Short-term Treatment with Liver-targeted siRNA JNJ-3989 Achieves Durable HBsAg Suppression in Chronic Hepatitis B, Paving the Way Toward Functional Cure

August 29, 2020 News /BioValleyBIOON/ -- In recent days, the European Association for the Study of the Liver (EASL) 2020 Digital International Liver Congress™ (Digital ILC 2020) was grandly held. EASL is a world-renowned authoritative association for liver disease research, and the International Liver Congress™ (ILC) organized by this association is the most influential international conference in the field of hepatology globally.Meetingone of them. The ILC aims to showcase the best clinical practices and science in the field of liver diseases, introduce the latest trends in hepatology, and present cutting-edge scientific advancements. Due to the impact of the COVID-19 pandemic, this year’s annual meeting will be held online from August 27th to 29th (Central European Summer Time).

At this conference, RNAi therapeutics company Arrowhead and its partner Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson (JNJ), announced Phase 2 clinical data from the Phase 1/2 AROHBV1001 study evaluating the dual therapy of JNJ-3989 (formerly ARO-HBV) and nucleos(t)ide analogs (NAs) for the treatment of chronic hepatitis B (CHB).

JNJ-3989 is a liver-targeted, subcutaneously administeredsiRNAAntiviral drugs,Designed to treat HBV infection via the RNA interference (RNAi) mechanism. Currently, JNJ-3989 is being developed as a potential functional cure for individuals with HBV infection.JNJ-3989 Can Silence All HBV Gene Products, and intervene upstream of the reverse transcription process targeted by nucleotide and nucleoside analogs under the current standard of care, which willEnable the body's innate immune defense system to clear the virus and achieve a functional cure.

Currently, Janssen is conducting a 48-week Phase 2b study to evaluate the functional cure rate of JNJ-3989 in combination with nucleos(t)ide analogs (NAs), with or without JNJ-6379, in patients with chronic hepatitis B (CHB). JNJ-6379 is an orally administered capsid assembly modulator (CAM) that blocks normal capsid assembly during HBV replication. Arrowhead and Janssen entered into a license and collaboration agreement in October 2018 for the development and commercialization of JNJ-3989.

The report released at this conference is titled:Short-term treatment with the RNAi therapeutic JNJ-3989 can achieve sustained hepatitis B surface antigen (HBsAg) suppression in patients with chronic hepatitis B (CHB) receiving nucleos(t)ide analogue (NA) therapy. (Click to view the detailed report)

Key Highlights of the Report: The AROHBV1001 study was conducted in patients with chronic hepatitis B (CHB). JNJ-3989 was administered on Days 0, 28, and 56, while patients concurrently received daily oral nucleos(t)ide analog (NA) therapy.

The objective of this analysis was to evaluate the sustained response of hepatitis B surface antigen (HBsAg), HBV RNA, hepatitis B e antigen (HBeAg), and hepatitis B core-related antigen (HBcrAg) from Day 0 of the study to the end of the study (Day 392, which is 48 weeks after the last dose of JNJ-3989). Sustained responders were defined as patients with chronic hepatitis B (CHB) who maintained a reduction in HBsAg levels of ≥1 log10 IU/mL from Day 0 to Day 392. Non-sustained responders were defined as CHB patients who exhibited a reduction in HBsAg levels of <1 log10 IU/mL from Day 0 to Day 392.

Analysis results include: (1)For the first time, data have shown that siRNA therapy induces a durable, post-treatment reduction in HBsAg levels of ≥1 log10 IU/mL in patients with chronic hepatitis B (CHB): within 48 weeks after the last dose of JNJ-3989, 39% of patients achieved a sustained response (HBsAg reduction ≥1 log IU/mL).（2）Reductions in HBV RNA, HBeAg, and HBcrAg were observed across all cohorts and were more pronounced in patients with sustained HBsAg response than in those without.(3) JNJ-3989 administered once every 4 weeks for 3 injections at a maximum dose of 400 mg demonstrated good tolerability and appeared to have a favorable long-term safety profile.(4) These results support longer-term evaluation of the JNJ-3989 plus NA combination regimen, with the aim of achieving a functional cure in patients with chronic hepatitis B (CHB).

Chronic hepatitis B (CHB) is a life-threatening chronic viral liver infection that can lead to cirrhosis (scarring of liver tissue) after long-term chronic infection, andLiver Cancer. The World Health Organization (WHO) states that hepatitis B is a global public health issue, affecting 292 million people worldwide. Although preventive vaccines are available, the cure rate for those infected remains low, and most patients will require lifelong treatment.

Currently, hepatitis B medications available on the market can only suppress viral replication but cannot eliminate the virus. Drugs based on RNA interference (RNAi) and antisense RNA technologies can highly specifically locate, bind to, and degrade HBV RNA transcripts, silence all HBV gene products, prevent the production of viral proteins, and intervene upstream of the reverse transcription process targeted by current standard-of-care nucleotide and nucleoside analogs. The knockdown of viral proteins is expected to restore the body’s innate immune defense system’s response to HBV, thereby clearing the virus and achieving a functional cure. Such drugs hold the promise of revolutionizing the treatment of hepatitis B.

Major Therapeutic Targets for HBV (Image source: Literature - DOI: 10.1080/13543784.2017.1333105)

Currently, multiple pharmaceutical companies are leveraging RNA interference (RNAi) and antisense RNA technologies to develop therapeutics for chronic hepatitis B. In addition to Johnson & Johnson/Arrowhead Pharmaceuticals (JNJ-3989, formerly known as ARO-HBV), these include Ionis/GlaxoSmithKline(Antisense RNA drugs: IONIS-HBVRx, IONIS-HBV-LRx), Vir/Alnylam (VIR-2218), Arbutus Biopharma (GalNAc-RNAi drug AB-729), Roche/Dicerna (DCR-HBVS), etc. (Bioon.com)

Original Source: Arrowhead and Collaborator Janssen Present Phase 2 Clinical Data on Investigational Hepatitis B Therapeutic JNJ-3989 at The Digital Liver Congress