ARO-HBV Reduces All Measurable Viral Products in Patients with Chronic Hepatitis B Virus Infection

The first results of a study on the use of monthly RNAi with ARO-HBV in patients with chronic hepatitis B virus infections indicate that the treatment effectively reduced all measurable viral products, including HBsAg.

The first results of a study on the use of monthly RNA interference (RNAi) with ARO-HBV (Arrowhead Pharmaceuticals) in patients with chronic hepatitis B virus infections indicate that the treatment effectively reduced “all measurable viral products, including HBsAg,” according to the study authors.

Chronic hepatitis B virus infection affects about 16 million individuals in the United States and Western Europe. US Centers for Disease Control and Prevention estimates indicate there were approximately 847,000 noninstitutionalized individuals with chronic hepatitis B virus infection in the United States in 2011-2012. The standard treatment for chronic hepatitis B virus infection is nucleotide/nucleoside analogs (NUCs) given daily as an oral dose, or an interferon injection regimen.

RNAi uses a gene’s own DNA sequence to turn off, or “silence” the gene. This process has shown promise as a limited therapy for individuals with chronic hepatitis B virus infection as it is capable of silencing hepatitis B virus messenger RNA (mRNA), resulting in the reduction of viral products, such as active or chronic hepatitis B surface antigen (HBsAg).

The use of RNAi in clinical practice has been limited by safety concerns and its intravenous delivery method. ARO-HBV—which comprises 2 small interfering RNAs (siRNAs), each directly conjugated to N-acetyl galactosamine to drive hepatocyte delivery and designed to silence all mRNA from covalently closed circular DNA (cccDNA) and host-integrated viral DNA—can be used without the need for additional delivery elements and is delivered subcutaneously.

As such, investigators led by Edward Gane, MBChB, MD, FRACP, MNZM, a professor of medicine at the University of Auckland, in New Zealand, are leading a phase 1/2 study, which is “evaluating the safety, tolerability, and pharmacokinetic effects of single-ascending doses of ARO-HBV in normal healthy adult volunteers, as well as the safety, tolerability, and pharmacodynamic effects of multiple-ascending doses of ARO-HBV in patients with chronic hepatitis B virus infection,” according to the clinical trial information.

A total of 6 cohorts of normal healthy volunteers (4 active and 2 placebo) will receive a subcutaneous dose of either 35mg, 100mg, 200mg, 300mg, or 400mg. "Chronic hepatitis B cohorts 2b-5b (n = 4, HBeAg pos or neg, NUC-treated or not on NUCs) are receiving monthly doses x 3 of 100mg, 200mg, 300mg, or 400 mg. Cohorts of HBeAg pos, NUC-naïve and experienced chronic hepatitis B (cohorts 8, 9 respectively, n = 4 each) are receiving 300 mg monthly x 3. NUC-untreated receive NUCs from day 1," according to the study abstract.

Preliminary data from the study indicate that in healthy volunteers who received a single dose of ARO-HBV or placebo (n = 30), and patients with chronic hepatitis B who received 3 monthly doses of ARO-HBV in combination with entecavir or tenofovir with greater than 6 weeks of available HBsAg data (n = 24), the single or multiple doses up to 400mg were well-tolerated. Furthermore, all patients with chronic hepatitis B virus infection had strong HBsAg responses (mean NADIR -1.9 Log10 [-98.7%], range -1.3 [-95.0%] to -3.8 Log10 [-99.98%]). In addition, NUC-naïve patients (cohort 8) and NUC-experienced patients (cohort 9) saw similar HBsAg reductions (mean HBsAg reduction on day 57 for cohort 8 [n = 4] -1.7 Log10; mean HBsAg reduction on day 57 for cohort 9 [n = 4] -1.9 Log10).

About 12% of all total subcutaneous injections resulted in mild injection-site reactions.

Bruce Given, MD, chief operating officer and head of research & development at Arrowhead spoke about the preliminary results in a statement by the pharmaceutical company, saying, “ARO-HBV continues to achieve high levels of activity across all [hepatitis B virus] patient types in the AROHBV1001 study and, additionally, ARO-HBV’s tolerability profile supports its continued development.”

The study, “First Results with RNA Interference (RNAi) in Chronic Hepatitis B (CHB) Using ARO-HBV,” was presented at the 2018 American Association for the Study of Liver Diseases (AASLD) Liver Meeting, November 9-13, 2018, in San Francisco, California.