GSK Terminates Phase II Clinical Trial of Therapeutic Hepatitis B Vaccine GSK3528869 Due to Lack of Efficacy

Dec 04, 2024 19:26 CST Updated 19:26

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On December 3, 2024, the well-known industry media *Endpoints News* reported that GSK had terminated the Phase II clinical trial (NCT03866187) of its investigational therapeutic hepatitis B (HBV) vaccine, GSK3528869.

According toCAccording to the query on clinicaltrials.gov, the trial status is terminated. The last update was on November 29, 2024. The reason for termination was that it failed to meet the pre-specified efficacy endpoint at the end of the primary phase of the trial, which was 24 weeks after the last vaccination.

GSK3528869 is a viral vector and adjuvant protein vaccine, consisting of two viral vectors (ChAd155-hIi-HBV, MVA-HBV) and a liposome combination adjuvant (AS01B-4).

GSK has high hopes for GSK3528869, hopingAchieving the goal of a functional cure for HBV by controlling and resolving the clinical sequelae of infection and reducing the need for further treatment.

Functional cure is currently recognized as the ideal treatment goal in the guidelines for the prevention and treatment of chronic hepatitis B both in China and internationally, which means sustained undetectable levels of hepatitis B DNA and the loss of hepatitis B surface antigen (HBsAg) after treatment.

To achieve this goal, multiple challenges need to be addressed, such as HBV latency, patient immune tolerance, and the high standards for persistent immune control.

Currently, the functional cure rate of monotherapy regimens is low. The application of current anti-HBV drugs, nucleos(t)ide analogs (NA),_S) and Pegylated Interferon (Peg-IFN-α) with monotherapy for chronic hepatitis B HB_SAg disappearance rate is less than 5%.

This time, the clinical failure of GSK3528869 did not disclose specific clinical data, and it happened quietly without any fanfare.

According to incomplete statistics, there are currently over 40 new drugs for the functional cure of hepatitis B in clinical trials. These can be roughly categorized into two main types: new drugs targeting the virus (DAA) and new drugs targeting the host (DHA). GSK3528869 belongs to the latter category.

In fact, all therapeutic hepatitis B vaccines belong to DHA, meaning that vaccine technology is used as a treatment method to activate the human immune system. These indirect antiviral agents also include compounds that activate the innate immune system, compounds that induce programmed cell death (apoptosis), monoclonal antibodies, and immune checkpoint inhibitors, among other drug forms.

Endpoints News called this clinical setback another blow to the development of hepatitis B drugs.

Roche cut four hepatitis B projects last quarter; Johnson & Johnson terminated the development of all its hepatitis drugs last year; Antios Therapeutics also went bankrupt last year due to safety issues with its hepatitis B drug; Altimmune announced in June this year that its chronic hepatitis B immunotherapy, HepTcell, was discontinued due to unsatisfactory clinical trial results...

Despite the frequent failures of clinical trials and the termination of R&D pipelines in the hepatitis B field, researchers' enthusiasm for exploration has not diminished. Take GSK as an example; apart from GSK3528869, GSK is also exploring various novel mechanism-based innovative drugs for hepatitis B targeting different mechanisms.

Among its pipeline drugs, the one with the fastest clinical progress is bepirovirsen (GSK836), co-developed by GSK and Ionis. The Phase 2b B-Together study of this drug showed that the HBsAg and HBV DNA clearance rate was 9% (5/55) for all enrolled patients; the HBsAg and HBV DNA clearance rate was 14% (5/37) for patients with baseline HBsAg ≤3000 IU/mL.

In addition, the trial results suggest that sequential treatment with GSK836 and Peg-IFN-α can increase the rates of HBsAg and HBV DNA loss. Currently, GSK836 is being tested in combination therapy trials with JNJ-3989 (ASO+siRNA) and GSK3965193 (PAPD5/7 inhibitor).

According to the latest data from the World Health Organization (WHO),As of 2022, the number of people with chronic hepatitis B worldwideThe number is 254 million, with 1.2 million new hepatitis B infections in 2022 alone, and approximately 1.3 million deaths from viral hepatitis.

China is a country with an especially high burden of hepatitis B globally. According to a study published in The Lancet Regional Health Western Pacific, a subsidiary of The Lancet, there are approximately 75 million people with hepatitis B in China, of which about 30 million are unaware that they are infected.

Despite a declining trend in the incidence of hepatitis B in recent years due to improvements in public health conditions, the promotion of vaccines, and the widespread use of various antiviral drugs, it remains the leading cause of liver cancer.

How to Further ImproveChronic Hepatitis B Treatment: Urgent and Critical. Currently,Combination of NAs drugs and interferonTreatment solutions become a hot spot in industry R&D.The emergence of new target/mechanism drugs such as RNA interference, antisense oligonucleotides, capsid inhibitors, and HBsAg inhibitors also providesHepatitis BThe treatment market offers diversified research directions.

However, it is worth noting that further research is still needed on when to combine treatments, how to sequence different drugs, the duration of treatment, and personalized treatment.

For this reason,New Drug Alliance for Liver DiseasesJoining hands with multiple outstanding organizations, it will take place in Shanghai, China, from December 13 to 14, 2024.Host2024 Annual Conference of the Hepatology New Drug Alliance & New Weight Loss Drug Forum. In"Seize the Opportunities of the Times, Overcome Stubborn Liver Diseases"Themed, jointly explore the new future of liver disease treatment.

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