Imdusiran Reduces HBsAg, Maintains Response After End of Treatment in Phase 2a Trials

Man-Fung Yuen, MD, PhD, DSc

Credit: ResearchGate

Data from a pair of phase 2a clinical trials are highlighting imdusiran’s ability to induce and maintain undetectable HBsAg levels in patients with chronic hepatitis B virus (HBV) when administered alongside pegylated interferon alfa-2α (IFN) or VTP-300 and standard-of-care nucleos(t)ide analogue (NA) therapy.^1,2

An RNA interference therapeutic specifically designed to reduce all HBV viral proteins and antigens, imdusiran targets hepatocytes using Arbutus Biopharma’s covalently conjugated N-Acetylgalactosamine (GalNAc) delivery technology enabling subcutaneous delivery. Clinical data has shown single and multiple doses of imdusiran to be safe and well-tolerated while also providing meaningful reductions in hepatitis B surface antigen and hepatitis B DNA. The agent is currently in multiple phase 2a clinical trials, including IM-PROVE I (AB-729-201) and IM-PROVE II (AB-729-202).^1,2

IM-PROVE I

IM-PROVE I enrolled 43 HBeAg-negative, NA-suppressed patients with chronic HBV infection. Following a 24-week lead-in with imdusiran 60 mg every 8 weeks added to ongoing NA therapy, patients were randomly assigned to of the following cohorts:

• A1: Imdusiran + NA + IFN weekly for 24 weeks (n = 12)
• A2: NA + IFN weekly for 24 weeks (n = 13)
• B1: Imdusiran + NA + IFN weekly for 12 weeks (n = 8)
• B2: NA + IFN weekly for 12 weeks (n = 10)

After completion of the IFN treatment period, patients underwent a 24-week follow-up on NA therapy alone and were then assessed for discontinuation of NA therapy. Patients with ALT levels < 2 times the upper limit of normal, undetectable HBV DNA, and HBsAg <100 IU/mL at 2 consecutive visits ≥ 24 weeks after the last dose of imdusiran qualified to discontinue all therapy.¹

Results showed some patients who received either 48 or 24 weeks of imdusiran and 24 weeks of IFN with their ongoing NA therapy achieved undetectable HBsAg at the end of treatment (33.3% and 23.1%, respectively) that was sustained 24 weeks after completing imdusiran and IFN treatment (33.3% and 15.4%, respectively). Of 6 patients with sustained HBsAg loss, all have seroconverted with high anti-HBsAg antibody levels (43.8 to >1000 mIU/mL suggestive of immune control).¹

Investigators noted 2 of the 6 patients have reached 12 weeks off all therapy while maintaining both undetectable levels of HBsAg and HBV DNA, while the remaining 4 patients are at various timepoints less than 12 weeks off therapy with undetectable levels of HBsAg and HBV DNA. Across the 4 treatment cohorts, 21 patients have discontinued all therapy and are in the follow-up period. So far, a single patient who received 12 weeks of IFN treatment with imdusiran and NA therapy has maintained undetectable levels of HBsAg and HBV DNA while off all therapy for 6 months, thereby achieving a functional cure.¹

Combination imdusiran and 24 weeks of IFN was safe and well-tolerated, with no serious adverse events related to imdusiran or IFN and no adverse events leading to discontinuation. The most common imdusiran-related treatment emergent adverse events were transient ALT elevations and injection site bruising, and the IFN-related reatment emergent adverse events were consistent with the known safety profile of IFN.¹

“This trial evaluated small groups of patients, yet there is reason to believe that the combination of imdusiran and IFN could potentially lead to a functional cure in those patients that remain off all therapy,” Man-Fung Yuen, MD, PhD, DSc, chief of the division of gastroenterology and hepatology at the University of Hong Kong, said.¹ “These data are extremely important for the HBV community, and I look forward to continuing to follow the patients who have discontinued all treatment.”

IM-PROVE II

The IM-PROVE II phase 2a trial enrolled 40 noncirrhotic, virally suppressed patients with chronic HBV who were on stable NA therapy. Patients received imdusiran 60 mg every 8 weeks for 24 weeks with ongoing NA therapy and were then randomly assigned to receive either VTP-300 or placebo at weeks 26 and 30, and conditionally at week 38 if they experienced a >0.5 log10 decline in HBsAg between weeks 26 and 34.²

Of note, the trial has been amended to include an additional cohort of 20 patients receiving imdusiran and NA therapy for 24 weeks followed by VTP-300 and up to 2 low doses of nivolumab, an approved PD-1 monoclonal antibody, with preliminary data expected in the second half of 2024.²

After completion of the treatment period at week 48, patients with ALT levels < 2 times the upper level of normal, HBV DNA < the lower limit of quantitation, HBsAg <100 IU/mL, and HBeAg negative discontinued NA therapy.²

Data from patients who were on stable NA therapy throughout the treatment period, received imdusiran 60 mg every 8 weeks for 24 weeks, and were then randomized to receive either VTP-300 or placebo at weeks 26 and 30 showed HBsAg reductions during the imdusiran lead-in period (-1.8 log10 by week 26) with 95% of patients achieving HBsAg <100 IU/mL before undergoing dosing in the treatment or placebo arm.²

At the end of treatment, 94% of patients in the treatment arm achieved HBsAg levels <100 IU/mL and 36% had <10 IU/mL compared to 84% and 21%, respectively, in the placebo arm. At 24 weeks after end of treatment, investigators observed lower HBsAg levels in the treatment arm (80% at <100 IU/mL and 60% at <10 IU/mL) compared to the placebo arm (16% and 0%, respectively).²

After week 48, 84% of patients in the treatment arm stopped NA treatment versus 53% in the placebo arm, with a single patient in the treatment arm achieving undetectable HBsAg and another having a >1.5 log10 decline between the last 2 visits during the NA-therapy discontinuation follow-up period.²

Treatment with imdusiran and VTP-300 was generally safe and well-tolerated, with no serious adverse events, grade 3 or 4 adverse events, or discontinuations due to treatment. The most common treatment-related adverse events were injection site-related (both imdusiran and VTP-300) and transient ALT increases (imdusiran).²

“These data show that adding imdusiran and VTP-300 to ongoing NA therapy in cHBV patients meaningfully reduces HBsAg after the end of the treatment period,” Kosh Agarwal, MD, consultant hepatologist and transplant physician at the Institute of Liver Studies at King’s College Hospital, London, said.² “I am impressed with the number of patients that qualified to stop NA therapy in the VTP-300 group and the clear separation in HBsAg levels between the treatment arm and placebo at Week 72.”

References:

1. Arbutus. Arbutus’ Imdusiran with Short Course Interferon Achieves Sustained Undetectable HBsAg, a Necessity for HBV Functional Cure. Press Release. June 5, 2024. Accessed June 12, 2024. https://investor.arbutusbio.com/news-releases/news-release-details/arbutus-imdusiran-short-course-interferon-achieves-sustained
2. Arbutus. Treatment with Arbutus’ Imdusiran and VTP-300 Achieves Statistical Significance in Lowering HBsAg Levels. Press Release. June 6, 2024. https://investor.arbutusbio.com/news-releases/news-release-details/treatment-arbutus-imdusiran-and-vtp-300-achieves-statistical