Phase 2 trial with bepirovirsen demonstrates possibility of a functional cure of chronic hepatitis B infection that is sustained after treatment is discontinued.
Bepirovirsen, an antisense RNA-based investigational agent, exerted effects possibly consistent with functional cure of hepatitis B virus (HBV) infection in some participants of a multi-national phase 2 trial.
The agent sustained the primary efficacy measures of reducing hepatitis B surface antigen (HBsAg) below the lower limit of detection (0.05 IU/ml) and HBV DNA level below the lower limit of quantification (20 IU/ml) for 24 weeks after treatment in approximately 10% of the trial participants with chronic HBV infection. That level of response was more likely with a loading dose, the longer of two tested regimens, and lower levels of HBsAg at baseline.
"Although this is a relatively low percentage of participants overall, it indicates the possibility of enhanced efficacy with the selection of patients according to baseline characteristics (low HBsAg level at baseline), with combination therapies, or both," indicated Man-Fung Yuen, MD, PhD, DSc, Department of Medicine, Queen Mary Hospital, School of Clinical Medicine, Li-Ka Shing Faculty of Medicine, and the State Key Laboratory of Liver Research, University of Honk Kong, Hong Kong, and colleagues.
The phase 2b trial assessed different dosages, durations and conditions by randomizing 457 participants with chronic HBV infection of not less than 6 months into 4 treatment groups on a 3:3:3:1 ratio: (group 1) 300mg bepirovirsen SC injections weekly for 24 weeks; (2) 300mg weekly for 12 weeks then 150mg for 12 weeks; (3) 300mg for 12 weeks then placebo for 12 weeks; (4) placebo for 12 weeks then bepirovirsen 300mg for 12 weeks.
Groups 1, 2, and 3 received loading doses of 300mg, and group 4 additional placebo, on days 4 and 11.Participants were stratified for analysis by whether or not they were also receiving stable regimens of a nucleoside or nucleotide analogue (NA) (entecavir or tenofovir disoproxil fumarate) treatment of the HBV during the trial.Participants were followed for up to 55 weeks, with a 24-week follow-up period after the 24-week treatment.
Although the primary outcome measures were attained by 9 to 10% overall, the investigators found that response was favored with 24 weeks vs 12 weeks of treatment (8.4% vs 1.6%), regardless of whether or not NA was used (6.2% vs 5.2%).It was noted, however, that no participant who was hepatitis B e antigen (HBeAg) positive and not receiving NA therapy attained the primary outcome.
Treatment response was more likely with a loading dose; and in those with lower baseline levels of HBsAg—in 19% of those whose baseline HBsAg was ≤3000IU/ml vs 7% with higher baseline levels.
"These findings may represent progress in the search for achieving a functional cure," indicate Yuen and colleagues. "Optimization of response will most likely require combination therapy to target multiple steps of the HBV life cycle, stimulate the immune system, or both."
In an accompanying editorial, Jay Hoofnagle, MD, Liver Disease Research Branch, Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, remarked on the need to develop curative agents despite availability of NA treatment that effectively suppresses HBV.
"Even with clearance of serum HBV DNA and of HBeAg, the replicative backbone of HBV (covalently closed circular DNA [cccDNA]) can persist in hepatocytes, protected ina micro-chromosome," he explained.
Hoofnagle pointed to other promising RNA-based agents, in addition to this representative of the"virsen" class; including the "sirans", which he describes as "more malleable" small interfering RNA molecules.
"What is needed is a regimen that would lead to clearance of both HBV DNA and HBsAg and allow for withdrawal of therapy without a risk of relapse," he declared, indicating the parameters for functional cure.