The addition of venous lactate level was added to the Schedule of Assessments at Days 1, 2, 29, 30, 57, 58, 85 and 86. The post-dose observation period was changed from 2 hours to 4 hours; patients were to remain at the clinical facility for 4 hours following administration of ARC-520 Injection or placebo. Additionally, on dosing days patients were dosed sequentially, with at least 30 minutes in between dose initiations. Dose administration was not to be initiated simultaneously in multiple patients. The oral antihistamine pre-treatment was updated to specify that the antihistamine used was in general to be an H1>H2 receptor blocker and would include diphenhydramine 50 mg, cetirizine 10 mg, chlorpheniramine 8 mg or hydroxyzine 50 mg. The Investigator was free to choose any of these antihistamines available locally and consistent with their country’s Marketing Authorization. The maximum blood volume collected from each patient was changed to not exceed approximately 830 mL (previously 820 mL) The protocol (Section 16.1.1) was amended to include information regarding the management of AEs (Section 10.11 of the protocol [Section 16.1.1]). The risk of infusion related reactions was updated to include both anaphylactic and nonanaphylactic or cytokine release syndrome. Cytokine Release Syndrome clinical management guidelines were added to the Appendices. Appendix 2 provided clinical guidelines for management of anaphylactic reactions. Appendix 3 provided clinical guidelines for management of cytokine release syndrome. The protocol was updated to include corrections of administrative, grammatical, formatting errors, and inconsistencies.

The total number of patients for the Heparc-2003 study was reduced from 90 to 48. Treatment Groups 1 and 2 were reduced from 15 to 8 patients and Treatment Groups 3 & 4 were reduced from 30 to 16 patients. The planning interim analysis was to be performed after 54 patients had completed their day 71 visit. This total was reduced from 54 to 25 patients. The number of pharmacokinetic patients was reduced from 24 to 12 patients to align with the reduction in patients enrolled. The following changes to the inclusion/exclusion criteria were also incorporated: The exclusion criteria were modified to include the following changes: • Exclusion Criterion #2 was modified to clarify that “severe” infection should not be evident within the 4 week screening window. This was done to avoid uncertainty around appropriate enrollment of patients that may have experienced mild infections such as upper respiratory infections or viral syndromes within the screening window. • Exclusion Criterion #4 was modified to increase the Liver Elastography score from 8 to 9. In the chronic hepatitis B population, Liver Elastography scores of 8 and 9 were both indicative of mild to moderate (F2-F3) liver fibrosis. It was not anticipated that this would have changed the risk to patients receiving ARC-520 Injection. • Exclusion Criterion #6 was modified to clarify that only drugs listed that were “systemically administered”, specifically systemically administered (oral, intravenous or depot) steroids or immunomodulators/immunosuppressants were excluded. This was done so as to not exclude patients using topical or inhaled products which were unlikely to suppress systemic innate or adaptive immune responses against HBV. • Exclusion Criterion #7 was modified from a detailed list of drugs to prescription medications based on principal investigator (PI) discretion within 14 days of administration of study treatment.

(continued) • Exclusion Criterion #9 was modified from diabetes mellitus to Non-alcoholic steatohepatitis (NASH) or homozygous or heterozygous familial hypercholesterolemia. There had been no indication that well controlled diabetics would have had a less favorable risk profile. However, the presence of NASH concomitantly with chronic hepatitis B adds a variable potentially making interpretation of transaminase changes difficult. Additionally, small interfering ribonucleic acid (siRNA) molecules used in ARC-520 Injection are targeted to hepatocytes using a cholesterol targeting ligand. Patients with familial hypercholesterolemia lack a normal low density lipoprotein (LDL) receptor and thus are not good candidates for ARC-520 Injection. • Exclusion Criterion #10 was updated with the blood cholesterol removed. Patients with elevated cholesterol were unlikely to have an increased risk profile. Additionally, the Sponsor had evaluated serum total cholesterol levels with HBsAg responses and no correlation had been identified. • Exclusion Criterion #11 was modified to clarify that “poorly controlled” autoimmune disease was excluded. • Exclusion Criterion #24 was modified to remove marijuana use as well as the timeframe for use of 3 months prior to screening, and to remove positive urine drug screen. Use of marijuana was not likely to alter the risk of study participation. • Exclusion Criterion #27 was modified to include only inherited or acquired hepatic disease, (eg, alcoholic liver disease, cirrhosis, Wilson’s disease, hemochromatosis or alpha-1 antitrypsin deficiency). This was done to exclude patients who have HBV and concomitant hepatic disease which could alter or obscure safety data interpretation. • Exclusion Criterion #29 was modified to clarify that presence of “poorly controlled” diseases was excluded.

(continued) The following criteria were removed as Exclusion for the study: • Concurrent use of dietary and/or herbal supplements. It was unlikely this would alter patient risk profile with regard to this study. • Medications known to prolong QTc intervals. No signs of QTc prolongation had been seen in clinical investigations of ARC-520 Injection to date. • Evidence of severe systemic acute inflammation, sepsis or hemolysis. The Sponsor believed patients with severe systemic inflammation, sepsis or hemolysis would be excluded by other criteria making this criterion redundant. • Positive reaction to bee venom allergy test (immunoglobulin E [IgE]). The Sponsor believed Exclusion Criterion #number 25 was sufficient to exclude patients at risk for hypersensitivity reactions to ARC-520. • History of fever within 2 weeks of screening. Presence of fever within 2 weeks of screening was unlikely to change patient risk profile. • Immunization with a live attenuated vaccine within 7 days of dosing. This was removed as immunization with a live attenuated vaccine within 7 days of dosing was unlikely to change patient risk profile. • Participation in excessive/physical activity within 7 days of screening or enrolment. This was removed as it was unlikely to change patient risk profile. The restrictions and concomitant medications section was updated to align with the modifications made to the exclusion criteria. The sample size considerations were updated to support the reduction in the number of patients in the study as well as the number of patients required for the interim analysis. Additionally typographical and administrative errors were corrected for clarification.

A further amendment was made to the global and Hong Kong specific protocols (Version 4.0; 19 Oct 2016); however these protocols were not fully approved in any country prior to study termination.