|
- 现金
- 62111 元
- 精华
- 26
- 帖子
- 30437
- 注册时间
- 2009-10-5
- 最后登录
- 2022-12-28
|
Novel agents for the treatment of chronic HBV infection have cure in their sights
Digital ILC 2020: Focused viral hepatitis sessions at Digital International Liver Congress™ 2020 reveal new drugs that aim to cure chronic HBV infection
Spink Health
IMAGE
IMAGE: Digital ILC 2020: Focused viral hepatitis sessions at Digital International Liver Congress™ 2020 reveal new drugs that aim to cure chronic HBV infection view more
Credit: The European Association for the Study of the Liver (EASL)
28 August 2020: Progress towards finding a cure for chronic hepatitis B virus (HBV) infection was showcased at this year's Digital International Liver Congress™ (DILC). Recent results from studies of several novel agents designed to achieve a functional cure for this chronic liver disease were presented at the congress to scientists from across the globe. While many of these early trials focused on safety and tolerability, they also showed some promising signs of progress in combating HBV infection.
Chronic HBV infection continues to exert a heavy toll worldwide despite the availability of effective vaccines and improved treatments. Two classes of drugs are currently approved for the treatment of HBV: nucleos(t)ide reverse transcriptase inhibitors (NRTIs) and interferon-?. These treatments can achieve viral suppression but rarely result in the loss of hepatitis B surface antigen (HBsAg), which is considered to be a 'functional' cure and the aspirational goal of HBV treatment. To date, no single agent or combination of treatments has achieved that goal.
The emerging therapies discussed at DILC 2020 exploit novel mechanisms of action to try and bring us closer to a cure, by disrupting the production of viral proteins such as HBsAg, inhibiting the HBV core protein directly, and targeting the immune system in order to control HBV.
Targeting the production of viral proteins
A total of four studies presented at DILC 2020 evaluated this strategy for HBV, either using RNA interference (RNAi) or antisense oligonucleotides to inhibit the ability of the virus to synthesize the components it needs to replicate.
Two studies involved the combination of NRTIs with novel RNAi therapies: JNJ-3989 (Arrowhead Pharmaceuticals/Janssen) and VIR-2218 (Vir Biotechnology, Inc./Alnylam Pharmaceuticals). In the first study, 40 patients with chronic HBV were treated with NRTIs plus three monthly doses of subcutaneous (sc) JNJ-3989 (100 mg, 200 mg, 300 mg, or 400 mg). At the HBsAg nadir, 39/40 (97.5%) patients achieved a ?1 log10 IU/mL reduction from Day 1 HBsAg values, and 22 (56%) of these had sustained HBsAg reductions (?1 log10 IU/mL) approximately 9 months after the last dose of JNJ-3989. In the second ongoing study, 24 patients with chronic HBV received NRTIs plus two sc injections of VIR-2218 at various doses. A subset of patients who received the 50 mg dose achieved maximal reductions in HBsAg at Week 12, with a mean reduction of 1.5 log10 IU/mL from baseline. A mean reduction from baseline in HBsAg of 1.0 log10 IU/mL was maintained through Week 28 in this cohort, and the therapy was generally well-tolerated without clinically significant ALT elevations.
Two novel antisense oligonucleotides were also presented at DILC 2020: ISIS 505358/GSK3228836 (Ionis Pharmaceuticals Inc./GlaxoSmithKline) and RO7062931 (Roche). They produced reductions in HBsAg in an early-phase clinical trial in patients with chronic HBV.
In a Phase 2a, randomized, double-blind, placebo-controlled study, doses of 300 mg ISIS 505358/GSK3228836 were administered by weekly sc injection to NRTI-naïve patients as well as patients receiving NRTIs (N=24). Significant reductions in HBsAg were observed in both patient groups from baseline to Day 29. In the NRTI-naïve group (n=12), average reduction reached -1.56 log10 IU/mL (p=0.001 vs placebo). Greater average reduction of -2.51 log10 IU/mL was observed in the group of NRTI-treated patients (n=5). Across both treatment groups, six patients had HBsAg reductions >3.0 log10 IU/mL, with levels falling below the limit of quantification (0.05 IU/mL) in four individuals.
In a Phase 1 study of RO7062931, a GalNAc LNA antisense oligonucleotide, 59 patients with chronic HBV infection on NRTI therapy received sc RO7062931, at various doses and dosing intervals, over a 4-week period. The treatment was well-tolerated and dose-dependent reductions in HBsAg were observed. Largest mean nadir HBsAg reductions of 0.5 log IU/mL were observed with the 3 mg/kg weekly RO7062931 dosing regimen.
Targeting the HBV core protein
Another way of inhibiting the virus is to target its component proteins directly. This strategy was used in a study involving 26 patients with HBeAg-negative chronic hepatitis B who were virologically suppressed after a mean duration of 4 years of NRTI therapy. In the study, in addition to maintaining their NRTI, patients were randomized to receive either the novel oral HBV core inhibitor, ABI-H0731 (Assembly Biosciences, Inc.) 300 mg once daily or placebo for 24 weeks. At Week 24, ABI-H0731 produced deeper viral suppression with an increase in the percentage of patients with HBV DNA <5 IU/mL (undetectable using sensitive polymerase chain reaction methodology) from baseline (63% of patients at baseline vs 94% at Week 24 compared with 80% vs 70% with placebo). In this virologically suppressed population, HBsAg levels were not significantly changed from baseline in both treatment groups. Overall, ABI-H0731 was generally safe and well-tolerated.
Inducing immune responses to HBV
In the last few years, the way that HBV can evade the pattern recognition capabilities of the innate immune system has been increasingly explored. Promoting a more complete immune response to the virus is another potential avenue to fighting persistent infection. This strategy was investigated in a Phase 2, randomized, double-blind, placebo-controlled study that explored the efficacy and safety of 24 weeks of treatment with a toll-like receptor 8 (TLR8) agonist, selgantolimod. Thirty-nine virally suppressed adults with chronic HBV infection received oral selgantolimod 1.5 mg or 3.0 mg, or placebo once weekly for 24 weeks. Dose-proportional increases in cytokines and changes in NK, DC, and CD8+ T cells were observed. The treatment was well-tolerated and, at Week 48, 5% had a loss of HBsAg and 16% HBeAg-positive patients had achieved HBeAg loss.
"The development of novel therapeutics for persistent HBV infection is currently one of the most vibrant fields in hepatology," said Dr Tobias Böttler, from the University Hospital Freiburg, Germany, and an EASL Governing Board member. "With so many different approaches that show promising results regarding HBsAg-decline, and even HBsAg-loss, we appear to be edging closer to the development of a functional cure."
###
About The International Liver Congress™
This annual congress is EASL's flagship event, attracting scientific and medical experts from around the world to learn about the latest in liver research and exchange clinical experience. Attending specialists present, share, debate and conclude on the latest science and research in hepatology, working to enhance the treatment and management of liver disease in clinical practice. This year, the congress is being held entirely digitally due to the global health situation. The Digital International Liver Congress™ 2020 will take place from 27-29 August 2020. For more information on attendance and registration, please visit https://ilc-congress.eu/.
About The European Association for the Study of the Liver (EASL)
Since its foundation in 1966, this not-for-profit organization has grown to over 4,500 members from all over the world, including many of the leading hepatologists in Europe and beyond. EASL is the leading liver association in Europe, having evolved into a major European association with international influence, and with an impressive track record in promoting research in liver disease, supporting wider education, and promoting changes in European liver policy.
Contact
For more information or to speak to an expert, please contact Sean Deans in the ILC Press Office at:
- Email: [email protected]
- Telephone: +44 (0) 1444 811099
Session details
Session title: General session II
Date and time session: Friday 28 August 2020, 13.30-13.45
Presenter: Edward Gane
Abstract: Short-term treatment with rna interference therapy, jnj-3989, results in sustained hepatitis b surface antigen supression in patients with chronic hepatitis b receiving nucleos(t)ide analogue treatment
Session title: Hepatitis B and D - Drug development
Date and time of session: Friday 28 August 2020 11.00-11.15
Presenters: Man-Fung Yuen
Abstracts: Hepatitis B virus (HBV) surface antigen (HBsAg) inhibition with ISIS 505358 in chronic hepatitis B (CHB) patients on stable nucleos(t)ide analogue (NA) regimen and in NA-naive CHB patients: phase 2a, randomized, double-blind, placebo-controlled study
Session title: Hepatitis B and D - Drug development
Date and time of session: Friday 28 August 2020 11.15-11.30
Presenters: Edward Gane
Abstract: Preliminary safety and antiviral activity of VIR-2218, an X-targeting HBV RNAi therapeutic, in chronic hepatitis B patients
Session title: Hepatitis B and D - Drug development
Date and time of session: Friday 28 August 2020 11.30-11.45
Presenters: Man-Fung Yuen
Abstract: RO7062931 antisense oligonucleotide Phase 1 study demonstrates target engagement in patients with chronic hepatitis B on established nucleos(t)ide therapy
Session title: Hepatitis B and D - Drug development
Date and time of session: Friday 28 August 2020 11.45-12.00
Presenters: Scott Fung
Abstract: Antiviral activity and safety of the hepatitis B core inhibitor ABI-H0731 administered with a nucleos(t)ide reverse transcriptase inhibitor in patients with HBeAg-negative chronic hepatitis B infection
Session title: Hepatitis B and D - Drug development
Date and time of session: Friday 28 August 2020 12.00-12.15
Presenters: Edward Gane
Abstract: Efficacy and Safety of 24 Weeks Treatment with Oral TLR8 Agonist, Selgantolimod, in Virally-Suppressed Adult Patients with Chronic Hepatitis B: A Phase 2 Study
Author disclosures
Scott Fung has been a consultant for Assembly, Gilead, and Spring Bank Pharmaceuticals, and has received speaking and teaching fees from Gilead.
Edward Gane is a scientific advisory board member for AbbVie, ALIGOS, Assembly Biosciences, Gilead Sciences, Janssen, Roche, and VIR Bio. He is also a speakers' bureau member for AbbVie, Gilead Sciences, and Mylan.
Man-Fung Yuen has been a consultant for AbbVie, Arbutus Biopharma, Assembly Biosciences, Bristol Myers Squibb, Clear B Therapeutics, Dicerna Pharmaceuticals, Gilead Sciences, GlaxoSmithKline, Janssen, Merck Sharp and Dohme, and Spring Bank Pharmaceuticals.
References
1. Liang TJ, et al. Present and future therapies of hepatitis B: From discovery to cure. Hepatology. 2015;62(6):1893-908.
2. Revill PA, et al. Meeting the challenge of eliminating chronic hepatitis B infection. Genes (Basel). 2019;10(4). pii: E260.
3. Yuen MF, et al. Safety, pharmacokinetics, and antiviral effects of ABI-H0731, a hepatitis B virus core inhibitor: a randomised, placebo-controlled phase 1 trial. Lancet Gastroenterol Hepatol. 2020;5(2):152-66.
4. Ma Z, et al. Interaction between Hepatitis B Virus and Toll-Like Receptors: Current Status and Potential Therapeutic Use for Chronic Hepatitis B. Vaccines (Basel). 2018;6(1):6.
Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.
Media Contact
Sean Deans
[email protected]
44-014-448-11099
|
|
发表于 2020-8-28 09:40