Elebsiran + PEG-IFN alfa combo ENSUREs higher HBsAg loss

The addition of elebsiran, an investigational small interfering ribonucleic acid (siRNA), to pegylated interferon (PEG-IFN) alfa led to a higher rate of hepatitis B surface antigen (HBsAg) loss in patients with chronic HB virus (HBV) infection compared with PEG-IFN alfa alone, according to the ENSURE study presented at EASL 2025.

“The ENSURE study is the first to include a randomized, PEG-IFN alfa-controlled design aimed at evaluating the contribution of elebsiran to the [combination] treatment of elebsiran and PEG-IFN alfa for functional cure,” said the researchers.

This ongoing phase II study involved 55 virologically suppressed noncirrhotic participants with HBV infection who were treated with nucleos(t)ide reverse transcriptase translocation inhibitor (NRTI) therapy. They were randomized in a 1:1:1 ratio to receive subcutaneous elebsiran 100 mg (n=18) or 200 mg (n=19) every 4 weeks in addition to PEG-IFN alfa weekly for 48 weeks or PEG-IFN alfa alone (n=18). NRTI therapy was administered daily until NRTI stopping criteria were met at week 72. [EASL 2025, abstract LBP-016]

By week 72 (24 weeks after end of treatment [EOT]), patients treated with either dose of elebsiran and PEG-IFN had a higher rate of HBsAg loss than those treated with PEG-IFN alfa only (33.3 percent [100 mg] and 21.2 percent [200 mg] vs 5.6 percent).

Of the 10 participants in the combination group who experienced HBsAg loss at EOT, seven patients with anti-HBs titres of ≥100 IU/L and one patient with a titre of ≥10 but <100 IU/L achieved sustained HBsAg loss at 24 weeks post-EOT. The researchers noted that “sustained HBsAg loss post-EOT is critical for functional cure in patients with HBV infection.”

Taken together, compared with PEG-IFN alfa alone, patients who received elebsiran and PEG-IFN alfa combination treatment had a higher HBsAg loss rate at 24 weeks post-EOT, suggesting the additive benefit of siRNA, said the researchers.

Safety

In terms of safety, the incidence of grade 3–4 treatment-emergent adverse events (TEAEs) was similar between the combination therapy and PEG-IFN alfa alone arms (27.8 percent [100 mg] and 31.6 percent [200 mg] vs 33.3 percent).

However, one patient in the 200-mg elebsiran and PEG-IFN alfa combination arm experienced serious TEAE, but the investigator regarded it as unrelated to elebsiran.

Most TEAEs were laboratory abnormalities, such as elevated ALT and AFP levels and decreased neutrophil and platelet counts. These abnormalities resolved after EOT and were consistent with the known side effects of PEG-IFN alfa, according to the researchers.

Overall, elebsiran and PEG-IFN combination therapy was generally safe and well tolerated in patients with chronic HBV infection, they noted.