Virus World

Bepirovirsen, an antisense oligonucleotide therapy aided in preventing chronic hepatitis B in patients in a Phase II trial.  GSK has announced study results from its Phase IIb trial (NCT04449029) of bepirovirsen for chronic hepatitis B (CHB), indicating that the antisense oligonucleotide therapy could help treat CHB independently or in combination with nucleoside/nucleotide analogues (NAs). Bepirovirsen demonstrated clearance of hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA long term, in patients on concurrent NA and those not-on-NA therapy. The current treatment for the condition includes NAs, often taken for life due to their ability to suppress the virus. Chris Corsico, Senior Vice President of Development at GSK: “Today’s results from the study are a promising step forward… We look forward to confirming these findings for bepirovirsen in our Phase III study starting next year, [and] exploring potential sequential therapy options with the aim of helping more people living with chronic hepatitis B achieve functional cure.” The trial investigated the efficacy and safety of 12 or 24 weeks of bepirovirsen treatment on stable NA treatment or not-on-NA treatment at study start. A loading dose of Bepirovirsen was given at day 4 and 11. A dose of 300mg per week was administered for 24 weeks, resulting in 9 percent of patients on NA and 10 percent of patients not-on-NA, achieving HBsAg levels below the Lower Limit of Detection (LLOD) and HBV DNA levels below the Lower Limit of Quantification (LLOQ). Patients with low baseline hepatitis B surface antigen levels responded best to treatment. The findings showed 16 percent of patients on NA and 25 percent not-on-NA achieved appropriate LLOD and LLOQ levels.

Further data on the chronic hepatitis B clinical trial

The research investigating Bepirovirsen was made up of two parallel cohorts. One for patients receiving NA treatment and the other for patients not-on-NA. Volunteers were randomised into 1 of 4 treatment arms within each cohort:

• Arm 1: 300mg with a loading dose for 24 weeks
• Arm 2: 300mg with a loading dose for 12 weeks then 150mg for 12 weeks
• Arm 3: 300mg with a loading dose for 12 weeks then placebo for 12 weeks
• Arm 4: Placebo with a loading dose for 12 weeks then 300mg Bepirovirsen without a loading dose for 12 weeks.

There were no safety signals to prevent further development. Adverse events (AEs) leading to treatment discontinuation occurred in 17 participants, with 0–4 percent frequency in participants on-NA, and 0–7 percent frequency in participants not-on-NA. Serious AEs (SAEs) were reported in six (3 percent) of participants on NA and 11 (5 percent) of participants not-on-NA. One SAE in the on NA and three in the not-on-NA population were considered related to treatment. To obtain data on the drug’s long-term durability, trial participants will be investigated for an additional 33 months. Patients who continue to have no serologic evidence of HBsAg or HBV DNA will have the option of stopping NA therapy, offering the possibility of a functional cure. Results of the Phase IIb trial have been published in the New England Journal of Medicine and will be presented at the American Association for the Study of Liver Diseases’ (AASLD) Liver Meeting 2022.

Results of the Phase 2 trial published in The Lancet (Nov. 8, 2022):

https://doi.org/10.1056/NEJMoa2210027 

Spring Bank Pharmaceuticals is stopping work on an experimental treatment for hepatitis B virus after serious side effects, including one patient death, were reported in a mid-stage study. The Spring Bank (NASDAQ: SBPH) drug, inarigivir soproxil, was the company’s lead therapeutic candidate. No details were released about the side effects observed in the clinical trial. Hopkinton, MA-based Spring Bank said Wednesday that it will work with outside experts and clinical trial investigators to care for the patients in the Phase 2b study, and to better understand what happened. Going forward, the company plans to focus on its immuno-oncology and inflammation research. Spring Bank’s stock price slid more than 23 percent to $1.30 per share after the news was announced Wednesday morning.

Inarigivir was designed to selectively activate a protein in liver cells called retinoic acid-inducible gene 1. This approach was hoped to block replication of the hepatitis B virus and kick off the interferon signaling pathways that are part of the body’s antiviral defense. The company also hoped that this dual mechanism would make it attractive as part of a combination treatment with other hepatitis B therapies. Spring Bank had tested inarigivir in partnership with Gilead Sciences (NASDAQ: GILD). Separate Phase 2 studies evaluated a 200 mg dose of that drug in combination with Gilead’s tenofovir disoproxil fumarate (Viread) and tenofovir alafenamide (Vemlidy). Spring Bank says the patient death occurred in a Phase 2 study that tested a 400 mg dose of inarigivir by itself after patients stopped treatment with other antiviral therapies. With its lead hepatitis B drug now sidelined, Spring Bank will turn its attention to cancer and inflammatory drugs developed with its stimulator of interferon genes (STING) agonist platform. The most advanced of those drug candidates, SB 11285, is currently in a Phase 1a/1b study testing it in cancer. In a prepared statement, Spring Bank president and CEO Martin Driscoll said that he hopes to have enough data by the end of this year to support advancing that drug to Phase 2...

An antisense drug developed by GlaxoSmithKline has been shown to suppress the hepatitis B virus (HBV) in a  phase 2 trial, raising hopes of a “functional cure” for the widespread disease. HBV affects an estimated 260 million people worldwide, according to GSK. While drugs to treat it are available – such as Gilead’s polymerase inhibitor Viread (tenofovir) – there is still no curative treatment, and the company hopes that GSK3228836 could fill that void. Most people are able to shake off HBV infection in time, but in a majority of children and a minority of adults, HBV infection can become chronic and lead to cirrhosis as well as liver cancer, whilst also allowing transmission of the virus to others. Chronic HBV kills around 900,000 people every year. In the phase 2a trial, GSK3228836 was able to reduce two biomarkers of chronic HBV infection – hepatitis B surface antigen (HBsAg) and hepatitis B virus DNA – compared to placebo after four weeks treatment. The trial involved four patients previously treated with antivirals and 12 who were new to drug therapy for HBV, and across both groups there were six patients who had a 3-log (99.9%) or greater reduction in HBsAg levels after 29 days. 

In four of the big responders, levels of the biomarker fell below the limit of detection, and in one case that persisted for six months. Meanwhile, five of 12 previously-untreated patients had 2-log (90%) or a greater reduction in HBV DNA. The results are still preliminary but according to GSK show clear signs of a therapeutic effect that will be tested in a phase 2b programme, due to start before the end of the year. The company’s senior vice president for development, Christopher Corsico, said that the results are “a potential step forward toward the goal of assessing sustained functional cure for people with chronic hepatitis B.” The company’s senior vice president for development, Christopher Corsico, said that the results are “a potential step forward toward the goal of assessing sustained functional cure for people with chronic hepatitis B.” Experts talk about a functional cure in HBV – defined as the complete loss of HBsAg – because it is impossible to tell biologically if the virus has been eliminated from the body. That is because viral DNA fragments can lurk in cells, hiding from current drug therapy and evading the immune system. GSK3228836 is designed to target viral DNA directly, which could give it a chance of targeting all traces of the virus in the body, and prevent it from becoming a chronic infection. GSK licensed the drug from longstanding partner Ionis as part of a two-drug deal last year, paying $25 million upfront with milestone payments taking the value of the deal up to $262 million.

If either of the antisense drugs covered by that license make it through to market, that would look like a very good deal, particularly given the sheer scale of HBV infection worldwide. The first drugs that were able to effect a cure for chronic hepatitis C virus (HCV), such as Gilead’s Harvoni (sofosbuvir/ledipasvir), quickly amassed blockbuster revenues, although that tailed off quickly as the pool of available patents declined. Analysts at William Blair have suggested that the market for an HBV cure could be around the same size as HCV, which peaked at around $10 billion a year. There’s competition coming through the industry pipeline though. Last year, Roche paid a whopping $200 million upfront to license an RNA interference drug for HBV from Dicerna called DCR-HBVs (now RG6346), with another $1.47 billion in potential milestones. The drug is in phase 1/2 development. Meanwhile, Johnson & Johnson paid $175 million upfront for Arrowhead Pharma’s RNAi candidate ARO-HBV (now JNJ-3989) which is also in a phase 2 trial.

The discovery of an unusual hepatitis B virus from shrews offers new opportunities of better understanding the chronic progression of the disease. International research teams were able to demonstrate that an important protein which is essential for the development of a chronic course of infection is not present in this virus. DZIF scientists at the Charite—Universitaetsmedizin Berlin and the University of Giessen are leading the research.

Infection with the hepatitis B virus (HBV) is one of the major global health problems. The high number of chronic cases is particularly problematic: More than 240 million people around the world are chronically infected with this virus and over 887,000 of those infected die each year of the long-term consequences such as liver cirrhosis and liver cancer. The chronification of HBV infection that often goes undetected for decades is one of the fundamental characteristics of this virus.

An important protein that is required for the chronification of the infection is not present in the virus in shrews. "Without this immunomodulator, HBeAg, the disease could not become chronic," emphasises Prof. Dr. Jan Felix Drexler, DZIF scientist at the Charite—University Medicine Berlin and DZIF researcher in the research field "Emerging Infections." And this applies to all known HBVs in mammals. They form this protein during the infection. This immunomodulator suppresses the body's specific immune response to HBV so that the infection cannot heal and becomes chronic—often with very high viral concentrations in the blood. When this viral protein is not present, the body's immune system can successfully fight the infection. This is not the case with the newly discovered HBV in shrews. The researchers examined almost 700 shrew samples from Europe and Africa and despite the absence of HBeAg, those animals that were infected still showed high concentrations of HBV in the blood. Another characteristic of the newly discovered virus is that it does not use the liver bile acid transporter to enter the liver cells as is the case with HBV in humans and apes, but takes an unknown path into the cell. 

The studies were published on P.N.A.S. on August 1, 2019:

https://doi.org/10.1073/pnas.1908072116