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JNJ-3989 achieves sustained reductions in hepatitis B surface antigen

Keith Alcorn
29 August 2020

Johnson & Johnson’s short interfering RNA treatment for hepatitis B resulted in sustained reductions in hepatitis B surface antigen when combined with nucleoside analogue drugs, Professor Edward Gane of Auckland City Hospital, New Zealand, told the Digital International Liver Congress this week.

He was presenting results of a phase 2a study of the combination of JNJ-3989 and a nucleoside or nucleotide analogue.

Hepatitis B is a chronic infection. Current treatments can suppress viral replication and reduce liver damage but cannot cure the infection.

Nucleoside or nucleotide analogues (NRTIs) block hepatitis B virus replication but do not block the production of hepatitis B surface antigen nor prevent the replenishment of the pool of cccDNA in hepatocytes which supports viral replication if NRTI therapy is stopped. NRTI treatment must continue indefinitely to control hepatitis B replication.

Combining NRTIs with antivirals which directly block viral entry into hepatocytes, or prevent the production of viral proteins, is judged more likely to deliver a functional cure for hepatitis B infection – viral suppression without the need for treatment.

Achieving a functional cure is likely to require a combination of drugs. “Functional cure” means that all antigens (e.g. HBsAg, HBeAg) and the HBV DNA of the virus disappear from the blood, and only antibodies remain. The cccDNA of the hepatitis B virus however remains in the liver cells. So far, it is not possible to also eliminate hepatitis B cccDNA from liver cells, which would be closer to a “sterilizing cure”.

Arrowhead and Johnson & Johnson are developing a small interfering RNA agent, JNJ-3989, as an antiviral for use in combination with an NRTI.

The small interfering RNA (siRNA) binds to messenger RNA (mRNA), preventing transcription of mRNA involved in the production of viral proteins, including HBV polymerase and hepatitis B surface antigen.

JNJ-3989 is given by subcutaneous injection, in combination with daily oral dosing of an NRTI (tenofovir or entecavir). Preliminary results from this phase 2 study, reported in 2019, showed that three doses of JNJ-3989 given at days 0, 28 and 56 were well tolerated and resulted in reductions in hepatitis B surface antigen, HBeAg, hepatitis B RNA and hepatitis B core antigen 8 weeks after the third injection.

Professor Edward Gane presented longer-term follow-up from the phase 2 study at the International Liver Congress.

The AROHBV1001 phase 2a open-label study recruited people positive or negative for HBeAg, both NRTI-experienced and NRTRI-naïve. Four groups of eight were assigned to ascending doses of JNJ-3989 (100mg-400mg) and two groups of four (one NRTI-naïve, one NRTI-experienced) were assigned to a 300mg dose.

This analysis reviewed hepatitis B surface antigen responses 48 weeks after the last JNJ-3989 dose. Sustained response was defined as a > 1 log10 IU/ml reduction in hepatitis B surface antigen at week 48.

Dosing groups were predominantly male and Asian, and the majority in groups 1-4 were HBeAg negative. Eighty per cent of all study participants were NRTI-experienced.

The mean hepatitis B surface antigen titre at baseline was approximately 4 log IU/ml. The mean nadir reduction in hepatitis B surface antigen ranged from -1.72 log10 IU/ml in the 100mg group to -2.04 log10 IU/ml in the 300mg group. Thirty-four out of 40 participants achieved a nadir reduction of >1 log10 IU/ml and 15 out of 38 (34%) achieved a sustained response at 48 weeks. The mean reduction at 48 weeks in the sustained response group was -1.74 log10 IU/ml.

Hepatitis B surface antigen sustained responders also had sustained reductions in HBV RNA, HBeAg and HBcoreAg.

The investigational treatment continued to be well tolerated with no new drug-related adverse events reported beyond day 85. Adverse events consisted of mild injection site reactions (7), mild muscle pain (2) and abdominal pain (2), 2 mild cases of hyperbilirubinemia and 1 severe creatine kinase elevation (likely due to taking creatine health supplements prior to study entry). No grade 2 ALT elevations were observed during the study, suggesting that JNJ-3989 does not have an adverse effect on the liver.

Short-term siRNA treatment can result in sustained hepatitis B surface antigen reduction, the study investigators concluded, supporting future studies of 48 weeks of JNJ-3989 and NRTIs, with or without JNJ-6379, a capsid assembly modulator.


Gane E et al. Short-term treatment with RNA interference therapy, JNJ-3989, results in sustained hepatitis B surface antigen supression in patients with chronic hepatitis B receiving nucleos(t)ide analogue treatment. Journal of Hepatology, supplement 1 [International Liver Congress], GS10, S20, 2020.