Imdusiran Demonstrates Favorable Safety Profile in Early Hepatitis B Trial

Advancing Functional Cure Strategies for Chronic Hepatitis B

Chronic hepatitis B virus (HBV) infection continues to pose a major global health challenge, impacting millions worldwide and contributing significantly to liver-related morbidity and mortality [1, 2]. Despite the availability of effective prophylactic vaccines and antiviral therapies, achieving a functional cure, characterized by sustained HBsAg seroclearance and unquantifiable HBV DNA, remains an elusive goal for most patients [3, 4]. Current treatments, primarily nucleos(t)ide analogues, effectively suppress viral replication but do not eliminate the viral reservoir, leading to lifelong therapy and persistent risk of liver complications [5, 6]. Consequently, there is an urgent need for therapeutic approaches that can overcome these limitations and lead to immune control and functional cure [7, 8]. Small interfering RNAs (siRNAs) represent a class of nucleic acid drugs designed to potently reduce viral antigens like HBsAg, thereby potentially enabling the host immune system to clear the infection [9, 10, 11, 12]. A new study now offers fresh insights into the initial clinical evaluation of such a therapeutic [13].

Imdusiran: A Targeted Approach to Viral Antigen Reduction

Achieving a functional cure for chronic hepatitis B (CHB) necessitates a sustained loss of hepatitis B surface antigen (HBsAg) and a sustained loss of hepatitis B virus (HBV) DNA. However, this outcome is unlikely with current therapies for CHB, which primarily suppress viral replication without eliminating the viral reservoir. To address this therapeutic gap, researchers are exploring new modalities, including small interfering RNA (siRNA) molecules.

A recent phase 1a/b trial, designated AB-729-001, investigated the N-acetylgalactosamine-conjugated, small interfering RNA imdusiran. This study specifically aimed to evaluate the safety, antiviral activity, and anti-HBV immune responses associated with imdusiran administration. Imdusiran represents a therapeutic strategy designed to reduce viral antigens, a critical step on the path to achieving immune control and, ultimately, a functional cure for CHB.

Trial Design and Participant Cohorts

The AB-729-001 study was a multi-center trial conducted at 11 centers and hospitals across several countries: three in Australia, one in New Zealand, three in Thailand, one in Hong Kong, two in South Korea, and one in Moldova. Part 1 of the study employed a double-blinded, single ascending dose design and consisted of four sequential dose groups. In this initial phase, healthy individuals aged 18-45 years were randomly assigned (2:1) to receive either imdusiran or placebo. The randomization utilized fixed block randomization, specifically a block number of two for 1:1 active:placebo sentinel dosing, followed by a block number of four for 3:1 active:placebo for the next four participants. Participants were assigned into three equal-sized cohorts, receiving subcutaneous imdusiran or placebo as a single dose of 60 mg, 180 mg, or 360 mg. To maintain study integrity, participants and investigators were masked to treatment assignment until Part 1 was complete.

Following Part 1, Parts 2 and 3 were open-label and focused on individuals with chronic hepatitis B. These participants were aged 18-65 years, could be HBeAg-positive or HBeAg-negative, and were either taking or not taking nucleoside or nucleotide (nucleos[t]ide) analogue therapy, which was continued during the imdusiran treatment period. Key inclusion criteria for these parts also mandated HBsAg concentrations of at least 250 international units per mL, no clinically significant abnormalities on liver ultrasound, and an absence of cirrhosis. In Part 2, participants received subcutaneous imdusiran as a single dose of 60 mg, 90 mg, or 180 mg. Part 3 involved repeat doses of 60 mg or 90 mg administered every 4, 8, or 12 weeks for up to 48 weeks. The primary endpoint for all parts of the study was to evaluate the frequency and severity of treatment-emergent adverse events, discontinuations due to adverse events, and laboratory abnormalities. Safety in healthy participants (Part 1) was evaluated until day 29 after dosing, while safety in participants with chronic hepatitis B (Parts 2 and 3) was evaluated until week 48 of follow-up. For participants who discontinued nucleos(t)ide analogue therapy after completing imdusiran treatment and meeting eligibility criteria, safety was evaluated until month 36 of follow-up. All individuals who received at least one dose of study drug comprised the safety population and were included in safety analyses. The study was registered with the Australia New Zealand Clinical Trials Registry under ACTRN12619000954123 for Part 1, ACTRN12619001197123 for Part 2, and ACTRN12620000295943 for Part 3, and is now complete.

Enrollment for Part 1 occurred between July 16 and August 30, 2019, with 18 individuals enrolled, all of whom (100%) were male. Of these, 12 individuals (67%) were randomly assigned to imdusiran, and six individuals (33%) were randomly assigned to placebo. For Part 2, between September 3, 2019, and June 11, 2020, 43 individuals were assessed for eligibility, with 22 (51%) ultimately enrolled. Among the enrolled Part 2 participants, 15 (68%) were male and seven (32%) were female. Part 3 assessed 78 individuals for eligibility between April 30, 2020, and June 26, 2021, leading to the enrollment of 43 (55%) participants. In Part 3, 26 (60%) were male and 17 (40%) were female. Across all parts, all 83 enrolled participants received at least one dose of imdusiran or placebo and were included in the safety analyses.

Safety and Tolerability Findings

The safety analysis of imdusiran across all parts of the AB-729-001 study revealed a favorable tolerability profile. Notably, no participants discontinued imdusiran owing to an adverse event, and no dose-related trends in reported treatment-emergent adverse events (TEAEs) were observed across groups. Furthermore, there were no deaths reported throughout the study. In Part 1, which involved healthy individuals, the most commonly reported TEAEs occurring in two or more participants included an increase in alanine aminotransferase concentration (n=2; both reported as treatment-related), dizziness (n=2), medical device site reaction (n=3), headache (n=2), and oropharyngeal pain (n=2).

For participants with chronic hepatitis B, specific TEAEs were observed. In Part 2, where patients received single doses of imdusiran, the most commonly reported TEAEs were transient injection-site pain (n=5; all reported as treatment-related), headache (n=4; two treatment-related), an increase in alanine aminotransferase (n=3; two treatment-related) concentrations, an increase in aspartate aminotransferase (n=2; one treatment-related) concentrations, and dizziness (n=2).

In Part 3, which involved repeat dosing in chronic hepatitis B patients, the most frequently reported TEAEs included coronavirus infection (n=18), injection-site pain (n=8; all of which were reported to be treatment-related), injection-site erythema (n=4; all treatment-related), headache (n=4), upper respiratory tract infection (n=4), pyrexia (n=4), fatigue (n=3; one treatment-related), and injection-site bruising (n=3; all treatment-related). Importantly, all reported TEAEs across the entire study were classified as grade 1. The study also confirmed no clinically relevant changes in clinical laboratory values over time, no clinically relevant changes in vital signs over time, and no clinically relevant changes in electrocardiogram values over time were noted in any part of the study.

Clinical Implications and Future Directions

The comprehensive safety analysis from the AB-729-001 phase 1a/b trial provides crucial insights for the continued development of imdusiran. The study concluded that single doses of imdusiran were safe and well tolerated in healthy individuals, as observed in Part 1. Furthermore, single doses of imdusiran were safe and well tolerated in individuals with chronic hepatitis B (Part 2), and importantly, multiple doses of imdusiran were safe and well tolerated in individuals with chronic hepatitis B (Part 3). These findings, which reported all treatment-emergent adverse events as grade 1 and no discontinuations due to adverse events, underscore a favorable safety profile for imdusiran across different dosing regimens and patient populations.

These robust safety and tolerability data are clinically significant because they support drug development of imdusiran as a future treatment targeting functional cure for chronic hepatitis B. Achieving a functional cure, characterized by sustained loss of hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA, remains an unmet need with current therapies. The favorable safety profile observed in this early-phase trial suggests that imdusiran, an N-acetylgalactosamine-conjugated small interfering RNA designed to reduce viral antigens, could be a viable candidate for further investigation in larger clinical trials. The study was funded by Arbutus Biopharma.

References

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