
10. History of hepatocellular carcinoma (HCC) or findings suggestive of possible HCC 
11. Active clinically significant diseases including:   
• Evidence of history of chronic hepatitis not caused by HCV, including drug-induced 
hepatitis, hemochromatosis, Wilson’s disease, alpha-1-antitrypsin deficiency, 
alcoholic liver disease, and autoimmune hepatitis 
• Cardiac abnormalities/dysfunction that may interfere with subject treatment, 
assessment, or compliance with the protocol, including unstable angina, unstable 
congestive heart failure and unstable arrhythmia 
• Malignant disease or suspicion or history of malignant disease within previous 
5 years (except for adequately treated basal or basosquamous cell carcinoma) 
• Any medical condition requiring chronic use of immunosuppressive drugs (e.g., for 
organ transplantation). 
 
• Subject with intestinal malabsorption (eg, structural defects, digestive failure, or 
enzyme deficiencies with the exception of lactose intolerance) 
• Any other clinically significant medical condition that, in the opinion of the 
investigator, would jeopardize the safety of the subject or impact the validity of the 
study results 
12. Clinically significant abnormal ECG at Screening, as determined by the investigator. 
13. Any of the following laboratory parameters at Screening: 
• Alanine aminotransferase (ALT) or AST > 10 x ULN 
• Total bilirubin > 3 mg/dL (> 51.3 μmol/L) 
• Albumin < 2.8 g/dL (< 28 g/L) 
• International Normalized Ratio (INR) > 2.2 unless subject has a stable INR on an 
anticoagulant 
• Hemoglobin < 10 g/dL 
• Hemoglobin A1c (HbA1c) > 8.5% 
• Platelet count < 50 x 109/L 

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• Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 as estimated by the 
Modification of Diet in Renal Disease (MDRD) formula 
• Concomitant grade ≥2 toxicity of both lipase and amylase per Division of AIDS 
criteria (https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf) 
Note:  Retests of Screening laboratory parameters or assessments may be permitted 
once in certain scenarios with medical monitor approval. Such scenarios may include 
lab processing error, results inconsistent with subject’s historical values/medical 
history, or other extenuating circumstances such as a recent or intercurrent illness 
potentially affecting Screening laboratory results. 

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5. 
STUDY TREATMENTS 
5.1. 
Description and Handling of Study Treatments 
5.1.1. 
Test Products 
The study drugs will be provided by the Sponsor. BEM (manufactured by 
 
 or 
.) will be provided as 275-mg tablets (A2--275 mg tablets). 
RZR (manufactured by 
) will be provided as 90-mg capsules. 
Neither of the study drugs are authorized for marketing in any country.  Justification for the 
doses is provided in Section 1.2. 
5.1.2. 
Control Product(s) 
No control products will be used in this study. 
5.1.3. 
Packaging and Labeling 
The Sponsor will be responsible for ensuring that study drug(s) are manufactured in accordance 
with applicable Good Manufacturing Practice regulations and requirements. The labels for the 
study drug(s) will meet applicable local regulatory requirements. Refer to the Pharmacy Manual 
for specific labeling information.  
5.1.4. 
Storage and Handling 
Study drugs should be stored and handled under the conditions described on the label. 
5.2. 
Method of Assigning Subjects to Treatment 
A unique subject number will be assigned to each subject at Screening. Once assigned, it will not 
be re-assigned to another subject. All subjects will receive the same treatment regimen of BEM 
and RZR for 8 weeks.  
5.3. 
Blinding 
This study is not blinded. 
5.4. 
Dosing and Administration 
5.4.1. 
Dispensing 
Site staff will administer the first dose of study drugs at each subject’s Day 1 visit. Site staff will 
supply each subject with enough study drug.  
5.4.2. 
Administration Instructions 
Subjects will take two (2) 275-mg tablets of BEM and two (2) 90-mg capsules of RZR once 
daily for 8 weeks (56 days). Study drugs will be taken together orally in the morning, at 
CCI
CCI
CCI

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approximately the same time each day. Study drugs can be taken with water  and with or without 
food. 
For missed dose(s), subjects will be instructed to take the missed dose(s) of study drugs as soon 
as possible during the same day. Subjects will be instructed not to double the next dose with a 
missed dose (doses should be a minimum of 6 hours apart). 
In case of an incomplete dose (i.e., 1 or more tablets and/or capsules missed), the subject should 
take the rest of the missed tablets and/or capsules as soon as possible on the same day; they 
should not add the rest of the missed dose to their next dose and take more than 2 BEM tablets 
and 2 RZR capsules at the next dose. 
Subjects will receive their first dose of study drugs in the clinic on Day 1. Thereafter subjects 
may self-administer the study drugs at home except for subjects who agree to additional PK 
and/or PK-VK sampling as part of a substudy. These subjects will be required to take their study 
drug in the clinic on certain days (see Section 5.4.3 and Table 3). 
5.4.3. 
Dosing for Optional PK-only Substudy and PK-VK Substudy 
Subjects participating in the optional serial PK-only substudy and/or the optional PK-VK 
substudy will have additional blood samples collected at certain visits. The first samples will be 
collected pre-dose so study staff will remind these subjects not to take study drugs on the 
substudy visit days until instructed to do so during the visit (see Section 6.7). The date and time 
of the sample collections and dosing will be recorded. 
5.4.4. 
Treatment Compliance 
Subjects will be instructed to bring back all bottles of study drugs in their original containers at 
every study visit through EOT. Study drug dosing by the subjects will be reconciled using pill 
counts at each visit by the investigator or designee to monitor adherence to the dosing regimen.  
In addition, subjects may be contacted by site staff or visited by home nursing between 
scheduled visits to ensure compliance with the dosing schedule. 
5.5. 
Study Drug Accountability 
Investigators or designees will facilitate study drug accountability by maintaining complete and 
accurate records of all study drugs. These include acknowledging the receipt of each shipment of 
study drug, maintaining subject dispensing records, and accounting for returned or destroyed 
study drug. 
At EOS (see Section 3.1), all unused study drugs and containers will be returned to the Sponsor 
(or designee) or destroyed, per the instruction of the Sponsor.  
5.6. 
Stopping Rules 
5.6.1. 
Individual Virologic Stopping Rules 
Treatment will be discontinued in any subject with on-treatment virologic failure, defined as any 
one of the following: 

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• Confirmed 1 log10 increase in HCV RNA from post-baseline nadir 
• Confirmed increase in HCV RNA ≥ LLOQ in any subject who achieved HCV RNA 
< LLOQ 
Confirmation should be performed as soon as possible after an initial HCV RNA value that may 
indicate virologic failure is reported.  
After completion of study-related procedures in the current study, the investigator may offer an 
approved poststudy HCV treatment regimen consistent with local standard-of-care treatment 
guidelines to subjects who have on-treatment virologic failure or posttreatment virologic relapse. 
For those subjects who generally comply with the study protocol and experience lack of efficacy 
(failure to achieve SVR12 or SVR24) with the investigational regimen, the Sponsor may 
reimburse the investigator for the cost of a course of poststudy medication depending on local 
drug access and reimbursement policies. 
5.6.2. 
Individual Safety Stopping Rules 
Treatment will be discontinued in any subject who experiences any one of the following: 
• Confirmed elevation of ALT and/or AST > 5 x baseline or post-baseline nadir, and 
> 5 x ULN 
• Confirmed elevation of ALT and/or AST > 15 x ULN 
• Confirmed elevation of ALT and/or AST > 3 x post-baseline nadir, is > 3 x ULN, and 
total bilirubin > 2 x ULN, without any alternative causes or reason for these 
elevations  
• Confirmed new onset ≥ grade 3 elevation in creatinine or decreased GFR 
< 30 mL/min/1.73 m2 
• Any SAE or grade 4 AE (including any confirmed grade 4 laboratory abnormality 
reported as an AE) that are considered by the investigator to be related to study drugs, 
Note:  To warrant treatment discontinuation, a grade 4 laboratory abnormality 
should have clinical findings expected to be associated with the laboratory 
abnormality. Subjects with isolated asymptomatic laboratory abnormalities without 
any clinical correlations are allowed to remain on treatment with continued 
monitoring according to the preference of the investigator.  
• Pregnancy during treatment (i.e., in female study subjects) 
A confirmed value is defined as one that is repeated at the next subsequent test. Any of the above 
laboratory results and all ≥ grade 3 new onset laboratory abnormalities must be repeated as soon 
as possible, preferably within 48 hours upon reporting of the initial value. 
Additional follow-up and medical care, beyond what is specified in the protocol, is described in 
Section 5.6.3.  
5.6.3. 
Study Stopping Rules 
The study will be paused in any of the following scenarios: 

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• If > 3 of the first 60 subjects experience (a) confirmed elevation of ALT and/or AST 
> 5 x baseline or post-baseline nadir, and > 5 x ULN OR (b) confirmed elevation of 
ALT and/or AST > 15 x ULN OR (c) any SAE or grade 4 AE which are considered 
by the investigator to be related to study drugs 
• If > 15 subjects at any time during the trial experience (a) confirmed elevation of 
ALT and/or AST > 5 x baseline or post-baseline nadir, and > 5 x ULN OR (b) 
confirmed elevation of ALT and/or AST > 15 x ULN 
• Any SAE or grade 4 AE which is considered by the investigator to be related to study 
drugs 
• After three or more similar grade 3 or higher AEs considered by the investigator to be 
related to study drugs 
Any of these circumstances will result in no additional subjects being enrolled. Subjects who are 
tolerating treatment may continue to receive study drugs. The Sponsor will collect and review all 
the available data with the clinical investigators and with regulatory authorities, to obtain 
agreement on a plan forward. 
 
Note:  ALT/AST increases associated with virologic failure would not trigger the above stopping 
rules. 
5.7. 
Premature Discontinuation 
Subjects may voluntarily discontinue treatment or withdraw from the study at any time. They 
may also be removed from the study at the discretion of the investigator or Sponsor at any time. 
The investigator may withdraw a subject at any time if it is determined that continuing the study 
would result in a significant safety risk to the subject. 
Premature treatment discontinuation may occur for any of the following reasons: 
• Noncompliance with the protocol requirements 
• Pregnancy 
• On-treatment virologic failure, as defined in Section 5.6.1 
• Adverse event precluding further study participation due to safety concerns or 
compliance issues 
• Subject request 
• Investigator request 
• Sponsor request 
Subjects who prematurely discontinue treatment should have an Early Termination (ET) visit and 
be asked to return for the scheduled post-treatment follow-up visits. 
In subjects who require additional care after their participation in the trial has ended or been 
completed, such as that necessary to monitor an AE(s), continued follow-up and care will be 

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provided until resolution of the AE(s). For those who experience a lack of efficacy and virologic 
failure, refer to Section 5.6.1 for additional reimbursable treatment/care. 
5.8. 
Prior Therapy, Concomitant Therapy, Permitted Therapy, 
Cautionary Therapy, and Prohibited Therapy 
5.8.1. 
Prior Medication 
• Subjects must be DAA-treatment-naïve, except that prior exposure to (peg)interferon 
with or without ribavirin is acceptable as long as it was not administered with a DAA 
(inclusion criterion 7, Section 4.2). 
• Subjects are prohibited from use of other investigational drugs within 30 days prior to 
dosing in this study (exclusion criterion 6, Section 4.3) 
5.8.2. 
Concomitant Medication 
Concomitant therapy consists of any medication (eg, prescription drugs, over the counter drugs, 
vaccines, herbal or homeopathic remedies, nutritional supplements) used by a subject in addition 
to study drug treatment. All such medications should be reported to the investigator and recorded 
on the Concomitant Medications electronic Case Report Form (eCRF).  Concomitant 
medications should be used according to their label. 
5.8.3. 
Permitted Therapy 
Subjects are also permitted to use the following therapies during the study: 
• Acetaminophen (paracetamol), ibuprofen 
• Anti-inflammatory drugs 
• Prophylactic anticoagulation with low-dose aspirin, direct factor Xa inhibitors, or 
direct thrombin inhibitors 
• Prescribed medications for concomitant conditions as per medical history, such as 
chronic supplementary oxygen, antihypertensives, antidiabetic medications, 
rheumatologic medications, or respiratory medications (e.g., chronic 
inhaled/intranasal/oral steroids) 
• Hormonal contraceptives (see Section 5.9) 
• Hormone replacement therapy 
• Direct acting COVID medications (Paxlovid, molnupiravir, remdesivir, favipiravir, 
monoclonal antibodies, convalescent plasma). See Section 5.8.5 for additional details. 
• Other COVID standard-of-care (SOC) therapies without direct antiviral effects (i.e., 
corticosteroids) 
5.8.4. 
Cautionary Therapy 
Herbal Therapies 

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Concomitant use of herbal therapies is not recommended because their PK, safety profiles, and 
potential drug-drug interactions (DDIs) are generally unknown. 
Mitigation of Other Potential DDIs 
COVID treatments with concerns for DDIs: 
While remdesivir and Paxlovid are permitted, staggered dosing as specified below must be 
followed to minimize DDI. 
Remdesivir: 
As BEM and remdesivir share a common target and metabolic activation pathway, there is a 
potential for PK or PD drug interactions between the two, during concomitant administration of 
both drugs. Study drug must be dosed at least 2 hours before remdesivir. 
Paxlovid: 
As ritonavir is a major P-glycoprotein (P-gp) inhibitor (see below), subjects enrolled in the study 
who are taking Paxlovid should not take Paxlovid until at least 2 hours after taking BEM/RZR. 
See below for additional P-glycoprotein – based DDIs 
For more details regarding potential DDIs, refer to the BEM and RZR Investigator’s Brochures. 
P-glycoprotein-Based Inhibition 
Concomitant use of P-gp inhibitors is permitted but must be taken at least 2 hours after 
administration of study drug. Common examples of P-gp inhibitors include cyclosporine, 
carvedilol, imidazoles, macrolides, ritonavir, and verapamil. 
For a full list of P-gp inhibitors, refer to:  https://go.drugbank.com/categories/DBCAT002667 
Subjects taking digoxin must do so at least 2 hours after taking study drug. 
Gastrointestinal Acid Reduction-Based Interaction 
Gastrointestinal acid reducing agents such as proton-pump inhibitors, H2 blockers and antacids 
may reduce the solubility of BEM. Subjects taking these agents will do so at least 2 hours after 
taking study drug. 
Permitted concomitant medications should be administered only as medically necessary during 
the study. Any use of concomitant medications should be recorded and entered into the case 
report form.  
For more details regarding the effects of co-administered therapies on RZR and BEM, refer to 
the respective Investigator’s Brochures. 
5.8.5. 
Prohibited Therapy 
Concomitant use of the following is prohibited: 
• Investigational drugs (other than protocol-mandated study treatment) 
• HCV treatments (other than protocol-mandated study treatment)  
• Hydroxychloroquine or amiodarone 

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• Strong and moderate inducers of cytochrome P450 3A and/or P-gp including anti-
infectives (nafcillin, rifampin), anticonvulsants (carbamazepine, phenytoin, 
phenobarbital), endothelin antagonists (bosentan), and wakefulness-promoting agents 
(modafinil). For a comprehensive list of cytochrome P450 3A inducers, refer to: 
https://go.drugbank.com/categories/DBCAT000492; for a comprehensive list of P-gp 
inducers, refer to: https://go.drugbank.com/categories/DBCAT002666  
5.9. 
Contraception Requirements 
A female is considered to be of childbearing potential if she is postmenarchal, has not reached a 
postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than 
menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian 
tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian 
agenesis). The definition of childbearing potential may be adapted for alignment with local 
guidelines or regulations. Females of childbearing potential must be established on their chosen 
method of contraception at screening. 
Female subjects of childbearing potential must agree to remain abstinent (refrain from 
heterosexual intercourse) or use one of the following methods of acceptable effective 
contraception 8 during the treatment period and for 30 days after the final dose of study drugs: 
• Bilateral tubal ligation 
• Male sterilization 
• Hormonal contraceptives 
• Intrauterine devices (whether or not they are hormone-releasing) 
• Male or female condom with or without spermicide (male and female condom cannot 
be used together) 
• Sexual abstinence  
Note: The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the subject. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation 
methods) and withdrawal are not adequate methods of contraception. If required per 
local guidelines or regulations, locally recognized adequate methods of contraception 
and information about the reliability of abstinence will be described in the local 
Informed Consent Form (ICF). 
• Cap, diaphragm, or sponge with spermicide. 
Should acceptable effective methods of contraception be more restrictive than the methods listed 
above per local regulations, guidance, or investigator practice, a more restrictive list may be 
included within the site/country-specific Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC)-approved ICF. 
 

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6. 
STUDY PROCEDURES AND GUIDELINES 
Study-specific assessments are summarized in Table 2. An “X” indicates when the assessments 
are to be performed. The screening window is 28 days but may be extended to 42 days for 
extenuating circumstances with Sponsor approval. Such circumstances may include awaiting 
reporting of laboratory results or scheduling assessment of cirrhosis (e.g., FibroScan®) if 
needed. 
When feasible, visits may be conducted remotely (e.g., via telephone or telemedicine), in clinic, 
or at home. 
 

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Table 2: 
Schedule of Assessments 
Screeninga  Baseline 
Treatment Period 
Follow-up Period 
± 1 day 
± 3 days 
 
+ 3 days 
ET 
Following Last Treatment Visit; 
± 5 days 
Study Week/Day: 
Day -28 to 
Day -1 
Day 1b 
Week 
1 
Day 8 
Week 2 
Day 15 
Week 4 
Day 29 
Week 6 
Day 43 
Week 8 
Day 57c 
Week 4 
Week 12 
Week 
24 
Eligibility 
Informed consent 
X 
Medical history 
X 
Demographics 
X 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Physical Examination and Vital Signs 
Complete physical examination 
X 
X 
X 
X 
Symptom-targeted examination  
X 
X 
X 
X 
X 
Vital signs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height (screen only) and weight 
X 
X 
 
 
X 
 
X 
X 
 
 
 
Triplicate 12-lead ECGd 
X 
X 
X 
X 
X 
X 
Liver staging 
X 
 
 
 
 
 
 
 
 
 
 
Laboratory 
Clinical labs and urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
HBV (HBsAg), HCV (anti-
HCV Ab), and HIV screen; 
hemoglobin A1c 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy teste 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
Pharmacodynamics and Pharmacokinetics 
HCV genotyping 
X 
 
 
 
 
 
 
 
 
 
 
HCV RNA quantitation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Viral resistance samplef 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Screeninga  Baseline 
Treatment Period 
Follow-up Period 
± 1 day 
± 3 days 
 
+ 3 days 
ET 
Following Last Treatment Visit; 
± 5 days 
Study Week/Day: 
Day -28 to 
Day -1 
Day 1b 
Week 
1 
Day 8 
Week 2 
Day 15 
Week 4 
Day 29 
Week 6 
Day 43 
Week 8 
Day 57c 
Week 4 
Week 12 
Week 
24 
PK Sampleg 
X 
X 
X 
X 
X 
X 
X 
Optional PK-only substudyh 
 
 
 
Serial blood sampling at any treatment period visit as early as 
Week 2 
 
 
 
Optional PK/VK substudyh 
 
Days 1, 2, and 3 
 
 
 
Study Intervention 
Study drug administration 
 
X 
At-home dosing for full treatment period (Days 1-56) unless 
otherwise specified 
 
 
 
 
Review compliance with study 
drugsi 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Adverse Event and Concomitant Medication Monitoring 
Concomitant medicationsi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
AEsi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
SAEsi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs = adverse events; anti-HCV Ab = anti-HCV antibody; APRI = aspartate aminotransferase (AST) to platelet ratio index; BMI = body mass index; ECG(s) = 
electrocardiogram(s); ET = early termination; HBsAg = Hepatitis B virus surface antigen; HBV = Hepatitis B virus; HCV = Hepatitis C virus; HIV = Human Immunodeficiency 
virus; PK = pharmacokinetic; SAEs = serious adverse events; VK = viral kinetics 
a Screening window may be extended to 42 days for extenuating circumstances with Sponsor approval. 
b Day 1 assessments performed prior to dosing. 
c The last dose is on Day 56. The last visit of the treatment period shall occur no sooner than Day 57 and no later than Day 60 (inclusive). 
d Three consecutive determinations collected, with no less than 1 minute between individual ECGs. Complete ECGs prior to any blood draws. 
e For females of childbearing potential, serum or urine is acceptable. 
f Plasma samples collected for resistance testing. At least one baseline resistance sample is needed (Screening and/or Day 1 predose); there is no protocol 
deviation if there is one evaluable baseline sample for resistance testing. In addition, the resistance sample is not required for screening and eligibility purposes. 
g On Day 1, the PK sample will be obtained predose. The sampling time and time of last dose must be recorded. 
h See Table 3  
i Subjects may be contacted between visits to assess compliance, concomitant medications, and AEs/SAEs. 

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Table 3: 
Optional PK-only and PK-VK Substudies:  Sampling Schedule 
Visit 
Serial PK-Only Substudy 
Sampling Time  
Serial PK/VK Substudy Sampling Time 
 
Day 1 
Not applicable a 
PK Sample a: 0.5 (± 15 minutes),  
1 (± 15 minutes), 2, 3, 4, 6, 8 hours postdoseb 
VK Sample a: 0.5 (± 15 minutes),  
1 (± 15 minutes), 2, 3, 4, 6, 8 hours postdoseb 
Day 2 
Not applicable 
PK Sample: Pre-dose (~24 hours post Day 1 dose) c 
VK Sample: Pre-dose (~24 hours post Day 1 dose) c 
Day 3 
Not applicable 
PK Sample: Pre-dose (~48 hours post Day 1 dose) c 
VK Sample: Pre-dose (~48 hours post Day 1 dose) c 
Any planned 
Treatment-Period Visit, 
as early as Week 2 a 
0.5 (± 15 minutes), 1 (± 15 
minutes), 2, 3, 4, 6, and 8 
hours postdoseb 
Not applicable 
 a No additional predose samples are needed on Day 1 for either substudy nor at the Week 2 (or later) visit for the 
PK-only substudy; the results of the pre-dose PK and viral load samples that will be collected as part of the main 
study visit schedule will also be used as pre-dose values for the substudy analyses. 
b ± 30-minute sampling window for postdose samples, unless otherwise specified. 
c ± 2-hour sampling window 
PK = pharmacokinetic; VK=viral kinetics 
6.1. 
Medical History and Demographics 
± 2-hour sampling window 
Complete medical history will be obtained at Screening. Information about HCV disease history 
will be collected, including prior treatments (if treatment-experienced), response to prior 
treatment and prior assessment(s) of cirrhosis (if available). Subjects will also be questioned 
about alcohol and drug use. 
Demographic data (age, gender, ethnicity/race, body weight, height, Body Mass Index [BMI]) 
will be recorded.  
6.2. 
Physical Examination and Body Weight 
A complete physical examination will be performed by a medically qualified individual at 
specified visits. The complete physical examination will include a review of the following: head 
and neck, ears/nose/throat, lymph nodes, heart, lungs, abdomen, musculoskeletal, neurological, 
skin, and general appearance.   
At visits not requiring a complete physical examination, a symptom-targeted physical exam will 
be done if medically indicated. 
Body weight will be recorded, and BMI will be calculated at specified visits (height is to be 
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6.3. 
Vital Signs 
Vital sign measurements (body temperature, pulse rate and blood pressure) will be measured at 
each specified visit after subjects have had at least 3 minutes of rest. Vital signs can also be 
monitored during the study when judged necessary by the investigator or designee. 
6.4. 
12-Lead Electrocardiogram 
Triplicate ECGs will be collected after subjects are supine for 5 minutes. Each reading will be 
performed no less than 1 minute apart from each other. The mean QTcF value from the three 
readings will be used to include subjects in the study (per the inclusion criterion) and mean 
values of the triplicate readings will be used for analysis. 
For visits in which ECGs and blood draws are both performed, ECGs will be conducted prior to 
the blood draw since the blood draw can impact the ECG reading. 
6.5. 
Liver Staging 
Liver staging is to be determined at Screening as specified in inclusion criterion 10 (Section 4.2). 
6.6. 
Laboratory Evaluations 
Clinical laboratory evaluations will be performed at specified visits. The following tests will be 
conducted only at Screening: 
• Serologies for HCV (anti-HCV antibody), HBV (HBsAg), and HIV 
• HbA1c 
The following hematology, serum chemistry, coagulation, and urinalysis evaluations will be 
conducted at specified visits. The investigator or designee will assess each abnormal value to 
determine if it is clinically significant.  
• Hematology: hematocrit, hemoglobin, platelet count, red blood cell count, white 
blood cell count with differential (absolute) including lymphocytes, monocytes, 
neutrophils, eosinophils, basophils, reticulocyte count, and mean corpuscular volume 
• Coagulation: INR, prothrombin time 
• Chemistry: ALT, AST, albumin, alkaline phosphatase, creatine kinase, creatinine, 
blood urea nitrogen or urea, eGFR calculation (MDRD), total bilirubin (reflex to 
direct bilirubin), glucose, amylase, lipase, potassium, sodium, bicarbonate, or total 
carbon dioxide 
• Urinalysis: appearance, blood, color, glucose, leukocyte esterase, pH, protein, 
urobilinogen. Reflex to microscopic urinalysis if dipstick result is abnormal 
• Serum or urine pregnancy test on females of childbearing potential 
Laboratory samples will be sent to a central laboratory for analysis. However, for an individual 
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laboratory to obtain “STAT” results, if needed for safety assessment, this includes Screening 
assessments.  
The total volume of blood withdrawn during the course of the study should not exceed 500 mL 
per subject over any two-month period. However, it is possible that the total blood donation may 
be higher if repeat blood samples are required for safety assessments. 
6.7. 
Pharmacodynamics and Pharmacokinetics 
6.7.1. 
Hepatitis C Virus Genotyping, RNA Levels, and Mutation Analysis 
• HCV genotyping will be performed at Screening 
• HCV RNA levels will be determined at Screening, Baseline and at each subsequent 
visit 
Note:  HCV genotyping and HCV RNA quantitation will be performed using a 
validated commercial assay. 
• Samples will be collected at each visit to assess resistance.  
Additional samples for assessing HCV RNA levels will be obtained in an optional PK-VK 
substudy, which is described in Section 6.7.3. 
6.7.2. 
Pharmacokinetic Sampling for All Subjects 
For all subjects, a single blood sample for PK analysis will be collected at Baseline (before the 
first dose; Table 2); the sampling time will be recorded. During the other planned treatment 
period visits, a single blood sample for PK analysis will be obtained before the subject is 
released from the clinic; the date and time of the last dose of study drugs and of the PK sample 
will be recorded. 
Additional samples for PK analyses will be obtained as part of the optional PK-only substudy 
described in Section 6.7.3. 
6.7.3. 
Optional Substudies 
At clinical sites that agree to participate, optional PK-only and PK-VK substudies will be 
conducted on approximately 100 subjects who provide consent to participate in either or both 
substudies (Table 3).  In addition to the samples normally collected at scheduled visits, these 
subjects will provide additional samples as shown in Table 3. Subjects participating in either or 
both of these studies should take their study drug in the clinic on sampling days after the predose 
samples are collected. 
Date and time will be recorded for the following: 
• last dose of study drug 
• each PK and/or VK sample collection 
• dosing   

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Blood samples will be collected by direct venipuncture. However, as an option to the subject or 
if judged necessary by the clinical staff, blood samples may be collected from an indwelling 
cannula (stylet catheter that requires no flushing), which will be placed in the forearm vein of the 
subject. 
6.7.4. 
Sample Processing, Storage, and Shipping 
All samples will be processed, split (as applicable), stored, and shipped according to the sample 
processing instructions supplied by the central laboratory. 
Blood samples may be stored for up to 10 years under the control of the Sponsor. Samples may 
be used by the Sponsor, Sponsor partner, or by other companies belonging to or collaborating 
with the Sponsor only for the testing specified in this protocol. 
6.7.5. 
Bioanalytical Methods for Pharmacokinetic Samples 
Plasma concentrations of the study drugs and their metabolites (as appropriate) will be measured 
according to validated bioanalytical methods. Samples from all subjects who received at least 
one dose of both study drugs will be analyzed. 

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7. 
ADVERSE EVENTS 
7.1. 
Definitions 
An AE is defined as any untoward medical occurrence in a subject administered a medicinal 
product(s) and which does not necessarily have to have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (for example, an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product(s), whether or not considered related to this medicinal product(s). The worsening of a 
pre-existing condition (i.e., clinically significant change in frequency and/or intensity) that 
occurs during study participation is also an AE. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
drug(s) caused the AE. ‘Reasonable possibility’ means there is evidence to suggest a causal 
relationship between the drug(s) and the AE. A suspected adverse reaction implies a lesser 
degree of certainty about causality than adverse reaction, which means any AE caused by a 
drug(s). 
An AE may be: 
• A new illness 
• Worsening of a concomitant illness 
• An effect of the study medication(s); it could be an abnormal laboratory value as well 
as a significant shift from baseline within normal range which the qualified 
investigator or medically qualified designate considers to be clinically significant 
Symptoms or conditions reported prior to consent are not AEs; these will be recorded as part of 
medical history. 
Surgical procedures themselves are not AEs. They are therapeutic measures for conditions that 
required surgery. The condition for which the surgery is required is an AE, if it occurs/, or 
worsens during the study period. Planned (elective) surgical measures and the conditions(s) 
leading to these measures are not AEs, if the condition(s) existed or was (were) known before the 
time of informed consent. In the latter case, the condition should be reported as medical history. 
An SAE or reaction is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity (defined as a substantial 
disruption of a person’s ability to conduct normal life functions) 
• Is a congenital anomaly or birth defect 

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• Is an important medical event that may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed above (according to medical 
judgment of the qualified investigator) 
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities that require medical or surgical intervention or lead to study 
drug interruption, modification, or discontinuation must be recorded as an AE, as well as an 
SAE, if they meet the definition above. In addition, laboratory or other abnormal assessments 
(eg, ECG, X-rays, vital signs) that are associated with signs and/or symptoms must be recorded 
as an AE or SAE if they meet the definition of an AE or SAE as described above. If the 
laboratory abnormality is part of a syndrome, record the syndrome or diagnosis (e.g., anemia), 
not the laboratory result (i.e., decreased hemoglobin). Laboratory abnormalities that do not 
require medical intervention or action are generally not considered AEs. 
Laboratory abnormalities will be graded based on the Division of AIDS (DAIDS) Table for 
Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 9. If a value falls within 
the local laboratory normal range, then it will not be graded. For AEs associated with laboratory 
abnormalities, the event should be graded on the basis of the clinical severity in the context of 
the underlying conditions; this may or may not be in agreement with the grading of the 
laboratory abnormality. 
7.1.1. 
Severity Assessment 
The investigator or the designated person will provide an assessment of the severity of each AE 
by recording a severity rating on the appropriate AE reporting page of the subject’s eCRF. In 
classification of AEs, the term “severe” is not the same as “serious.” Severity is a description of 
the intensity of a specific event (as in mild, moderate, or severe chest pain). The term “serious” 
relates to a participant/event outcome or action criteria, usually associated with events that pose a 
threat to a participant’s life or functioning and meets one or more of the SAE criteria described 
above. 
The DAIDS criteria 9 will also be used for assessing AEs. All AEs will be graded as grade 1 
(mild), grade 2 (moderate), grade 3 (severe), grade 4 (potentially life-threatening), or grade 5 
(death) according to the DAIDS criteria. Every effort will be made to obtain an adequate 
evaluation of the severity. 
7.1.2. 
Causality Assessment 
The qualified investigator or a medically qualified designate will determine the relationship of 
any AE to study drugs using the following guidelines in Table 4. 

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Table 4: 
Adverse Event Relationship to Study Drug 
Relationship to Drug 
Comment 
Reasonable Possibility 
There is evidence to suggest a causal relationship between the drug(s) and the 
adverse event (eg, the adverse event is uncommon and known to be strongly 
associated with drug exposure or is uncommon in the study population, but not 
commonly associated with drug exposure). 
No Reasonable Possibility 
There is no evidence to suggest a causal relationship between the drug(s) and 
the adverse event. 
7.2. 
Routine Reporting 
For the purposes of this study, all AEs (serious and non-serious) will be recorded in the eCRF 
from the time of informed consent until 4 weeks after the last dose of study drugs. All SAEs will 
be recorded from the time of informed consent until the end of the study. 
During these periods, all AEs spontaneously reported by the subject, observed by the clinical 
staff, or elicited by general questioning will be recorded and reported in the eCRF. 
Any AE which remains unresolved as of the last visit will require follow-up until the AE has 
been resolved, a reasonable explanation for its persistence found, or is deemed chronic or stable 
by the investigator. It is the investigator’s responsibility to ensure subjects experiencing AEs 
receive appropriate follow-up, treatment where required, and that every action is well 
documented. 
Classification of AEs will be performed by System Organ Class and Preferred Term using The 
Medical Dictionary for Regulatory Activities (MedDRA). 
Electronic case report form procedures for AE and SAE reporting can be found in the eCRF 
completion guidelines. Paper SAE forms are to be used only if the Electronic Data Capture 
(EDC) system is unavailable. 
7.3. 
Serious Adverse Event Reporting 
Clinical sites must notify the Sponsor and its designee 
 of any SAE, without 
regard to causality, within 24 hours after becoming aware of its occurrence. Any non-serious AE 
which worsens and eventually meets the criteria for an SAE must also be reported as a new SAE. 
Information regarding SAEs will be transmitted using the Serious Adverse Event Form in the 
EDC system; this form must be completed by a member of the investigational site staff within 
24 hours of awareness. The form should include a clearly written narrative describing signs, 
symptoms and treatment of the event, diagnostic procedures, as well as any relevant laboratory 
data and an assessment of the causal relationship between the event and the investigational 
product(s). Information not available at the time of the initial report (e.g., an end date for the AE, 
laboratory values received after the report, or hospital discharge summary) must be reported as 
soon as it is available.  
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In the event EDC entry is not possible (e.g., system failure or access problems at the site), the 
site should complete the paper Serious Adverse Event Form and provide it within 24 hours of 
awareness to the contacts listed below:  
Email (primary): 
 
 
Fax (back-up): 
 
 
Email (back-up): 
 
 
Contact information for the Sponsor’s physician is also listed below, should the sites need to 
contact the Sponsor to discuss any medical, safety-related questions or SAEs: 
 
 
 
  
 
If 
 is not reached by telephone call, and does not confirm receipt of a notifying text or 
email, the following Atea Clinical contact should be notified: 
 
 
 
 
An unlisted (unexpected) AE is one in which the nature or severity is not consistent with the 
applicable product reference safety information. For investigational product(s), the expectedness 
of an AE will be determined by whether or not it is listed in the Investigator’s Brochure(s). At 
this time in the clinical development of BEM, there are no clinical AEs or clinically significant 
laboratory abnormalities that are considered to be “expected” with BEM, at any dose level. 
Investigators will be notified, and the Investigator Brochure will be updated, if any pattern of 
tolerable AEs or laboratory abnormalities is found to be related to BEM dosing during studies 
going forward. 
All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the subject’s participation in the study, must be followed until any of the 
following occurs: 
• the event resolves; 
• the event stabilizes; 
• the event returns to baseline if a baseline value is available; 
• the event can be attributed to agents other than the study drugs or to factors unrelated 
to study conduct; 
PPD
PPD
PPD
PPD
PPD
PPD

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• it becomes unlikely that any additional information can be obtained (subject or health 
care practitioner refusal to provide additional information, lost to follow-up after 
demonstration of due diligence with follow-up efforts). 
Any SAE reports will be reported by the investigators (or designee) to their local IRB/IEC in 
accordance with local reporting requirements and reporting timelines. 
Similarly, the Sponsor (or designee) will determine whether an SAE must be reported in an 
expedited manner to regulatory authorities, in accordance with local requirements. If so, the 
Sponsor (or designee) will report the event to the local regulatory authorities (eg, EudraVigilance 
Clinical Trials Module) in accordance with applicable reporting timelines. Aggregate and 
periodic reporting (e.g., annual report, DSUR, etc.) to regulatory authorities will be satisfied 
based on local requirements.  
7.4. 
Pregnancy Reporting 
From Day 1 through the last follow-up visit (or until 30 days after the last dose of study drug for 
subjects who prematurely discontinue and do not enter the follow-up period), all initial reports of 
pregnancy in female subjects must be reported to the Sponsor (or designee) using the contact 
information described in Section 7.3.  
Within 24 hours of their knowledge of the event, investigational staff must complete and submit 
the Pregnancy Notification Form . Pregnancies will be followed up to determine the outcome, 
including spontaneous or voluntary termination, details of birth, presence or absence of any birth 
defects, congenital anomalies or maternal and/or newborn complications. After the expected 
pregnancy end date, the Sponsor or designee will provide the site with the designated Pregnancy 
Outcome Form for completion and reporting to the 
 Abnormal pregnancy 
outcomes are considered SAEs and must be reported using the designated Serious Adverse Event 
Form.  
Any female study subject who becomes pregnant during treatment must immediately discontinue 
study drugs. 
Pregnancy reporting will be in accordance with local requirements, and may be adapted per 
country as required by regulations. 
 
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8. 
STATISTICAL ANALYSES 
The following sections briefly summarize the statistical analysis. A statistical analysis plan 
(SAP) describing the detailed methodology will be prepared prior to database lock. 
Results of all efficacy analyses will be presented by genotype and cirrhotic status. 
Interim and final analyses will be reported/posted in accordance with local/regional 
requirements. 
8.1. 
Analysis Populations 
8.1.1. 
Screened Patients 
Screened Patients will include subjects who have signed the study informed consent. 
8.1.2. 
Safety Population 
The safety population will include all subjects who received at least one dose of either study 
drug. 
8.1.3. 
Per Protocol Population 
The PP population will consist of all subjects who: 
• Meet all inclusion/exclusion criteria 
• Do not receive concomitant medications that are prohibited due to their potential impact 
on HCV viral load or the pharmacokinetic concentration of either agent (BEM or RZR) 
• Have a collected or imputed posttreatment viral load assessment at posttreatment Week 
12 (posttreatment Week 4 for lead-in subjects) unless the subject discontinues early for 
virologic failure or AE, in which case the ET visit may be used 
• Complete treatment (being in ≥90% compliance with the study drug regimen), 
discontinue treatment early due to virological failure or discontinue treatment early due to 
a drug-related AE 
Note:  Compliance will be calculated using drug compliance data collected on the eCRF. 
The Sponsor expects approximately 95% of the enrolled subjects to meet these criteria. 
This population will be used for all efficacy analyses.  
8.1.4. 
PK Compliant Per-Protocol (PK-PP) Population 
The PK Compliant Per-Protocol Population will include subjects who: 
• Meet all inclusion/exclusion criteria. 
• Do not receive concomitant medications that are prohibited due to their potential impact 
on HCV viral load or the pharmacokinetic concentration of either agent (BEM or RZR). 

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• Have a collected or imputed posttreatment viral load assessment at posttreatment Week 
12 (posttreatment Week 4 for lead-in subjects), unless the subject discontinues early for 
virologic failure or AE, in which case the ET visit assessment may be used. 
• Complete treatment, discontinue treatment early due to virological failure, or discontinue 
treatment early due to a drug-related AE. 
− Completing treatment is defined as being in ≥90% compliance with the study drug 
regimen (as calculated using drug compliance data collected on the eCRF), and 
− Adequate exposure will be corroborated by a Pharmacokinetic Review Committee 
that is blinded to all other study data. The PK Review Committee will utilize trough 
PK measurements collected during the dosing period of the study. 
All efficacy analyses will be performed on this population. 
8.1.5. 
Pharmacokinetic Populations 
The PK population will include all subjects who received at least one dose of both study drugs 
taken together and for whom evaluable plasma concentration data are available. 
The serial PK-only substudy population will include all subjects who received at least one dose 
of both study drugs taken together and for whom evaluable drug concentration data are available 
for the visit when serial blood samples were collected. The serial PK/VK substudy population 
will include all subjects who received at least one dose of both study drugs taken together and for 
whom evaluable drug concentration and VK (HCV RNA) data are available for the visit when 
serial blood samples were collected. 
8.2. 
Endpoints 
8.2.1. 
Primary Endpoint 
The primary efficacy endpoint is SVR12.  
8.2.2. 
Secondary Endpoints 
Secondary efficacy endpoints include: 
• Virologic failure  
• SVR24. 
8.2.3. 
Exploratory Endpoints 
Exploratory endpoints include: 
• Resistance to either study drug (BEM or RZR) 
• SVR12 in subgroups defined by demographics and/or baseline characteristics 
• HCV RNA changes from baseline 
• Exposure-response relationships 

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8.2.4. 
Safety Endpoints 
Safety endpoints are the incidence of AEs, SAEs and, AEs resulting in treatment discontinuation; 
clinical laboratory abnormalities; vital sign measurements; and ECG parameters. 
8.3. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics (including age, sex [male/female], race [American 
Indian or Alaska Native; Asian; Black or African American; Native Hawaiian or Other Pacific 
Islanders; White; Other], region, BMI, weight) will be summarized using means, standard 
deviations, medians, and ranges for continuous variables and proportions for categorical 
variables, as appropriate. Summaries will be presented by treatment group. Demographics and 
baseline characteristics will be listed by subject. Other data to be listed by subject will include 
urinary drug screen, serology results, medical history, baseline physical examination findings, 
and prior and concomitant medications. 
8.4. 
Efficacy Analyses 
8.4.1. 
Primary Analyses 
In this analysis, results are pooled across genotypes and cirrhosis status as it is expected that 
efficacy will be consistent across these groups. To evaluate the robustness of results, additional 
analyses, including summarization by genotype and cirrhosis status, will be carried out.  
The proportions of subjects in the PP population(s) achieving SVR12 will be estimated and 
presented with associated two-sided 95% confidence intervals (CIs), which will be constructed 
using the Wilson score method.  Reasons for failure to achieve SVR12 will be summarized. 
8.4.2. 
Secondary Analyses 
Secondary analyses will include: 
• The proportion of subjects in the PP population(s) experiencing virologic failure (on 
treatment or post-treatment relapse) by 12 weeks post treatment), estimated and 
presented with 95% CIs. 
• The proportion of subjects in the PP population(s) achieving SVR24, analyzed using 
the same method as for SVR12.  
Additional exploratory analyses will be performed and may include (but not be limited to) the 
following: 
• The proportion of subjects in the PP population(s) achieving SVR12 by baseline 
NS5A and NS5B RAVs (yes/no), estimated and presented with 95% CIs.  
• Emergence of NS5A and NS5B RAVs in the PP population(s), tabulated with 
proportions and CIs in subjects who experience virologic failure  
• Assessment of response (e.g., SVR12 rates) by demographics and/or baseline 
characteristics including prior HCV treatment, baseline viral load, etc. 

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• HCV RNA change from baseline over time 
• Exposure-response relationships 
Additional details will be provided in the SAP. 
8.5. 
Safety Analyses 
Study treatment exposure (such as treatment duration and total dose received) will be 
summarized with descriptive statistics.  
Treatment-emergent AEs and graded laboratory abnormalities, defined as any new or worsening 
AE/laboratory parameter beginning on or after the first dose of study drugs through 4 weeks after 
the last dose, will be included in the analysis. 
Incidence and frequency of subjects experiencing AEs, SAEs, AEs resulting in treatment 
discontinuation, and AEs resulting in study discontinuation will also be summarized. Adverse 
events will be coded using MedDRA. The incidence and frequency of subjects with treatment-
emergent adverse events will be tabulated by primary SOC and PT. The tabulation of the number 
of subjects with treatment-emergent AEs will also be provided by grade and relationship to study 
drug.  
Changes from baseline in laboratory tests and vital signs will be summarized. Laboratory 
abnormalities will be graded in accordance with the DAIDS severity scale9 where applicable. 
Shift tables for treatment-emergent laboratory abnormalities will be presented. 
8.6. 
Pharmacokinetic Analyses 
Plasma concentrations of the study drugs and metabolites over time will be listed by time point 
and summarized using descriptive statistics, as applicable.  
Derived PK parameters (e.g., Cmax and AUC) will be summarized descriptively for subjects 
participating in the optional substudy.  
Additional details will be provided in the SAP. 
8.7. 
Interim Analyses 
An interim analysis will be performed on data from the lead-in group using the PP population(s). 
The proportion of subjects achieving SVR4, defined as HCV RNA < LLOQ at 4 weeks 
posttreatment, will be presented with 2-sided 95% CIs using the Wilson score method. Virologic 
failure, defined as either on-treatment failure or posttreatment relapse by 4 weeks posttreatment, 
will also be estimated and presented with 95% CIs. A virologic failure rate of >10% that is not 
due to poor compliance (> 
 in the lead-in group) will close the study to further 
enrollment.  
Safety will also be evaluated, including AEs and clinical laboratory evaluations. The study will 
also be closed to further enrollment if any study stopping rules are met (Section 5.6.3). 
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9. 
ETHICS 
9.1. 
Institutional Review Board (IRB)/ Independent Ethics Committee 
(IEC) 
This protocol and the ICF will be submitted to an IRB or IEC prior to initiation of the study and 
the study will not start until the IRB or IEC, as applicable, has approved the documents. 
9.2. 
Ethical Conduct of the Study 
This study will be conducted in compliance with the study protocol, the ethical principles in the 
latest version of the Declaration of Helsinki, the International Conference on Harmonisation 
(ICH) Guideline E6 (R2) for Good Clinical Practices (GCP) and local regulations. 
9.3. 
Participant Information and Consent 
Before inclusion in the study, each prospective subject will be given a full explanation of the 
purpose of the study, the procedures to be carried out, and the potential hazards. Once this 
essential information is provided to the subject, the subjects will be required to read, sign and 
date a written informed consent form prior to enrollment. Subjects will be assured that they may 
withdraw from the study at any time without jeopardizing their medical care. They will be given 
a copy of their ICF. 
If an amended or revised ICF is introduced during the study, each subject’s further consent must 
be obtained. 
Subjects will also be consented for participation in the optional PK-only substudy and/or the 
optional PK-VK substudy. Separate consent is required for participation in each substudy. 
9.4. 
Subject Confidentiality and Personal Data Protection 
The investigators and the Sponsor (and organizations processing data on its behalf [Processors]) 
will preserve the confidentiality of all subjects taking part in the study, in accordance with GCP 
and local regulations. Subjects will be identified by a unique subject identifier on all study 
documents provided to the Sponsor (and Processors). In compliance with local regulations/ICH 
GCP Guidelines, it is required that the investigator and institution permit authorized 
representatives of the Sponsor, of the regulatory agency(s), and IRB/IEC access to review the 
subject’s original medical records for verification of study-related procedures and data.  
Supplemental Information for Participating Sites Located in the European Union (EU) 
The collection of data from European patients in the study constitutes a processing of personal 
data within the meaning of Article 4 of the General Data Protection Regulation (EU) 2016/679 of 
the European Parliament and of the Council of 27 April 2016 (GDPR).  
At an organizational level, to meet European requirements the Sponsor has appointed a certified 
Data Protection Officer (DPO) in charge of ensuring compliance with data protection 
regulations. The DPO oversees the conduct of the required Data Protection Impact Assessment 
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operations. All Processors are bound by a data protection agreement (DPA). If personal data are 
transferred to a third country within the meaning of the General Data Protection Regulation 
(GDPR), the DPA contains the Standard Contractual Clauses established by the European 
Commission. The DPO is also in charge of any data subject request and can be contacted directly 
by the data subject through the email provided in the patient information sheet. 
The subjects and healthcare professionals involved in this study will be informed on the type of 
data collected and processed about them, for which objective and on which legal basis; they will 
also be informed about their rights on their personal data, and how to exercise their rights. 
At a technical level, the Sponsor has implemented and maintains, and requires that Processors 
have implemented and maintain, measures such that personal data are stored in a secured 
environment, encrypted, and partitioned from other data. Access to personal data is limited to 
relevant staff through access policies. All persons accessing data are bound by a confidential 
clause or professional secrecy. 
Subjects will be assigned a unique identifier (data pseudonymization) and will not be identified 
by name in eCRFs, study databases, study-related forms, study reports, or any related 
publications. The key to identify subjects is stored in a secure manner by each study site.  
The Sponsor will regularly review its technical and organizational security measures and update 
them to take into account any evolution on technological developments. The Sponsor may apply 
additional specific statutory requirements, where applicable in the national laws. 
Besides technical and organizational measures, the Sponsor, by means of internal measures and 
imposed contractual clauses to Processors, further maintains the confidentiality of records and 
personal data of subjects. 
The Sponsor has put in place a functional process of reporting of any data breach occurring at the 
Sponsor’s or Processor’s facilities and premises which involve personal data of subjects in the 
clinical study.  In case of the occurrence of any data breach, the Sponsor, in consultation with its 
DPO, will immediately apply relevant measures to mitigate the risks to data subjects as 
appropriate in relation to the specific context of the data breach, taking into account its source, 
underlying intentions, possibilities of recovery, etc. Any data breach presenting risks to the rights 
and freedoms of data subjects will be reported to the relevant supervisory data protection 
authority within 72 hours of the Sponsor becoming aware of the data breach. In addition, in case 
of occurrence of a high-risk breach, subjects will be informed by the Sponsor (via clinical study 
site). 

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10. 
DATA COLLECTION, RETENTION, AND MONITORING 
10.1. 
Case Report Forms 
Source documents will be used to record all study-related data. Designated site staff will use the 
source document entries to enter the data required by the protocol into the eCRFs. 
Representatives of the Sponsor, the CRO, or their designee(s) will train designated site staff on 
accessing and using the web-based EDC system. Investigational site staff will not be given 
access to the EDC system until the required training is completed and documented. One eCRF 
will be completed for each subject enrolled in the study. All source data and eCRFs will be 
reviewed, evaluated, and signed by the investigator (or designee), as required. 
The original source documents and a copy of the corresponding eCRFs will be retained by the 
investigator. Copies of the eCRFs will be provided to the Sponsor (or designee). 
10.2. 
Data Management and Processing 
Data from eCRFs and other external data (e.g., laboratory data) will be entered into the eCRF or 
merged with a clinical database as specified in the data management plan. Quality control and 
data validation procedures will be applied to ensure the validity and accuracy of the clinical 
database. 
In accordance with the vendor’s applicable data management procedures, the clinical database 
will be reviewed and checked for omissions, apparent errors, and values requiring further 
clarification using computerized and manual checks and listings. Data queries requiring 
clarification will be issued in the eCRF and sent to the study site for resolution. Only authorized 
personnel will make corrections to the clinical data in the eCRF, and all corrections will be 
documented in an audit trail. 
10.3. 
Quality Assurance 
This study will be conducted in accordance with standard operating procedures of the CRO(s) 
that will conduct the study. These standard operating procedures are designed to ensure 
adherence to ICH Guideline E6 (R2) for GCP.  
All vendors and clinical sites will be subject to inspection by the Sponsor (or designee) to ensure 
that the data are generated, documented, and reported in compliance with the study plan and 
applicable local regulatory requirements. 
10.4. 
Record Retention 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product or at least 25 years after the end of the trial, 
whichever is longer. However, these documents should be retained for a longer period however 
if required by the applicable regulatory requirement(s) or if needed by the Sponsor. 

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10.5. 
Monitoring of the Study 
In the event of any local disease outbreak or global pandemic (eg, COVID-19), any training or 
monitoring described in this section may be conducted remotely or via telephone or video. 
Depending on the situation over time at each site, it is possible that trainers or monitors may be 
on-site. 
Before study initiation, representatives of the Sponsor or its designee(s) will review the protocol 
and eCRF with the investigators and their staff and perform study-specific training.  
During the study, the study monitor and CRO will check documentation, either remotely or on-
site, to ensure completeness of records, accuracy of entries on the eCRFs, adherence to the 
protocol and to GCP, progress of enrollment, and confirmation study drug supply/logistics. Key 
study personnel must be available to assist the study monitor during remote or on-site visits. 
The investigator must maintain source documents for each subject in the study, which may 
consist of case and visit notes (hospital or clinic medical records). All information on eCRFs 
must be traceable to these source documents in the subject's file. For any on-site visits, the 
investigator must give the study monitor access to any relevant source documents to confirm 
their consistency with the eCRF entries. The investigator must also keep records documenting 
the informed consent process. Information in source documents that could identify the subjects 
(such as the subjects’ names) will not be forwarded to the Sponsor (or its designee(s)). 
Depending on COVID-19 restrictions, the Sponsor or its representative(s) may visit the study 
facilities in order to maintain current knowledge of the study through review of the records, 
comparison with source documents, observation and discussion of the conduct and progress of 
the study. The clinical site will then permit any trial-related monitoring, audits, IRB/IEC review, 
and regulatory inspection(s) by providing direct access to source data/documents. 
 

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11. 
ADMINISTRATIVE PROCEDURES 
11.1. 
Adherence to Protocol 
Excluding an emergency in which proper treatment is required for the protection, safety and 
well-being of the study subjects, the study will be conducted as described in the approved 
protocol and performed according to ICH/GCP and local regulatory guidelines.  
If amendments to the protocol and/or amendments or revisions to the ICF are required, the 
modifications will be documented and submitted to an IRB/IEC for approval. 
11.2. 
Investigator Responsibilities and Delegation of Investigator Duties 
The investigator will ensure that all personnel involved in the trial are adequately qualified and 
informed about the protocol, any amendments to the protocol, the study treatments, and their 
trial-related duties and functions. 
The investigator will maintain a list of subinvestigators and other appropriately qualified persons 
to whom he/she delegates significant trial-related duties. 
11.3. 
Premature Termination or Suspension of a Study 
The Sponsor or its representative may terminate the study at any time for scientific or corporate 
reasons. 
If the trial is prematurely terminated or suspended for any reason, the investigator (or designee) 
should promptly inform the trial subjects, should assure appropriate follow-up for the subjects 
and should inform the regulatory authority(ies)/IRB/IEC, when required. 
11.4. 
Publications 
This is a multicenter clinical trial sponsored by Atea Pharmaceuticals. Any formal presentation 
or publication of data collected for this study will be considered as a joint presentation or 
publication by the clinical investigator(s) and the Sponsor. As is customary for multicenter trials, 
publication or presentation of data from individual study centers will not be allowed prior to the 
publication of the principal study abstract(s) and manuscript(s), without the explicit written 
permission of Atea Pharmaceuticals. Subsequent publications or presentations of data from the 
study must receive review and approval from Atea Pharmaceuticals before submission.  
Any publication of data generated from this study will adhere to the guidelines delineated in the 
Good Publication Practice for Communicating Company-Sponsored Medical Research: GPP3 10.  
In addition, Atea Pharmaceuticals will determine authorship of the principal study manuscript(s) 
in accordance with guidance provided by the 2022 International Committee of Medical Journal 
Editors (ICMJE) Recommendations for the Conduct, Reporting, Editing, and Publication of 
Scholarly Work in Medical Journals11. The publication or presentation of any study results shall 
comply with all applicable privacy laws. 
 

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12. 
REFERENCES 
1. World Health Organization (WHO). Hepatitis C Fact Sheet. Available at 
http://www.who.int/news-room/fact-sheets/detail/hepatitis-c. 2022.Accessed 18 May 
2022. 
2. Viral Hepatitis C Surveillance Report 2019.  Available at: 
https://www.cdc.gov/hepatitis/statistics/2019surveillance/HepC.htm  
3. EPCLUSA® (sofosbuvir and velpatasvir) tablets, for oral use. US Prescribing 
Information. Gilead Sciences, Inc. Foster City, CA. August 2017. 
4. HARVONI® (ledipasvir and sofosbuvir) tablets, for oral use. US Prescribing 
Information. Gilead Sciences, Inc. Foster City, CA. April 2017. 
5. MAVYRET™ (glecaprevir and pibrentasvir) tablets, for oral use. US Prescribing 
Information. AbbVie, Inc. North Chicago, IL. August 2018. 
6. European Medicines Agency. Committee for Medicinal Products for Human Use. 
Guidelines on the evaluation of direct acting antivirals for the treatment of chronic 
hepatitis. 23 June 2016. https://www.ema.europa.eu/en/documents/scientific-
guideline/draft-guideline-clinical-evaluation-direct-acting-antivirals-treatment-chronic-
hepatitis-revision-1_en.pdf.  Accessed 22 Nov 2022. 
7. AASLD/IDSA HCV Guidance Panel. Hepatitis C guidance: AASLD-IDSA 
recommendations for testing, managing, and treating adults infected with hepatitis C 
virus. Hepatology. 2015 Sep;62(3):932-954. doi: 10.1002/hep.27950.  
8. Head of Medicines Agency: Clinical Trial Facilitation Group (CTFG). Recommendations 
related to contraception and pregnancy testing in clinical trials. Version Date 09 Sept 
2020. Available at: https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2020_09_HMA_CTFG_Contraception_guidance_
Version_1.1_updated.pdf 
9. U.S. Department of Health and Human Services, National Institutes of Health, National 
Institute of Allergy and Infectious Diseases, Division of AIDS. Division of AIDS 
(DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 
2.1. [July 2017]. Available from:  
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf 
10. Battisti WP, Wager E, Baltzer L, et al. Good Publication Practice for Communicating 
Company-Sponsored Medical Research: GPP3. Ann Intern Med. 2015;163(6):461-464. 
https://doi.org/10.7326/M15-0288 
11. Uniform Requirements for Manuscripts. https://www.icmje.org/icmje-
recommendations.pdf