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Home Arrowhead and Janssen Announce New Clinical Data for RNAi-Based JNJ-3989 in Dual and Triple Combination Therapies for Functional Cure of Chronic Hepatitis B

Arrowhead and Janssen Announce New Clinical Data for RNAi-Based JNJ-3989 in Dual and Triple Combination Therapies for Functional Cure of Chronic Hepatitis B

Nov 14, 2019 16:08 CST Updated 09:14
Johnson & Johnson

Healthcare Product Manufacturers, Health Service Providers

Arrowhead Pharmaceuticals

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Janssen Pharmaceuticals

Pharmaceutical R&D Developer


November 14, 2019/BioValleyBIOON/--The 70th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) was held in Boston, USA, from November 8 to 12, 2019. The AASLD Annual Meeting (The Liver Meeting) is currently the largest and most authoritative hepatology conference in the world.MeetingEach year, more than 9,000 hepatologists and liver disease research professionals from around the world convene to share and discuss breakthrough research findings, new treatment guidelines, and the latest therapeutic advances in the field of hepatology.

At this conference, RNAi therapeutics company Arrowhead Pharmaceuticals and its partner Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson, announced Phase II clinical data for the dual therapy of JNJ-3989 (formerly ARO-HBV) with nucleos(t)ide analogs (NAs), as well as the initial clinical data for the triple therapy regimen comprising JNJ-3989, JNJ-6379, and NAs.

Currently, Janssen is conducting a Phase IIb study of the triple combination therapy of JNJ-3989, JNJ-6379, and NA for the treatment of chronic hepatitis B virus (HBV) infection. Janssen and Arrowhead Pharmaceuticals entered into a license and collaboration agreement in October 2018 to develop and commercialize JNJ-3989.

JNJ-3989 is a liver-targeted, subcutaneously administered antiviral agent designed to treat hepatitis B virus (HBV) infection via an RNA interference (RNAi) mechanism. Currently, JNJ-3989 is being developed as a potential functional cure for individuals with HBV infection. JNJ-3989 silences all HBV gene products and intervenes upstream of the reverse transcription process targeted by standard-of-care nucleotide and nucleoside analogues, thereby enabling the body’s innate immune defense system to clear the virus and achieve a functional cure. JNJ-6379 is an orally administered capsid assembly modulator (CAM) that blocks normal capsid assembly during HBV replication.

The clinical data announced at this meeting are as follows:

——Dose Response of RNAi Drug JNJ-3989 Combined with NA in the Treatment of Chronic Hepatitis B in an Expanded Cohort:

In the AROHBV1001 study conducted in patients with chronic hepatitis B, JNJ-3989 combined with nucleos(t)ide analogs (NAs) demonstrated potent inhibitory effects on HBsAg, HBV DNA, and HBV RNA, whereas the reductions in HBeAg and hepatitis B core-related antigen (HBcrAg) were less pronounced.

Specifically: (1) The decline in HBsAg was similar in HBeAg-positive and HBeAg-negative patients; (2) The expanded cohort receiving 100–400 mg of JNJ-3989 confirmed previous findings, with similar declines in HBsAg at these doses; 97% (31/32) of these patients achieved an HBsAg reduction of ≥1.0 log10 (90%).
; (3) The 25 mg and 50 mg doses of JNJ-3989 significantly reduced HBsAg levels, although the effect was slightly less pronounced than that observed with the higher dose.; (4) The response of HBsAg to JNJ-3989 is consistent with its ability to silence HBV RNA from cccDNA and host-integrated viral DNA (the primary source of HBsAg in certain CHB populations); (5) JNJ-3989 was well tolerated during treatment with up to three doses administered once every 4 weeks (Q4W) at doses up to 400 mg; (6) Overall, JNJ-3989 demonstrated anti-HBV properties, which are required for an effective RNAi therapy.。

—First Clinical Data on RNAi-Based Triple Therapy for Hepatitis B (NJ-3989, JNJ-6379, NA)

This is the first clinical study to investigate the safety and efficacy of triple therapy consisting of an RNAi drug (JNJ-3989, 200 mg administered once every 4 weeks [Q4W] for three doses), a capsid assembly modulator–nucleocapsid (CAM-N) inhibitor (JNJ-6379, 250 mg once daily for 12 weeks), and a nucleos(t)ide analogue (NA; once daily) in patients with chronic hepatitis B. In this study, the triple therapy was well tolerated. During the treatment period, all treated patients with chronic hepatitis B exhibited significant reductions in HBsAg, HBV DNA, and HBV RNA levels, whereas reductions in HBeAg and HBcrAg were less pronounced. Specifically: (1) All patients (n=12) achieved an HBsAg reduction of ≥1.0 log10 IU/mL (90%) (range: -1.01 to -2.26 log10 IU/mL); (2) The reduction in HBsAg was similar in both HBeAg-positive and HBeAg-negative patients.

Currently, studies evaluating the long-term treatment with this triple therapy are underway, aiming to assess the functional cure rate in patients with chronic hepatitis B.

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

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 CancerThe 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 drugs available on the market can only suppress viral replication but cannot eliminate the virus. Drugs based on RNA interference (RNAi) and antisense RNA technology can highly specifically seek out, bind to, and destroy 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 natural immune defense system’s response to HBV, thereby clearing the virus and achieving a functional cure. Such drugs hold the promise of revolutionizing hepatitis B treatment.

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.

Notably, at this conference, Gilead Sciences presented new clinical data on GS-9688 (selgantolimod), a novel investigational drug for the functional cure of hepatitis B. GS-9688 is an oral, selective Toll-like receptor 8 (TLR8) small-molecule agonist. In a multicenter, randomized, double-blind Phase II study involving 48 chronic HBV-infected patients who had achieved virologic suppression, GS-9688 (administered orally once weekly) in combination with oral antiviral agents (OAVs) demonstrated favorable tolerability during the extended dosing period and exhibited dose-dependent pharmacodynamic activity. The clinical activity of GS-9688 was also evaluated: among patients receiving GS-9688, 5% achieved a reduction in hepatitis B surface antigen (HBsAg) or hepatitis B e antigen (HBeAg) levels of ≥1 log10 IU/mL by Week 24 of treatment. (Bioon.com)