Chronic hepatitis B infection affects about 16 million people in the United States and Western Europe. Estimates of the American Centers for Disease Control and Prevention indicate that in 2011-2012 there were approximately 837,000 non-institutionalized people with chronic hepatitis B infection in the United States in the United States. Standard treatment for chronic hepatitis B virus infection is nucleotide / nucleoside analogs (NUC) administered daily as an oral dose or interferon injection regimen.
RNAi uses its own gene DNA sequence to disable or "mute" the gene. This process has been promising as a limited therapy for people with chronic hepatitis B virus infection because it is capable of suppressing hepatitis B virus information RNA (mRNA) , resulting in the reduction of viral products, such as the active hepatitis B surface antigen (HBsAg).
The use of RNAi in clinical practice was limited due to safety reasons and the method of intravenous administration. ARO-HBV, which contains 2 small interfering RNAs (siRNAs), each directly coupled to N-acetyl-galactosamine to deliver hepatocytes and designed to silence all mRNA from covalently closed circular DNA (cccDNA) and integrated into the host viral DNA, without the need in the case of additional delivery elements, it is delivered subcutaneously.
As such, researchers led by Edward Gane & # 39; MBChB, MD, FRACP, MNZM, professor of medicine at the University of Auckland, New Zealand, are conducting a phase 1/2 study that is' safety assessment, tolerance and pharmacokinetic action of individual doses of ARO-HBV in healthy adult volunteers, as well as the safety, tolerability and pharmacodynamic effect of increasing doses of ARO-HBV in patients with chronic hepatitis B, "according to the clinical trial information.
A total of 6 cohorts of healthy volunteers (4 active and 2 placebo) will receive a subcutaneous dose of 35 mg, 100 mg, 200 mg, 300 mg or 400 mg. "Chronic cohorts of hepatitis B 2b-5b (n = 4, HBeAg pos or neg, treated with NUC or not on NUC) receive monthly doses of 3 x with 100 mg, 200 mg, 300 mg or 400 mg of HBeAg pos, NUC cohort – naive and experienced chronic hepatitis B (cohorts 8, 9, n = 4, respectively) receive 300 mg per month x 3. NUC-treated receive NUC from day 1, "according to the study summary.
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-month doses of ARO-HBV in combination with entecavir or tenofovir Six weeks of available HBsAg data (n = 24), single or multiple doses up to 400 mg were well tolerated. In addition, all patients with chronic hepatitis B virus infection showed strong HBsAg responses (mean NADIR -1,9 Log10 [-98.7%], range -1.3 [-95.0%] to -3,8 Log10 [-99.98%]). In addition, patients previously untreated with NUC (group 8) and patients with NUC (cohort 9) observed a similar reduction in HBsAg (mean reduction in HBsAg at day 57 for cohort 8). [n = 4] -1.7 Log10; average HBsAg reduction at 57 days for cohort 9 [n = 4] -1.9 Log10).
Approximately 12% of all subcutaneous injections resulted in mild reactions at the injection site.
Bruce Given, general manager and director of Research and Development at Arrowhead, spoke about the initial results of the pharmaceutical company statement, saying: "ARO-HBV continues to achieve a high level of activity in all [hepatitis B virus] types of patients in the AROHBV1001 trial, and additionally the ARO-HBV tolerance profile supports its further development. "
The study "First results with RNA interference (RNAi) in chronic hepatitis B (CHB) using ARO-HBV" was presented at the meeting of the American Association for the Prevention of Liver Diseases (AASLD), which was held on 9-13 November 2018, in San Francisco, California.