Bepirovirsen shows promise in controlling chronic HBV infection

Weekly bepirovirsen treatment may help reduce HBsAg* and hepatitis B virus (HBV) DNA levels in patients with chronic HBV infection, the phase IIb B-Clear study showed.

“[B]epirovirsen at a dose of 300 mg/week for 24 weeks … resulted in 9–10 percent of participants having HBsAg and HBV DNA loss for 24 weeks after the end of bepirovirsen treatment,” said the authors. The results did not differ based on receipt or non-receipt of nucleoside/nucleotide analogue (NA) therapy.

The 457 adults in the multinational study had chronic HBV infection for ≥6 months and HBsAg >100 IU/mL. Of these, 227 and 230 were receiving and not receiving NA therapy**, respectively. They were randomized 3:3:3:1 to receive subcutaneous bepirovirsen 300 mg for 24 weeks (group 1), 300 mg for 12 weeks followed by 150 mg for 12 weeks (group 2), 300 mg for 12 weeks followed by placebo for 12 weeks (group 3), or placebo for 12 weeks followed by bepirovirsen 300 mg for 12 weeks (group 4). Bepirovirsen was administered as two injections/week and groups 1, 2, and 3 received 300-mg loading doses of bepirovirsen on days 4 and 11. Those on NA therapy continued their regimen during the trial.

Patients with hepatitis C, HIV, hepatitis D, cirrhosis, or hepatocellular carcinoma, or those exposed to interferon-containing therapy in the prior 12 months were excluded.

Among patients receiving NA therapy, HBsAg level below the limit of detection (0.05 IU/mL) and HBV DNA level below the limit of quantification (20 IU/mL) for 24 weeks after end of bepirovirsen treatment without initiation of new anti-HBV medication was documented in 9, 9, 3, and 0 percent of patients in groups 1, 2, 3, and 4, respectively. Among patients not on NA therapy, 10, 6, 1, and 0 percent in groups 1, 2, 3, and 4, respectively, experienced the primary outcome event. [The Liver Meeting 2022, abstract 5015; N Engl J Med 2022;387:1957-1968]

In patients in group 1 with low baseline HBsAg levels (≤3 log₁₀ IU/mL), the primary outcome was documented in 16 and 25 percent of those receiving and not receiving NA therapy, respectively, compared with 6 and 7 percent, respectively, of those with higher baseline HBsAg levels (>3 log₁₀ IU/mL).

An analysis suggested that a baseline HBsAg cutoff of 3,000 IU/mL may predict response, the authors noted.

In HBeAg-negative patients in group 1, 10 and 14 percent of those receiving and not receiving NA therapy, respectively, experienced a primary outcome event, while in HBeAg-positive patients, only those receiving NA therapy experienced a primary outcome event (6 percent).

Sixty-three and 59 percent of patients in group 1 receiving and not receiving NA therapy, respectively, had HBsAg <100 IU/mL at treatment end, which reduced to 38 and 29 percent, respectively, at 24 weeks after treatment end. HBsAg levels were below the limit of detection in 26 and 29 percent, respectively, at treatment end, and 12 and 14 percent, respectively, at 24 weeks after treatment end.

Among patients who were HBeAg-positive and hepatitis B e antibody-negative (anti-HBe) at baseline, 11 and 20 percent of patients receiving and not receiving NA therapy, respectively, experienced seroconversion.

At baseline, 91 and 70 percent of those receiving and not receiving NA therapy, respectively, had ALT levels ≤ULN, with 17 and 41 percent, respectively, experiencing increases in ALT to ≥3 times ULN by end of follow-up.

In the first 12 weeks, adverse events (AEs), including injection-site reactions, pyrexia, and ALT elevations, were more common in the bepirovirsen than placebo group, with eight serious AEs occurring in the bepirovirsen and none in the placebo group.

At week 48, more patients not receiving than receiving NA therapy experienced AEs. The most common AEs in all patients were injection-site reactions. Seventeen patients discontinued trial medications due to AEs. Seventy-four patients experienced grade 3–4 AEs, ranging from 0–16 percent and 17–23 percent in those receiving and not receiving NA therapy, respectively. Three and five percent of patients, respectively, experienced serious AEs, with one and three events, respectively, deemed related to bepirovirsen. No deaths were documented.

There was no major difference in the safety profile of bepirovirsen in this trial compared with other regimens, the authors said.

A role for bepirovirsen?

“HBsAg loss is rarely achieved with currently available HBV treatments,” said the authors.

“New approaches to therapy are needed because of the unique complexity of HBV replication and its ability to persist despite profound viral suppression,” added Dr Jay Hoofnagle, programme director at the Division of Digestive Diseases & Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, US, in an accompanying commentary. [N Engl J Med 2022;387:1996-1998]

“These [present] findings may represent progress in the search for achieving a functional cure,” the authors said, calling for more extensive trials to confirm these results.