Recently, the U.S. FDA approved GSK's new drug application for Hibsago (bepirovirsen), a new drug for chronic hepatitis B. This is the world's first approved antisense oligonucleotide (ASO) drug for chronic hepatitis B.
updated the status of its Phase 1 clinical trial for another hepatitis B candidate, GSK3965193 , to " terminated ," citing "strategic decision" as the reason. The U.S. Clinical Trials Registry also marked the project as terminated.
One pipeline reached market approval, while another drug candidate abruptly halted its first human trial. What kind of R&D choices does GSK make in the hepatitis B drug race?
The experiment was terminated.
According to publicly available information in the clinical trial registry, this study, numbered NCT05330455 , is a phase I/IIa, multipart, randomized, double-blind, placebo-controlled first-in-human trial (FTIH) that was initiated on April 14, 2022, and enrolled 74 participants at 14 centers in 6 countries around the world.
The study design consisted of several parts: Parts one and two evaluated the safety, tolerability, and pharmacokinetics of single and multiple doses in healthy subjects; Part three evaluated the efficacy of GSK3965193 in reducing hepatitis B surface antigen (HBsAg) levels in patients with chronic hepatitis B, who could also choose to receive open-label bepirovirsen treatment subsequently; Part four evaluated the safety and tolerability of the combination therapy of GSK3965193 and bepirovirsen, as well as the potential of this combination therapy to achieve sustained virological response in patients with chronic hepatitis B infection.
Let's review some key dates in the registration information: On May 10, 2026, the trial's status changed from "active, no longer recruiting" to "terminated"; on June 16, 2026, the relevant trial data was released to the public for the first time; and in October, the registration status was finally updated to "terminated". In other words, the trial had actually been suspended for about five months before this information was updated to the public.
Regarding the reason for termination, a GSK spokesperson confirmed that the trial had indeed been stopped, emphasizing that it was a proactive choice made by the company based on strategic considerations. There were no safety issues, no deaths occurred during the trial, and regulatory and ethics bodies did not intervene. As of press time, GSK's pipeline on its official website still lists GSK3965193 as a Phase I project. Fierce Biotech reported that when they inquired with GSK whether the discontinuation of the trial meant the direct termination of the drug candidate, GSK did not provide a clear answer.
Although the official statement clarifies that it is unrelated to safety, the industry will still look for reasons in the past research and development experience of the target. Many pharmaceutical companies have followed the technical route of GSK3965193, and most of the previous research and development attempts have been stuck on the same problem.
The Toxicity Problem of PAPD5/PAPD7 Tracks
GSK3965193 is a dual-target inhibitor of PAPD5/PAPD7. The termination of this project has sparked industry discussion due to the theoretical potential of the target itself, as well as the series of setbacks encountered during its research and development.
PAPD5 and PAPD7 are non-classical polyadenylate polymerases in host cells. Hepatitis B virus (HBV) utilizes post-transcriptional regulatory elements (PRE/SLα) on its own RNA to recruit host protein complexes containing PAPD5/PAPD7, modifying and protecting the poly(A) tail of viral mRNA, prolonging the half-life of viral transcripts, and increasing surface antigen expression. PAPD5/7 inhibitors accelerate viral mRNA degradation by blocking this host pathway, thereby reducing HBsAg levels. Theoretically, continuously reducing antigen load helps alleviate the suppression of HBV-specific immunity, creating conditions for breaking immune tolerance in chronic infection. For functional cure of hepatitis B, i.e., the continued undetectability of HBV DNA and HBsAg after drug discontinuation, sustained suppression of HBsAg is considered a key prerequisite, which is why this target was once highly anticipated.
However, the toxicity problem remains a persistent challenge along this technological route. A review of publicly available information reveals several projects that have failed: Roche's RG7834, the first PAPD5/7 inhibitor to enter clinical trials, was halted in Phase I due to neurotoxicity; Gilead's GS-8873 was suspended before even entering clinical trials after neurophysiological abnormalities were observed in monkey experiments. Arbutus' AB-161 was initially considered promising, representing a new generation of molecules in this field. Early data showed significantly better neurotoxicity than older drugs, and no safety concerns were reported in a Phase I single-dose trial in healthy individuals. However, a subsequent 90-day repeated-dose toxicology study in dogs revealed male reproductive toxicity, ultimately leading to the project's complete cessation.
In other words, when GSK3965193 was advancing into clinical trials, several candidate molecules targeting the same target had already failed due to issues with toxicity or insufficient therapeutic window, and the field itself was shrouded in considerable safety concerns.
The root of the problem lies in the target itself. PAPD5 does not only target viral proteins; it also participates in the processing of human mRNA. This makes it difficult for drugs to precisely differentiate between the target and the virus, resulting in a very small safety margin and making it difficult to avoid the risk of off-target toxicity.
Based on the disclosed Phase I, Part 3 data for GSK3965193, no serious treatment-related adverse events or grade 2 or higher adverse events occurred in this part; the most common adverse reactions were dizziness, fatigue, taste disturbances, and headache. Considering the frequent neurotoxicity associated with this target in the past, the study also specifically included nerve conduction function tests at baseline, day 15, and day 29, and the results showed no significant abnormalities.
However, one point is noteworthy in the complete trial information disclosed in the clinical trial registry: Part 2B of this study was originally designed with three treatment cycles (TP), but based on the safety and tolerability results observed in the second treatment cycle, the third treatment cycle was not conducted. After completing Phase 3, the study was terminated due to strategic decisions, therefore no subjects were recruited for Phase 4. GSK's official statement is that the termination of this trial was a strategic adjustment and not driven by safety issues, but the trial registry records show that tolerability-related signals were indeed observed during the study. Therefore, this information needs to be interpreted in a comprehensive and comparative manner.
GSK3965193 was one of the few projects still progressing in the PAPD5/PAPD7 target area. GSK terminated the trial citing strategic adjustments, making it impossible for outsiders to directly determine whether it also encountered similar toxicity issues. However, a clear industry fact is that with GSK's withdrawal, the once-promising PAPD5/7 inhibitor pipeline has gradually ceased operations.
pipeline contraction
The termination of this project should be viewed within the framework of GSK's overall hepatitis B strategy.
The newly approved bepirovirsen is the core of GSK's hepatitis B strategy. Bepirovirsen is an antisense oligonucleotide drug derived from a technology license from Ionis. It has been approved by the FDA for use in combination with nucleoside (acid) analogue reverse transcriptase inhibitors (NrtIs) to treat chronic hepatitis B virus infection. The dosage regimen is 300 mg subcutaneously: twice weekly for the first two weeks, once weekly from weeks 3 to 24, for a total of 24 weeks.
Data from the B-Well Phase III study supporting bepirovirsen's approval showed that in adult patients with HBsAg ≤3000 IU/mL, 24% of the Hibsago treatment group met the criteria for discontinuing existing medications, while none in the placebo group did; 19% of patients achieved functional cure, meaning that HBV DNA and HBsAg were undetectable for at least 24 weeks after stopping all treatment; in contrast, less than 1% of patients receiving existing standard treatment achieved functional cure after one year of treatment. Data presented at the European Association for the Study of the Liver (EASL) Congress in May of this year further showed that in the subgroup with HBsAg ≤1000 IU/mL, the functional cure rate increased to 26%, and this group accounts for approximately 45% of chronic hepatitis B patients worldwide . This drug was first approved in Japan in August of this year.
With its flagship product in hand, GSK's strategy for its subsequent pipeline has become clearer. At the beginning of this year, GSK had several drug candidates as backups after bepirovirsen, but the pipeline has now been reshuffled. The TLR8 agonist GSK5251738 was discontinued in the Q1 2026 pipeline evaluation; the GSK3965193 trial was terminated, and its future is uncertain. Currently, GSK's entire hepatitis B pipeline essentially consists of only two drugs: the already marketed bepirovirsen, and a Phase II siRNA drug, GSK5637608, developed by Arrowhead and acquired by GSK from Johnson & Johnson.
From a broader industry perspective, GSK's decision is not an isolated incident; it is also a microcosm of the paradigm shift in hepatitis B treatment.
For a long time, antiviral treatment for hepatitis B only offered two options: oral nucleoside (acid) analogs and interferon. Nucleoside analogs can strongly suppress viral replication, but they cannot clear cccDNA from the hepatocyte nucleus, requiring patients to take them long-term or even for life, and rebound is very common after discontinuation. Interferon treatment has a fixed course and offers a chance to clear the surface antigen, but its overall effectiveness is low, and it often causes side effects such as fever, rash, and decreased white blood cell count. It is precisely because of these limitations in existing treatments that "functional cure" has become the goal pursued by the industry, and it also determines the commercial value of new drugs. The emergence of bepirovirsen represents a crucial step from long-term viral suppression to achieving functional cure with a limited treatment course.
Meanwhile, with the gradual discontinuation of PAPD5/7 inhibitors, the differences between different technological approaches in the hepatitis B research field are becoming increasingly clear. Current research is mainly focused on nucleic acid drugs such as ASO and siRNA, which have more robust evidence, as well as direct virus-targeting approaches such as capsid inhibitors and HBsAg secretion inhibitors. From this perspective, the termination of this project is not just a research choice by GSK, but more like a signal that this technological approach is coming to an end.
Within GSK's internal pipeline, the siRNA candidate drug GSK5637608 is highly anticipated. It is positioned as the first step in a sequential treatment regimen. In clinical studies, it first lowers antigen levels, then is followed by bepirovirsen to exert an immune-activating effect, addressing the weakness of bepirovirsen in patients with high HBsAg levels.
Conclusion
Chronic hepatitis B affects hundreds of millions of people worldwide. In this field, the termination of each pipeline may mean the closure of a certain pathway, but the approval of each new drug points to a viable direction for subsequent research and development. GSK's recent decision also serves as a reminder to the industry: the final decision-maker in new drug development is never the mechanism hypothesis, but ultimately, it must pass the tests of safety, efficacy, and time. The exploration of the PAPD5/PAPD7 route has temporarily come to an end, but humanity's pursuit of a functional cure for hepatitis B has only just entered its second half.

Source: https://news.yaozh.com/archive/49298.html