The future of bepirovirsen
Bepirovirsen (bepi) consists of a microscopic string of DNA flanked by tiny amounts of RNA. Initial lab experiments suggested that it has antiviral activity against cells infected with hepatitis B virus (HBV). Subsequent lab tests and analysis of blood samples from people who took bepi confirmed its antiviral activity. Bepi reduces the ability of HBV-infected cells to release proteins and RNA that harm healthy cells.
In addition, bepi appears to activate cells of the immune system in the liver. Once activated, these cells engage in helping the immune system recognize and attack HBV-infected cells. As explained previously in this issue of TreatmentUpdate, two pivotal clinical trials with bepi had favourable outcomes. For the first time, it is possible to effect a functional cure in a large proportion (20%) of people with HBV.
However, the good news about bepi in clinical trials needs to be tempered by bearing in mind at least several points.
Cirrhosis and co-infections
The two clinical trials had carefully selected participants. People who had extensive liver injury (cirrhosis) and people who were co-infected with hepatitis C virus (HCV), hepatitis D virus (HDV) or HIV were excluded.
Cirrhosis
People with cirrhosis are likely to be ill and usually have multiple health conditions. Using a drug such as bepi that activates their immune system may not always be safe. Bepi manufacturer GSK is unlikely to initiate clinical trials of bepi in this population, so researchers will have to determine if a trial is feasible. If so, the research community will have to raise funds to conduct such a trial.
Co-infections
In the future, in people co-infected with HBV and HCV, doctors may try to first cure HCV. Anti-HCV therapies available today are highly effective and can result in cure rates of more than 95%. After co-infected people have been cured of HCV, therapy with drugs such as TAF (tenofovir alafenamide), TDF (tenofovir DF) or entecavir can help reduce HBsAg levels and may make some people suitable candidates for anti-HBV therapy with bepi.
Drugs such as bepi rely on the immune system to achieve a functional cure. One concern is that people with HIV have a weaker immune system than people without HIV. It is possible that rates of functional HBV cure in people with HIV and HBV may be lower than in people with HBV alone.
As part of combination therapy for HIV, many people are taking regimens that have activity against HIV and HBV. These regimens include at least the following drugs:
- TAF + FTC (emtricitabine)
- TDF + FTC
- TDF + 3TC
A clinical trial of bepi is planned for people with HIV who are co-infected with HBV. The trial needs to explore the safety of bepi in this population and also its effectiveness. Drugs such as bepi are broken down by the kidneys, and some people with HIV and HBV have severely impaired kidney function, so bepi may not be suitable for them.
Another challenge of using bepi in people with HIV is that they will have to stop taking nucleoside/nucleotide analogues at some point to find out if bepi can effect a functional cure of HBV. If bepi does not work, the cessation of nucleoside/nucleotide analogues could allow HBV to infect more liver cells.
In people co-infected with HBV and HDV, it may first be necessary to treat HDV with a drug such as bulevirtide (Hepcludex). Clinical trials will be needed to explore how best to effect a functional cure of HBV in people co-infected with HDV.
Healing of the liver
In theory, after successful treatment with bepi, the liver should begin the process of healing and should form new healthy liver cells to replace HBV-infected cells that have been destroyed by bepi. Studies are underway in people who have been treated with bepi whereby researchers remove a tiny portion of the liver (a biopsy) for analysis. They hope to find signs that the liver is regenerating.
Increasing the proportion of people with a functional cure
Treating people with low levels of HBsAg (hepatitis B surface antigen)
In the pivotal clinical trials of bepirovirsen reported earlier in this issue of TreatmentUpdate, participants were required to have relatively low levels of HBsAg (3,000 IU/mL or less before initiating bepi). Overall, about 20% achieved a functional cure.
In analyzing the data from these trials, researchers found that participants who entered the studies with an HBsAg level of 1,000 IU/mL or lower had a greater chance of achieving a functional cure. Around 24% of such people achieved a functional cure.
An additional course of bepi
In theory, it is possible that an additional course of bepi may help some people effect a functional cure. GSK first needs to conduct computer simulations to find out which people with HBV who received bepi may benefit from an additional course of this drug. If computer simulations suggest that an additional course of bepi is likely to help some people, GSK could then launch clinical trials of a second course of bepi to test this idea.
Small interfering RNAs (siRNA)
In a clinical trial called B-United, GSK is testing two drugs—daplusiran + tomligisiran (called “Daptom” by researchers). These drugs are small interfering RNA molecules (siRNA). The drugs work by interfering with messenger molecules (RNA) made by HBV-infected cells. The net result is that HBV-infected cells treated with Daptom produce lower levels of HBV-related proteins. This means that HBsAg can fall to very low levels. By helping to suppress HBsAg, Daptom can likely increase the proportion of people who can achieve a functional cure when subsequently treated with bepi.
In the B-United trial, participants will first receive Daptom. Subsequently, therapy with Daptom will cease and be replaced by bepi. In this way, researchers hope to significantly increase the proportion of people who can achieve a functional cure of HBV.
Long-term monitoring
People who benefited from bepi in the current trials need to be monitored over the long term to find out how long they remain functionally cured. Interim data have revealed that bepi’s benefits persist for at least two years. Additional monitoring will also be needed to assess whether bepi can reduce the long-term risk for liver cancer, a complication that can accompany chronic HBV.
Approval
A dossier on bepi is being reviewed by Health Canada. It is hoped that bepi will be approved in Canada in the fourth quarter of 2026. However, after its approval, bepi has to undergo additional reviews. GSK will also need to begin negotiating with provincial and territorial ministries of health to find a price that is affordable. If negotiations are successful (they can take up to two years), ministries of health would subsidize bepi for people with HBV.
—Sean R. Hosein
REFERENCES:
- Hou J, Lim SG, Buti M. Phase 3 results of bepirovirsen treatment for chronic hepatitis B virus infection. New England Journal of Medicine. 2026 Jun 25;394(24):2395-2406.
- Lok AS. A major step toward a cure for hepatitis B infection. New England Journal of Medicine. 2026 Jun 25;394(24):2471-2472.
- Yuen MF, Heo J, Jang JW, et al. Safety, tolerability and antiviral activity of the antisense oligonucleotide bepirovirsen in patients with chronic hepatitis B: a phase 2 randomized controlled trial. Nature Medicine. 2021 Oct;27(10):1725-1734.
- Ermler ME, Delahaye JL, Jordan W, et al. Bepirovirsen induces innate immune activation in the liver potentially through TLR8 signaling. JHEP Reports. 2026; in press.
- Spencer-Dene B, Mukherjee P, Alex A, et al. Localization of unlabeled bepirovirsen antisense oligonucleotide in murine tissues using in situ hybridization and CARS imaging. RNA. 2023 Oct;29(10):1575-1590.
- Joshi S, Freudenberg JM, Singh JM, et al. Immunomodulation by bepirovirsen may induce killing of infected hepatocytes (B-Together study). Hepatology International. 2026 Feb;20(1):46-58.
- Wedemeyer H, Gane E, Agarwal K, et al. siRNA JNJ-73763989 decreases HBsAg and HDV RNA in NA-treated hepatitis D patients but may cause ALT flares. Journal of Hepatology. 2026 May 15: S0168-8278(26)00282-5.
- Hong J, Rajwanshi VK. Antisense oligonucleotides as drugs with both direct and indirect antiviral actions. Antiviral Research. 2025 Aug; 240:106219.