information: Presentation of results at a congress
Announcement: presentation of results at the 53rd Annual International Liver Congress of the European Association for the Study of the Liver (EASL) in Paris
Company: Arbutus Biopharma (Canada)
Product: AB-506, AB-452 in combination with ARB-1467 and approved HBV therapies
- RNAi/siRNA HBV core protein, or capsid, is required for viral replication and core protein may have additional roles in cccDNA function. Arbutus Biopharma has developed capsid inhibitors as oral therapeutics for the treatment of chronic HBV infection. By inhibiting assembly of the viral capsid, the ability of hepatitis B virus to replicate is impaired, resulting in reduced cccDNA. AB-506 is Arbutus' next-generation capsid inhibitor, which showed striking potency and improved PK in preclinical studies. Arbutus will continue to focus on rapidly advancing AB-506 into clinical testing before proceeding with additional clinical evaluation of AB-423. Arbutus plans to file an Investigational New Drug (IND)/Clinical Trial Application (CTA) in mid-2018 (pending successful IND/CTA-enabling studies) for AB-506, which has the potential to be a 'best-in-class' capsid inhibitor based on its favorable drug-like properties and potent inhibition of HBV replication. This molecule has the potential for once-daily oral dosing, making it an ideal candidate for inclusion in a combination regimen.
- AB-452 is an once-daily, oral HBV DNA destabilizer to be used in a combination regimen to deliver a cure for chronic HBV. The molecule has shown synergistic effects when combined with two of Arbutus’ proprietary HBV RNAi agents in vitro. In vivo, twice-a-day oral administration of AB-452 resulted in up to 1.4 log10 reduction of serum HBsAg in a dose dependent manner and correlated well with liver HBV RNA levels. Pending successful IND/CTA-enabling studies, this product candidate could be the subject of an IND (or equivalent) filing in 2018.
- ARB-1467 comprises three RNAi triggers that target all four HBV transcripts and has been shown in preclinical studies to reduce all viral antigen levels as well as HBV DNA. ARB-1467 utilizes Arbutus’ proprietary lipid nanoparticle (LNP) platform, a clinically validated delivery technology, which has been tested in hundreds of patients.
Disease: hepatitis B
area: Infectious diseases
- • On April 12,2018, Arbutus Biopharma made two presentations supporting our drug combination approach at the 53rd Annual International Liver Congress of the European Association for the Study of the Liver (EASL) in Paris, France. In these studies, AB-506 and AB-452 exhibited distinct but complementary antiviral activities, supportive of inclusion in clinical combination regimens. Separately, compared to earlier RNAi therapies for HBV, more durable antiviral activity was achieved in vivo with AB-729, a GalNAc-enabled, subcutaneously delivered, RNAi candidate. Presentations Include:
- Oral Presentation #3503: “Preclinical Antiviral Drug Combination Studies Utilizing Novel Orally Bioavailable Investigational Agents for Chronic Hepatitis B Infection: AB-506, a Next Generation HBV Capsid Inhibitor, and AB-452, an HBV RNA Destabilizer” by Rene Rijnbrand, VP Head of Biology at Arbutus Biopharma
- When combined, the capsid inhibitor AB-506 and HBV RNA destabilizer AB-452 show distinct but mechanistically compatible antiviral activities that suggest feasibility of inclusion in a clinical combination regimen.
- Summary: We evaluated the anti-HBV activities of two novel orally administered agents, an HBV capsid inhibitor AB-506 and an HBV RNA destabilizer AB-452, in combination with approved standard of care (SOC) therapies: nucleos(t)ide analogs (NA), entecavir (ETV), tenofovir disproxil fumarate (TDF), tenofovir alafenamide (TAF), and our lead RNAi agent, ARB-1467. The in vitro dual combinations of AB-506 or AB-452 with approved NAs or ARB-1467 ranged from additive to moderately synergistic at reducing HBV rcDNA and HBsAg levels with no significant effects on cell viability. After a once-daily 7-day oral treatment period in HDI HBV mice, dual combinations of AB-506+AB-452, AB-506+TDF, and AB-452+TDF demonstrated a strong antiviral activity with mean 1.4, 1.9, and 2.2 log reductions in serum HBV DNA vs. the vehicle control, respectively, whereas the triple combination effected larger serum HBV DNA reductions, 2.8 log vs. the vehicle control. All AB-506 and AB-452 treated groups demonstrated reductions in liver HBV DNA, with negligible reduction observed with TDF alone. Serum HBsAg reduction was detected in AB-452 treated groups, and when combined with AB-506 and/or TDF there was no adverse effect on the ability of AB-452 to reduce HBsAg. These preclinical investigations suggest that these agents when combined have distinct but mechanistically compatible antiviral activities and may feasibly be used in future combination therapeutic regimens.
- Oral Presentation #2646: “Durable Inhibition of Hepatitis B Virus Replication and Antigenemia Using Subcutaneously Administered siRNA Agent AB-729 in Preclinical Models” by Amy Lee, Senior Director, Research at Arbutus Biopharma
- GalNAc siRNA offers the potential for subcutaneous delivery of siRNA therapies and showed more durable in vivo preclinical activity compared to earlier-generation siRNA agents for HBV.
- Summary: AB-729 is a next-generation siRNA therapeutic targeted to hepatocytes using our novel covalently conjugated N-acetylgalactosamine (GalNAc) delivery technology. This is a promising new subcutaneously administered agent, which acts on multiple HBV viral transcripts, enabling inhibition of viral replication and suppression of all viral antigens. AB-729 showed more durable in vivo preclinical activity than earlier-generation siRNA agents for the treatment of chronic HBV infection. In comparison to lipid nanoparticle (LNP)-mediated intravenous delivery, GalNAc-conjugated subcutaneous delivery of the same reference siRNA required a 10-fold greater dose to achieve similar mean maximum inhibition of serum HBsAg in AAV-HBV mice. However, HBsAg suppression in the LNP treatment group had fully resolved by Week 4 whereas the GalNAc treatment group nadir persisted from Week 2 through to Week 6. One dose of AB-729 was sufficient to achieve mean maximum HBsAg reductions of 1.4, 2.8 and 3.9 log10 at 1, 3 and 9 mg/kg, respectively, in AAV-HBV mice with baseline serum HBsAg 3.6 log10 IU/mL. In vivo AB-729 suppression of HBsAg was also highly durable, with 83%, 89% and 99%, respectively, of the mean maximal effect remaining at Week 10 after a single dose.