Aim stated in the registry record

“This study will evaluate the effect of a single dose of bepirovirsen on the QT interval corrected by Fridericia's formula (QTcF) as compared to placebo. The data generated will be used to model the relationship between bepirovirsen concentration and QTcF.” (opens the source at this quote in a new tab)

Purpose stated in the protocol

“This study will be conducted to evaluate the effect of bepirovirsen on cardiac repolarization and data generated will be used to conduct concentration-QTcF analyses for bepirovirsen.” (opens the source at this quote in a new tab)
“The exposure data collected from supratherapeutic single doses of bepirovirsen will be used to provide confidence that the risk of QT/QTcF interval prolongation at the therapeutic dose of 300 mg is low, along with the collected ECG measurements in the Phase 1 and 2a studies” (opens the source at this quote in a new tab)

Study dates and status in the registry record

Field	Registry entry
Recruitment status	“Completed”
Study start (actual)	“2024-07-18”
Primary completion (actual)	“2025-04-28”
Study completion (actual)	“2025-04-28”
Results first posted	“2026-07-10”
Other study identifiers	“205873”

Study location in the registry record

“This study has 1 location” (opens the source at this quote in a new tab)
“Austin, Texas, United States, 78744 -1645” (opens the source at this quote in a new tab)

Randomized, double-blind, placebo-controlled, parallel-group design

“A Phase 1, Randomized, Double-Blinded, Placebo-Controlled, Parallel Group Study to Evaluate the Effect of Bepirovirsen on Cardiac Conduction as Assessed by 12-lead Electrocardiogram in Healthy Volunteers” (opens the source at this quote in a new tab)

Planned 1:1 randomization and dose reduction under protocol amendment 2

“A total of approximately 46 participants will be enrolled and randomized 1:1 into parallel arms to receive a single supratherapeutic dose of bepirovirsen,” (opens the source at this quote in a new tab)
“participants dosed, 2 experienced tolerability issues related to systemic AEs” (opens the source at this quote in a new tab)
“A decision was made not to dose any further participants with bepirovirsen” (opens the source at this quote in a new tab)

Supratherapeutic doses stated in the prescribing information

“At supratherapeutic doses of 450 or 600 mg (1.5 and 2 times the recommended dosage) of HIBSAGO, clinically significant QTc interval prolongation was not observed.” (opens the prescribing information at this quote)

Key inclusion criteria

“Participant must be 18 to 55 years of age inclusive, at the time of signing the informed consent.” (opens the source at this quote in a new tab)
“Participants who are overtly healthy as determined by medical evaluation, including medical history, physical examination, laboratory tests, electrocardiogram (ECG) and vital signs.” (opens the source at this quote in a new tab)
“Body weight greater than equal to (>=) 50 Kilograms (kg) and Body mass index (BMI) within the range 19-32 Kilograms per square meter (kg/m^2) (inclusive).” (opens the source at this quote in a new tab)

Key exclusion criteria

“Known history of heart disease, including ischemic heart disease, cardiomyopathy, clinically significant cardiac arrhythmias, clinically significant valvular disease, or hypertensive heart disease.” (opens the source at this quote in a new tab)
“Positive test results for Hepatitis B surface antigen (HBsAg), hepatitis C antibody or hepatitis C RNA at screening or within 3 months prior to first dose of study intervention.” (opens the source at this quote in a new tab)
“Prior treatment with any oligonucleotide or small interfering Ribonucleic acid (RNA) (siRNA) within 12 months before dosing.” (opens the source at this quote in a new tab)

Arms in the registry record

Arm	Registry entry
Bepirovirsen, four injections	“Participant received four subcutaneous (SC) injections of Bepirovirsen dose level 1 on Day 1.”
Placebo, four injections	“Participants received four matching placebo SC injections on Day 1.”
Bepirovirsen, three injections	“Participant received three SC injections of Bepirovirsen dose level 1 on Day 1.”
Placebo, three injections	“Participants received three matching placebo SC injections on Day 1.”

Registered primary outcome and concentration-QTc method

“Geometric mean and 90 percent (%) Confidence Interval (CI) of predicted CFB QTcF adjusted for placebo at Cmax following supratherapeutic single doses of Bepirovirsen was presented using concentration QTc (C-QTc) analysis using exposure-response modelling.” (opens the source at this quote in a new tab)

Regulatory basis in the ICH E14 guidance

“The ICH E14 guidance, as adopted in the US FDA Guidance for Industry, E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs [Department of Health and Human Services, 2005], emphasizes the need to obtain clear and robust data through studies that assess the effect of new chemical entities on ECG parameters.” (opens the source at this quote in a new tab)
“A supratherapeutic dose is defined as a dose that provides exposures (mean Cmax) exceeding the high clinical scenario [ICH E14/S7B Questions and Answers 5.1, 2022].” (opens the source at this quote in a new tab)
“The primary endpoint is the change from baseline in Fridericia heart-rate-corrected QT interval (QTcF) under bepirovirsen exposure following a supratherapeutic single dose.” (opens the source at this quote in a new tab)

Hypothesis threshold of 10 msec

“For the primary estimand, the following 1-sided hypothesis is planned to be tested for QT prolongation following the supratherapeutic single dose of bepirovirsen against a predefined threshold of 10 msec using the C-QTcF analysis:” (opens the source at this quote in a new tab)

Planned sample size and power

“A sample size of approximately 46 participants with 1:1 randomization is chosen to obtain 42 evaluable participants to complete the study under the original design of receiving a single dose of either placebo or” (opens the source at this quote in a new tab)
“A size of 42 evaluable participants with concentration and ΔQTcF measured around Cmax provides at least 90% power to exclude that active drug caused more than a 10-msec QTcF effect at clinically relevant plasma levels” (opens the source at this quote in a new tab)

Enrollment and participants analyzed for the primary outcome

Arm	Started	Analyzed for the primary outcome
Bepirovirsen, four injections	“5”	“5”
Placebo, four injections	“5”	Not reported
Bepirovirsen, three injections	“18”	“18”
Placebo, three injections	“18”	Not reported

Analysis sets defined in the protocol

“All participants in the safety population with a valid ΔQTcF value (measurements at baseline as well as on-treatment with at least 1 post-dose time point).” (opens the source at this quote in a new tab)
“All participants in the Safety Set who had at least 1 non-missing PK assessment (NQ values will be considered as non-missing values).” (opens the source at this quote in a new tab)

Population for the primary analysis in the registry results

“Analysis was performed on pharmacokinetic (PK)/QTcF set that included all participants who were in both the QT/QTcF and PK populations with at least 1 pair of post dose PK and CFB QTcF data from the same time point as well as participants in the QT/QTcF population who received placebo.” (opens the source at this quote in a new tab)

Participant flow in the registry results

Milestone	Bepirovirsen, four injections	Placebo, four injections	Bepirovirsen, three injections	Placebo, three injections
Started	“5”	“5”	“18”	“18”
Completed	“5”	“5”	“18”	“18”
Not completed	“0”	“0”	“0”	“0”

Age in the registry results

Characteristic	Bepirovirsen, four injections	Placebo, four injections	Bepirovirsen, three injections	Placebo, three injections	Total
Overall number of baseline participants	“5”	“5”	“18”	“18”	“46”
Age (years), mean (SD)	“31.4(11.24)”	“33.2(4.02)”	“39.4(7.96)”	“38.6(10.29)”	“37.5(9.20)”

Primary outcome: placebo-corrected change from baseline in QTcF at Cmax

Arm	Participants analyzed	Geometric mean (ms)	90% CI (ms)
Bepirovirsen, four injections	“5”	“2.360”	“(-0.249 to 4.970)”
Bepirovirsen, three injections	“18”	“2.024”	“(-0.541 to 4.589)”

Bepirovirsen plasma PK parameters (geometric mean, geometric CV%)

Parameter	Bepirovirsen, four injections (n = 5)	Bepirovirsen, three injections (n = 18)
Cmax (µg/mL)	“16.88”	“15.77”
AUC(0-24) (h·µg/mL)	“204.01”	“169.80”
AUC(0-t) (h·µg/mL)	“215.04”	“177.21”
Tmax (h)	“4.10”	“3.38”

AUC extrapolated to infinity not calculated

“Data were not analyzed for AUC(0-infinity) as there were not enough data points collected for a terminal slope required to calculate AUC(0-infinity).” (opens the source at this quote in a new tab)

QTc conclusion in the prescribing information

“At supratherapeutic doses of 450 or 600 mg (1.5 and 2 times the recommended dosage) of HIBSAGO, clinically significant QTc interval prolongation was not observed.” (opens the prescribing information at this quote)

Deaths, serious adverse events, and other adverse events in the registry results

Event	Bepirovirsen, four injections	Placebo, four injections	Bepirovirsen, three injections	Placebo, three injections
All-cause mortality	“0/5 (0.00%)”	“0/5 (0.00%)”	“0/18 (0.00%)”	“0/18 (0.00%)”
Any other (not serious) adverse event	“5/5 (100.00%)”	“1/5 (20.00%)”	“15/18 (83.33%)”	“2/18 (11.11%)”
Injection site erythema	“5/5 (100.00%)”	“0/5 (0.00%)”	“14/18 (77.78%)”	“0/18 (0.00%)”
Injection site swelling	“4/5 (80.00%)”	“0/5 (0.00%)”	“13/18 (72.22%)”	“0/18 (0.00%)”
Injection site pain	“3/5 (60.00%)”	“0/5 (0.00%)”	“9/18 (50.00%)”	“0/18 (0.00%)”
Headache	“3/5 (60.00%)”	“0/5 (0.00%)”	“5/18 (27.78%)”	“1/18 (5.56%)”
Nausea	“3/5 (60.00%)”	“0/5 (0.00%)”	“3/18 (16.67%)”	“0/18 (0.00%)”
Pyrexia	“0/5 (0.00%)”	“0/5 (0.00%)”	“4/18 (22.22%)”	“0/18 (0.00%)”

Tolerability at 600 mg

“Single doses of HIBSAGO 600 mg (2 times the recommended dose) were administered subcutaneously in a clinical trial to 5 healthy adults. Two participants developed tolerability issues at this dose, with symptoms including headache, nausea, vomiting, myalgia, and dizziness which lasted 24 to 48 hours despite symptomatic treatment.” (opens the prescribing information at this quote)

Systemic symptoms described in the protocol

“Two of the 10 randomized participants exhibited a variety of symptoms of mild and moderate severity, including headache, nausea, vomiting, myalgia, and dizziness. These symptoms were associated with low-grade fever and/or elevated CRP, suggestive of a systemic inflammatory response. These participants experienced discomfort for up to 48 hours after dosing, despite symptomatic treatment.” (opens the source at this quote in a new tab)

Summary: study limitations

Study 205873 gave a single supratherapeutic dose of bepirovirsen to 5 participants by four injections and 18 by three injections, with 5 and 18 placebo recipients in the corresponding arms; the higher-dose arm was stopped after 2 participants had systemic tolerability issues, leaving 5 participants at that dose. The registry describes the dose only as “dose level 1”, and the prescribing information states the supratherapeutic doses as 450 and 600 mg. AUC extrapolated to infinity was not calculated because there were not enough data points for a terminal slope, and single-dose data in healthy volunteers do not describe QTc effects during the 24-week course in patients with chronic hepatitis B.

Limitations and caveats in the registry results

“Protocol specified AUC(0-inf) could not be calculated due to missing half-life estimates arising from the short period for PK sampling (not enough data points collected for a terminal slope required to calculate AUC[0-infinity]).” (opens the source at this quote in a new tab)