Brii Biosciences Limited announced the publication of promising Phase 2 ENSURE study results in Nature Medicine, demonstrating that combining the siRNA elebsiran with pegylated interferon alfa (PEG-IFNα) significantly improved hepatitis B surface antigen (HBsAg) loss rates compared to interferon monotherapy in chronic hepatitis B patients. The study also revealed the potential role of therapeutic vaccination in identifying patients most likely to benefit from curative treatments.
Enhanced Efficacy with Combination Therapy
The ENSURE study was conducted in two parts among virally suppressed chronic HBV patients. In Part I, participants naive to the therapeutic vaccine BRII-179 were randomized to receive 48 weeks of PEG-IFNα alone or in combination with elebsiran at doses of 200 mg or 100 mg administered every 4 weeks.
At 24 weeks post-end of treatment, HBsAg loss was observed in 21.1% of participants (4 of 19) receiving elebsiran 200 mg plus PEG-IFNα and 33.3% of participants (6 of 18) receiving elebsiran 100 mg plus PEG-IFNα, compared to only 5.6% (1 of 18) with PEG-IFNα monotherapy.
Therapeutic Vaccination as Patient Selection Tool
Part II of the study explored a novel patient response-guided treatment approach. Participants previously treated with 9 doses of elebsiran and BRII-179 in a completed Phase 2 study were categorized as BRII-179 anti-HBs responders or non-responders based on peak hepatitis B surface antibody levels (≥10 IU/L or <10 IU/L, respectively).
Among the 31 participants in this cohort who received 48 weeks of elebsiran plus weekly PEG-IFNα, HBsAg loss was achieved in 29.0% overall. Notably, BRII-179 anti-HBs responders demonstrated a substantially higher response rate of 42.1% (8 of 19) compared to 8.3% (1 of 12) in non-responders. Anti-HBs responders also achieved more rapid HBsAg reductions and HBsAg seroclearance compared to non-responders.
Safety Profile and Clinical Implications
The combination of elebsiran and PEG-IFNα was generally safe and well tolerated across all cohorts. The study's randomized, active-controlled design provided validation of elebsiran's clinical benefit over PEG-IFNα monotherapy, establishing an important benchmark for future siRNA development toward HBV functional cure.
"The ENSURE study was designed to provide much-needed clarity and to answer critical scientific questions about curative treatment for chronic hepatitis B," said Professor Jidong Jia, lead principal investigator of the ENSURE study. "It is encouraging to see that the 24-week follow-up data remain consistent with the EOT results, substantiating the added clinical benefit of elebsiran and pointing to the potential new roles of BRII-179 in priming and enriching CHB patients for achieving higher cure rates."
Immune System Priming Effects
The study revealed important observations about BRII-179's potential role in immune system priming. Participants previously treated with BRII-179 and elebsiran experienced faster decline and loss of HBsAg, suggesting that BRII-179 may prime the immune system for improved responsiveness to subsequent curative therapy.
Additionally, 50% of anti-HBs responders who achieved sustained HBsAg loss had baseline HBsAg levels exceeding 1,500 IU/mL when enrolled in the previous study, suggesting that BRII-179 may elicit anti-HBs responses in patients with high baseline HBsAg levels. With its favorable safety profile, BRII-179 could play a unique role in priming and enriching patients regardless of baseline HBsAg levels, potentially expanding the population eligible for future curative regimens.
Addressing Global Health Challenge
Hepatitis B virus infection affects more than 254 million people globally and is the leading cause of liver disease, with an estimated 820,000 deaths annually from complications of chronic HBV infection. The disease is of particular concern in China, where 87 million people are chronically infected.
Both elebsiran and BRII-179 have received Breakthrough Therapy Designation from China's National Medical Products Administration, with elebsiran receiving this designation in May 2024 and BRII-179 in November 2023.
