Johnson & Johnson's Two Investigational Therapies for Chronic Hepatitis B Designated as Breakthrough Therapy by CDE

Author | Sunshine

On July 12, the official website of the Center for Drug Evaluation (CDE) indicated that Johnson & Johnson's JNJ-56136379 tablets and JNJ-73763989 injection were proposed for breakthrough therapy designation, both for the treatment of chronic hepatitis B virus infection.

Chronic Hepatitis B (CHB) is a chronic disease caused by persistent hepatitis B virus (HBV) infection lasting more than six months, characterized by varying degrees of hepatic inflammation, necrosis, and/or fibrosis. Hepatitis B is classified as a Class B infectious disease, transmitted via mother-to-child transmission, blood, body fluids, and sexual contact. Its primary symptoms include recurrent fatigue, loss of appetite, aversion to fatty foods, discomfort in the hepatic region, and abdominal distension. Long-term HBV infection can lead to liver cirrhosis and liver cancer.

Globally, approximately 257 million individuals are chronically infected with the hepatitis B virus (HBV), with the African and Western Pacific regions accounting for 68%. Annually, an estimated 887,000 deaths are attributable to chronic hepatitis B-related diseases, among which cirrhosis accounts for 30% and primary hepatocellular carcinoma accounts for 45%. In China, among patients with cirrhosis and primary hepatocellular carcinoma, 77% and 84% are attributable to hepatitis B virus infection, respectively.

JNJ-56136379 tablets (JNJ-379) is a hepatitis B virus (HBV) capsid assembly inhibitor acquired by Johnson & Johnson through its acquisition of Alios BioPharma. It features a dual mechanism of action that inhibits both early and late stages of the HBV life cycle. As HBV DNA replication occurs primarily within the nucleocapsid, inhibiting HBV capsid assembly prevents DNA replication, resulting in the formation of morphologically normal but nucleic acid-deficient capsids, thereby providing a treatment for chronic hepatitis B.

Currently, JNJ-56136379 tablets for the treatment of chronic hepatitis B have advanced to Phase II clinical trials. In the first-in-human oral Phase I clinical study, 28-day administration of JNJ-56136379 tablets demonstrated favorable tolerability, safety, and antiviral activity, along with dose-dependent pharmacokinetic characteristics.

Source: PharmaCube NextPharma

JNJ-73763989 injection (ARO-HBV, JNJ-3989) is an siRNA therapy co-developed by Arrowhead Pharmaceuticals and Johnson & Johnson. JNJ-73763989 contains two siRNA sequences, each conjugated to GalNAc, which target hepatocytes to silence viral cccDNA and all mRNAs transcribed from viral DNA integrated into the host genome. It intervenes upstream of the reverse transcription process targeted by standard-of-care nucleotide and nucleoside analogs, thereby enabling the host's innate immune defense system to clear the virus and achieve a functional cure.

Currently, the JNJ-73763989 injection for the treatment of chronic hepatitis B has advanced to Phase II clinical trials. Clinical data from the Phase I trial (NCT04208386), presented at the 2021 Annual Meeting of the European Association for the Study of the Liver (EASL), demonstrated that JNJ-3989 effectively reduced all viral markers. Compared with other markers, HBsAg exhibited the most pronounced reduction, and this effect was more marked in HBeAg-positive patients than in HBeAg-negative patients. Reductions in HBeAg, HBcrAg, and HBV RNA were generally correlated with the reduction in HBsAg.

Source: PharmaCube NextPharma

Johnson & Johnson previously conducted a Phase I/II clinical trial (AROHBV1001) to evaluate the efficacy of a triple therapy combining JNJ-3989 (RNAi), JNJ-6379 (HBV capsid inhibitor), and NA. This was the first study to assess the safety and efficacy of the JNJ-3989 + JNJ-6739 + NA triple therapy in patients with chronic hepatitis B. The results demonstrated that the combination was well-tolerated and significantly reduced HBsAg levels as well as other measurable viral parameters in patients.