Potential Core Inhibitors in Hepatitis B Virus Presented at the AASLD, The Liver Meeting

Hepatitis B and C viruses affect over 300 million people worldwide in 2019, and World Health Organization estimates that 1.1 million individuals died during that same year from the effects of those 2 viruses, including cirrhosis, liver cancer, and other conditions that stem from chronic viral hepatitis. While all forms A, B, C, D, and E, of hepatitis can be controlled or prevented, no long-term cure for hepatitis B has been developed. Recently at the 2022 American Association for the Study of Liver Diseases (AASLD) The Liver Meeting, Assembly Bio, a company focused on finding a cure for highly potent hepatitis B (HBV). Infection Control Today^® (ICT^®) asked William Delaney, PhD, chief scientific officer of Assembly Bio, about the posters that Assembly Bio presented at AASLD The Liver Meeting.

ICT^®: A summary of the key information of these posters and why they are important.

William Delaney, PhD:The data Assembly Bio presented at AASLD in 2022 highlights the company’s progress in both advancing and broadening our early-stage virology programs. We presented preclinical data on or our next-generation, HBV core inhibitor candidate, ABI-4334 (4334), that demonstrate its nanomolar potency to disrupt the HBV replication cycle at multiple points (importantly at the point of cccDNA [viral reservoir] formation, which our first-generation core inhibitors haven’t been able to inhibit) and support its entry into clinical studies. The Phase 1a study evaluating the activity and safety of 4334 initiated in Q4.

We also presented the first data for 2 of our recently announced programs. This includes data highlighting the preclinical characterization of our small molecule potent, orally bioavailable viral entry inhibitors for HBV and hepatitis D virus (HDV). And, finally, we shared the first preclinical data on a novel series of orally bioavailable small molecule interferon-a receptor (IFNAR) agonists designed to inhibit HBV and engage the immune system with potential to offer efficacy, but also critically, improved tolerability (the major limitation of current biologic interferons) in HBV, as well as for other viruses such as HDV. The data from each are summarized in our press release from November 4, 2022.

ICT^®: What is the practical application for the key findings for infection preventionists from this study?

WD: Assembly Bio’s next generation core inhibitors, including 4334, and our IFNAR agonist program support a key aspect of our mission: to develop finite treatments and functional cures for hepatitis B. While vaccines for hepatitis B exist, there are an estimated almost 300 million patients living with hepatitis B worldwide, with up to a million people dying each year of HBV-related causes. There are treatments available, but they are lifelong and reduce–but do not eliminate–the virus, so cure rates are very low. We see a great unmet medical need here and an opportunity to improve outcomes for patients.

Many of us at Assembly Bio were part of the efforts to develop functional cures for hepatitis C, and we are working towards a parallel vision for hepatitis B. If patients achieve functional cure, they would no longer have detectable viral levels and we would expect, based on experience with other viruses (and based on the experience with chronic suppressive therapy in HBV and other viruses that reduced viral loads reduces infection rates), that they would no longer be able to infect others as well as result in improved prognosis for patients (lower lifetime risk of developing serious liver disease including fibrosis, cirrhosis and hepatocellular carcinoma). And, with a finite treatment/functional cure approach, we would also expect, as was the case with hepatitis C, that we can reach additional patients for whom a long-term chronic treatment may not be feasible, thus also reducing the infection disease burden and transmissibility overall.

Our HBV/HDV entry inhibitor program targets hepatitis delta coinfection in patients with HBV. HDV infection only occurs with HBV infection, with an estimated prevalence of 4.5%, but is responsible for a significant portion of the cirrhosis and liver cancer associated with HBV, around 20%. This is the case even when the patient is receiving standard of care treatment for HBV. Our goal for our HBV/HDV entry inhibitor program is to provide a treatment that lowers viral loads for HDV specifically, to help address this significant disease burden for patients with HDV. From an infection prevention standpoint, we would expect based on experience with chronic suppressive therapy for other viruses that lowering the viral load would also reduce transmissibility here as well.

ICT^®: What results surprised you, if any?

WD: Across the data presented from Assembly Bio’s programs, there were a number of insights for which we were seeing data for the first time and that will play an important role in informing our clinical development strategy for each of these approaches and investigational therapies.

In the poster presentation highlighting data from our next-generation core inhibitor, ABI-4334 (4334), this in vitro study was the first to demonstrate the potential of core inhibitors to inhibit double-stranded linear (DLS) DNA being delivered to the nucleus of hepatocytes; DLS HBV can be integrated into the human genome, so we are excited that this property of the compound may subsequently translate into limiting or preventing HBV integration. HBV integration is hypothesized to be a significant contributor to HBV-induced hepatocellular carcinoma (HCC). Additionally, phase 1 clinical data presented at the meeting from others in the field showed that short term treatment with core inhibitors may reduce circulating levels of Hepatitis B surface antigen (HBsAg)–a marker of cccDNA (viral reservoir) and currently a key endpoint for functional cure studies. These data are of interest to our 4334 development program as they support the potential for highly potent core inhibitors such as 4334 to have a meaningful clinical impact on the key endpoints.

Relative to our small molecule interferon-α receptor (IFNAR) agonist program and the data presented in our poster at AASLD, I noted with great interest the broad prevalence of Peginterferon α (PEG-IFN) in current and planned HBV cure studies. There is a clear industry focus – and demonstrated scientific support for – the role that PEG-IFN could play in finite and curative therapies for hepatitis B. Our IFNAR program builds upon this scientific rationale, evaluating a class of compounds that we hope will overcome the significant tolerability issues that have, to date, limited the utility and enthusiasm for using PEG-IFN in HBV cure combination studies.

And, finally, related to our poster highlighting the preclinical characterization of potent, orally bioavailable viral entry inhibitors for HBV and hepatitis D virus (HDV)we were highly encouraged by the rapid progress on our program and the highly potent activity achieved preclinically. Based on the potency and pharmacokinetic properties of our entry inhibitors we are optimistic that molecules from this program can be optimized for once-daily oral dosing which would overcome the inconvenience of the daily injectable therapy (bulevirtide) recently approved in Europe for HDV patients. We were also encouraged by new data presented at the meeting from bulevirtide, which targets the same viral entry mechanism as our program. These new data demonstrated that real world experience aligned with clinical studies–which is particularly notable because it shows us that there is high compliance among patients–and also showed durable efficacy for the entry mechanism of action even when looking at a longer period of almost 1.5 years.

Overall, we were glad to hear feedback from the scientific community at AASLD–and also see data from other studies that validate our approaches– and we are proud about how far that we’ve come in short time with our preclinical and clinical programs.

ICT^®: What, if any, future research will there be related to these results?

WD: For 4334, we have initiated a Phase 1a clinical study for this candidate and look forward to the data readout from that study in healthy volunteers in the first half of 2023.

For our HBV/HDV entry inhibitor and IFNAR agonist programs, both of these are progressing in preclinical studies. Assembly Bio anticipates advancing 2 of our research stage programs (which include these 2 programs as well as 2 additional programs) into development candidates next year. We are focused on progressing our programs rapidly and will plan to provide updates at future scientific conferences.

ICT^®: Is there anything else that you would like to add?

WD: We are really excited to see our next generation, more potent core inhibitors progress in the clinic. In addition to 4334, we have another next-generation core inhibitor, ABI-H3733, in a phase 1b study in patients with chronic HBV, and that study is on track to have initial data by the end of this year. We expect full data readouts from the 3733 Phase 1b study and the 4334 phase 1a study in the first half of next year. These next-generation core inhibitors have significantly increased potency against cccDNA formation, in particular, and we are looking forward to seeing clinical data from these programs as they progress.

We also thought this year’s AASLD was an exciting meeting with a lot of enthusiasm for advancing novel treatments for both HBV and HDV–it was great to see the academic and pharma communities coming together to present and discuss new clinical data and how to continue to move forward together as a field.

I want to thank ICT^® for giving us an opportunity to speak to your readers. Our mission is to develop innovative, investigational therapeutics targeting HBV and other serious viral diseases. One of the compelling aspects of working in therapeutics for viral disease is the ability to have an impact on treatment for patients facing significant disease burden and at the same time potentially reduce transmission and the population burden of the disease as well, and we appreciate your interest in our research and programs.