Addition of vebicorvir does not improve HBV markers in virologically suppressed patients
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Key takeaways:
- Triple therapy of vebicorvir, imdusiran and nucleos(t)ide reverse transcriptase inhibitor did not improve HBV markers.
- Trial was discontinued due to vebicorvir’s lack of efficacy.
BOSTON — Triple combination of vebicorvir, imdusiran and nucleos(t)ide reverse transcriptase inhibitor did not improve markers of active hepatitis B infection in virologically suppressed patients vs. treatment regimens without vebicorvir.
“For hepatitis B patients, combination regimens with agents of complementary mechanisms are likely to achieve finite duration of therapy,” Scott K. Fung, MD, associate professor of medicine at the University of Toronto and staff hepatologist at Toronto General Hospital, said during a presentation at The Liver Meeting. “Such potential agents include hepatitis B capsid assembly modulators, or CAMs, and small interfering RNAs or SiRNA.”
“The triple combination did not result in significantly greater on- or post-treatment improvements or reductions in markers of active HBV infection compared to the dual combination without VBR.”- Scott K. Fung, MD
He continued, “We all know that [nucleos(t)ide reverse transcriptase inhibitors] are a current standard of therapy that very effectively suppress HBV DNA to undetectable levels, but unfortunately, in most patients we do not see a durable off-treatment response.”
In an open-label study, Fung and colleagues assessed the safety and efficacy of triple combination vebicorvir (VBR), a first-generation CAM; imdusiran (AB-729), a GalNAc-conjugated small interfering RNA; and nucleos(t)ide reverse transcriptase inhibitor (NrtI) in virologically suppressed patients with hepatitis B e antigen-negative chronic HBV infection.
They randomly assigned 65 patients aged 18 to 50 years to receive VBR/imdusiran/NrtI (n = 32), VBR/NrtI (n = 16) or imdusiran/NrtI (n = 17) for 48 weeks. Participants were given oral VBR 300 mg once daily and subcutaneous imdusiran 60 mg every 8 weeks.
At week 48, patients could discontinue treatment and enter follow-up if alanine transaminase was less than two times the upper limit of normal, HBV DNA was below lower limit of quantification and hepatitis B surface antigen was less than 100 IU/mL. Participants who met the discontinuation criteria were offered off-treatment follow-up or NrtI alone and those who did not meet criteria continued NrtI alone. Only 56 patients completed the 48-week treatment period.
Baseline demographics and disease characteristics were similar among participants, with Fung noting that HBsAg titers were approximately 3 log 10 IU/mL and about one-third of patients had a titer below 1,000 IU/mL.
“In the VBR plus NrtI group, unfortunately, no patients met the treatment discontinuation criteria at week 48,” Fung told attendees. “In the double combination therapy without VBR — imdusiran plus NrtI — 80% reached the treatment discontinuation criteria, and in the triple combination group, 62% met criteria to discontinue all therapy.
“However, at the discretion of the principal investigator and because the study was terminated early, only 58% and 75%, respectively, of these two groups discontinued all therapy and entered the off-treatment follow-up period.”
According to end-of-treatment virologic response data, a higher proportion of patients in the triple combination group achieved HBV DNA, HBV RNA and HBsAg below the lower limit of quantitation compared with the other two groups.
Regarding on-treatment safety, more patients who received VBR reported treatment-emergent adverse events, Fung noted, most of which were grade 1 or 2. One patient in the triple therapy group had COVID-19, but it did not lead to study discontinuation. No deaths were reported in any treatment group but there were increases in ALT, mainly grade 1 and 2, in patients who received imdusiran and VBR.
During the off-treatment period, more adverse events were reported in the triple therapy group, most of which were grade 1 and 2.
“No participants receiving VBR plus NrtI met treatment discontinuation criteria,” Fung concluded, “and a greater proportion of those who received the double combination without VBR met the treatment discontinuation compared with the triple combination with VBR.”
He continued, “The triple combination did not result in significantly greater on- or post-treatment improvements or reductions in markers of active HBV infection compared to the dual combination without VBR. The clinical development of VBR has been discontinued, and the trial was terminated early — not for safety but for lack of additive efficacy of VBR to the triple therapy regimen.”