HE PATOLOGY
Stages of liver damage
showcased at this year’s Digital International Liver Congress. Recent results from studies of several novel agents designed to achieve a functional cure for this chronic liver disease were presented 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-α. 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 the event 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 the Congress evaluated this strategy for HBV, either using RNA interference (RNAi) or antisense oligonucleotides to inhibit the ability of the virus to synthesise 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 nine 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.
NOVEMBER 2020
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.
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 four years of NRTI therapy. In the study, in addition to maintaining their NRTI, patients were randomised 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, randomised, 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. These latest breakthroughs offer patients hope for the future – the development of novel therapeutics, for persistent HBV infection, is currently one of the most vibrant fields in hepatology. “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,” concluded Dr. Tobias Böttler, from the University of Freiburg, Germany, and an EASL Governing Board member.
CSJ About EASL
EASL, The European Association for the Study of the Liver, is a medical association dedicated to pursuing excellence in liver research, clinical practice of liver disorders, and in providing education to all those interested in hepatology.
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.
https://ilc-congress.eu/about-ilc-2020/ Next year, the International Liver Congress 2021, is scheduled to take place 22-25 June, in Amsterdam, The Netherlands. Details of the conference programme can be accessed at: https://
easl.eu/event/the-international-liver- congress-2021-2/
WWW.CLINICALSERVICESJOURNAL.COM l 51
©nmfotograf -
stock.adobe.com
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84 |
Page 85 |
Page 86 |
Page 87 |
Page 88 |
Page 89 |
Page 90 |
Page 91 |
Page 92 |
Page 93 |
Page 94 |
Page 95 |
Page 96 |
Page 97 |
Page 98 |
Page 99 |
Page 100
