GSK's Antisense Oligonucleotide Therapy GSK3228836 Receives First-in-China IND Approval for Chronic Hepatitis B

According to public information from the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration, GlaxoSmithKline’s (GSK) Class 1 new drug, GSK3228836 injection, has received implicit approval for a clinical trial, with the indication being “chronic hepatitis B.” GSK3228836 is an antisense oligonucleotide (ASO) drug, and global Phase 2a clinical trial results have demonstrated its potential to inhibit the hepatitis B virus. This marks its first approval for clinical trials in China.

Screenshot source: CDE official website

Hepatitis B virus (HBV) infection is the most common serious liver infection worldwide. Although current antiviral therapy with nucleos(t)ide analogues (NUCs) can suppress HBV replication, patients require lifelong medication. This is because, after entering the host, HBV integrates its genome into the host cell nucleus to form covalently closed circular DNA (cccDNA) and integrated sequences. These sequences have very long half-lives, and existing drugs can only reduce levels of hepatitis B surface antigen (HBsAg) and viral DNA, making it difficult to completely eradicate cccDNA.

Therefore, achieving a "functional cure" for hepatitis B has become the goal pursued by scientists. According to GSK's press release, a functional cure is defined as a state in which the virus is not completely eradicated but remains at very low levels, allowing it to be controlled by the immune system without the need for medication.

GSK3228836 (GSK’836) is an antisense oligonucleotide drug co-developed by GSK and Ionis Pharmaceuticals. Antisense oligonucleotides are small, synthetic single-stranded nucleic acid polymers with diverse chemical properties that can regulate gene expression through multiple mechanisms. In hepatitis B virus-infected livers, GSK3228836 specifically recognizes the viral mRNA used to produce viral antigens (disease-causing proteins) and recruits endogenous hepatic enzymes to degrade the viral mRNA, thereby reducing levels of the hepatitis B surface antigen (HBsAg).

Globally, GSK3228836 has entered Phase 2 clinical trials. This marks the first approval for clinical investigation of this drug in China, with the indication being “chronic hepatitis B.”

According to data presented by GSK at the European Association for the Study of the Liver (EASL) Congress in late August this year, GSK3228836 achieved positive results in its Phase 2a clinical trial for the treatment of chronic hepatitis B patients. The trial results demonstrated that hepatitis B surface antigen levels were reduced in patients treated with 300 mg of GSK3228836, both in those who had previously received nucleos(t)ide analogue (NA) therapy and in those who had not.

Among the 4 patients who had previously received nucleos(t)ide analogue (NA) therapy, those treated with antisense oligonucleotide (ASO) therapy exhibited a 2.51 log10 reduction in hepatitis B surface antigen (HBsAg) levels compared to placebo, with 3 of these patients achieving a reduction exceeding 3 log10;

Among the 12 patients who had not received nucleos(t)ide analogue (NA) therapy, the hepatitis B surface antigen (HBsAg) level decreased by 1.56 log10 (p=0.001), with three patients showing a reduction exceeding 3 log10. The mean HBV DNA level decreased by 1.66 log10 (p<0.001).

Pooled data from the two patient groups showed that a total of four patients had hepatitis B surface antigen (HBsAg) levels reduced below the limit of detection at the end of the 4-week treatment course. Furthermore, one nucleos(t)ide analogue (NA)-naïve patient and one patient with prior NA therapy exhibited sustained reductions in HBsAg levels, with follow-up extending up to 126 days post-treatment. In a press release, GSK stated that these results represent a potential step forward toward their goal of evaluating sustained functional cure in patients with chronic hepatitis B. GSK expects to initiate a Phase 2b clinical trial of GSK3228836 by the end of this year.

According to estimates by the World Health Organization (WHO), there are over 290 million people with chronic hepatitis B worldwide. It causes more than 800,000 deaths annually. In China, nearly 100 million people are infected with the hepatitis B virus, including over 28 million with chronic hepatitis B. HBV infection is the leading cause of liver cancer, which is the second leading cause of cancer-related deaths globally.

Source: Medical Overview

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