Four trials to watch over the next 12 months

The biggest unmet need for people with hepatitis B is a cure, but there are many trials looking to achieve a functional cure for the disease. GSK’s Bepirovirsen is pursuing a functional cure, showing very promising results in a Phase II trial in June 2022, and has now initiated a Phase III trial, expected to conclude in 2025. Functional cure is defined as the disappearance of hepatitis B surface antigen (HBsAg) and undetectable hepatitis B virus (HBV) six months after drug discontinuation.

With the World Health Organization estimating that 296 million people were living with chronic hepatitis B (CHB) infection in 2019, resulting in approximately 820,000 deaths, the need for a cure for hepatitis B cannot be overemphasized.

Dr. Henry Janssen, professor of medicine at the University of Toronto and director of the Liver Disease Center and Division of Hepatology at Toronto General Hospital, said the challenge is not the disappearance of HBsAg and HBV, but maintaining it. “To make it last, we thought we needed an immune modulator to do that,” explains Jensen, “so you have to stimulate the immune response in a way that keeps the virus in check without the virus ‘rebounding’ . “

Dr. Antonio Bertoletti, an infectious disease physician and professor at Duke-NUS Medical School in Singapore, said he thinks it is more important for hepatitis B trials to find groups of people who might be more effective than pursuing a one-size-fits-all treatment. “One bullet doesn’t fit all,” Bertoletti said. “Some patients need treatment, some patients may not need treatment, some patients have to be treated by activating adaptive immunity, and other patients need to respond by activating innate immunity. “I think this (patient selection) is a matter of the research community Something you should be committed to doing. “

Combination therapy or monotherapy?

The French ANRS Research Center is conducting an IP-CURE-B proof-of-concept (PoC) Phase II clinical trial (NCT05045261), which will end on June 30, 2024. The purpose of this study was to evaluate whether discontinuation of nucleotide or nucleoside analogues after treatment with selgantolimod (SLGN) can significantly reduce HBsAg compared with standard of care treatment of CHB (NUC). The study was divided into three groups: one with no intervention, one with NUC discontinued after 28 weeks, and the other with NUC discontinued at 28 weeks after 24 weeks of SLGN treatment.

Dr. Jordan Feld, a clinician-scientist at the Liver Clinic at Toronto Western Hospital and the McLaughlin-Rotman Center for Global Health, said TLR8 agonists are helpful but questions whether they are enough to achieve a functional cure. “In studies looking at TLR7 or TLR8, they were not sufficient by themselves to cause any real changes in viral parameters, particularly surface antigens.”

Meanwhile, Hannover Medical School is pursuing a functional cure with immunoglobulins in the phase II trial HBIG Cure (NCT05345990), which will end on August 1, 2023. Hepatitis B immune globulin (Hepatect, Nabi-HB, Zutectra, Neohepatect, Fovepta) mainly contains immunoglobulin G and serves as a passive immune preparation. Both cohorts were HBsAg-positive and HBeAg-negative, with one group receiving no treatment and the other group having received anti-HBV NUC therapy for at least 12 months before screening. The primary endpoint was the number of patients who were HBsAg negative at week 12 of treatment.

“This trial is very important for understanding the role of immunoglobulins. Can immunoglobulins really lead to a cure? I don’t think so,” explains Bertoletti. “I think patients may become S-antigen negative, but that’s just a mask. “I think this trial is more about the accumulation of knowledge. “

Dr. Antonio Bertoletti
Dr. Antonio Bertoletti believes that finding the right patient for the right treatment is more important than finding a one-size-fits-all approach.Image source: Duke-NUS Medical School

“I would be a little surprised if that alone changed everything,” Feld said. “Even if it did, you have to weigh whether it would only be useful in people with very low S levels, so how useful would it be?”

Testing the effects of peginterferon on specific genes

Another combination therapy is undergoing a phase 2 trial at Sun Yat-sen University (NCT03771677); however, this is not focused on finding a cure. Instead, researchers are trying to optimize the clinical treatment path of peginterferon α-2a in CHB subjects based on interferon gene mutation (IFNA2p.Ala120Thr) detection and interferon-stimulated genes (ISGs) detection gene profiling. The researchers hope that HBsAg will be cleared after 48 weeks. This interventional, nonrandomized, multicenter treatment study will observe the active control group continuing to receive entecavir, and the experimental group receiving pegylated interferon and NUC. The study will end on December 30, 2023.

“It’s an interesting concept. Translating this into clinical practice will be very difficult because the drug is not well tolerated and there may be only a small number of patients who have the gene that makes them sensitive to PEG-IFN treatment, but I Don’t know frankly,” Jensen explained. “I don’t think this is a truly new treatment for hepatitis B. We’ve done these types of PEG-IFN studies over the past 15 years, but not on this specific gene. If it works, this is definitely a step forward It’s a step forward that may only apply to a small percentage of patients.”

“Knockout Punch”

Gilead is conducting a Phase II trial (NCT04891770) to evaluate the safety and efficacy of SLGN-containing combination therapy for the treatment of chronic hepatitis B. The randomized, uncontrolled, open-label, multicenter study has enrolled 103 participants and is expected to conclude on January 1, 2024. The trial was divided into three experimental groups. In the first arm, patients will receive NUC, tenofovir alafenamide once daily and VIR-2218 once monthly. After 12 weeks, weekly SLGN and monthly nivolumab can be added. The second group will initially receive only VIR-2218 and then potentially weekly SLGN and monthly nivolumab. Patients in the third group received SLGN only once a week and nivolumab every four weeks for 24 weeks.

Dr. Jordan Field
Dr. Jordan Feld is a clinician-scientist at Toronto Western Hospital Liver Clinic and the McLaughlin-Rotman Center for Global Health. Photo credit: Toronto Hepatology Centre.

“This is an interesting study, and I would say the main and most important thing is VIR-2218, which is a very strong compound that reduces viral antigens and the virus itself,” Janssen said. “It brings down HBsAg significantly, but not enough to achieve a functional cure. So here, they’re giving immunomodulatory drugs in addition to that to give the final blow, which is to knock the opponent out.”

“The challenge is to study the right combination or the right drug in the wrong population, or in some small, wrong way,” Feld added. “So the order is wrong, the doses are wrong, the time intervals are wrong, and you could end up with a very effective therapy, but you just study it wrong and we conclude that it doesn’t work, and that’s It just doesn’t work as well as you study.”

Can they compete with GSK? Bepirovir?

Most of these studies are looking at functional cures like GlaxoSmithKline’s Bepirovesin, but do experts think any study will show similar levels of efficacy? “It’s hard to say,” Jensen admitted. “I think the Gilead study has the potential to be consistent with GlaxoSmithKline. For me, at the end of the day, the sustainability of the response is as important, if not more important, than getting the response itself.”

At the same time, Feld believes that bepirovirsen will be beneficial to the market, but not as a single therapy. “I think in the best-case scenario for Bepiro Wesson, we’re probably going to see about a 30% S-loss rate, and I hope that’s not where we end up,” Feld concluded.

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