Xalnesiran with or without an Immunomodulator in Chronic Hepatitis B
Journal
New England Journal of Medicine
Journal Volume
391
Journal Issue
22
Start Page
2098
End Page
2109
ISSN
0028-4793
1533-4406
Date Issued
2024-12-05
Author(s)
Jinlin Hou
Wenhong Zhang
Qing Xie
Rui Hua
Hong Tang
Luis Enrique Morano Amado
Sheng-Shun Yang
Cheng-Yuan Peng
Wei-Wen Su
Wan-Long Chuang
Dong Joon Kim
Anchalee Avihingsanon
Apinya Leerapun
Man-Fung Yuen
Tarik Asselah
Xieer Liang
Qingyan Bo
Filippo Canducci
Maria Teresa Catanese
Ethan Chen
Cong Cheng
Farouk Chughlay
Sudip Das
Katerina Glavini
Nelson Guerreiro
Yan Huang
Priyanka Kakrana
Rémi Kazma
Avinash Patil
Vedran Pavlovic
Bernadette Surujbally
Miriam Triyatni
Ruchi Upmanyu
Cynthia Wat
Edward Gane
Abstract
Xalnesiran, a small interfering RNA molecule that targets a conserved region of the hepatitis B virus (HBV) genome and silences multiple HBV transcripts, may have efficacy, with or without an immunomodulator, in patients with chronic HBV infection. We conducted a phase 2, multicenter, randomized, controlled, adaptive, open-label platform trial that included the evaluation of 48 weeks of treatment with xalnesiran at a dose of 100 mg (group 1), xalnesiran at a dose of 200 mg (group 2), xalnesiran at a dose of 200 mg plus 150 mg of ruzotolimod (group 3), xalnesiran at a dose of 200 mg plus 180 μg of pegylated interferon alfa-2a (group 4), or a nucleoside or nucleotide analogue (NA) alone (group 5) in participants with chronic HBV infection who had virologic suppression with NA therapy. The primary efficacy end point was hepatitis B surface antigen (HBsAg) loss (HBsAg level, <0.05 IU per milliliter) at 24 weeks after the end of treatment. Safety was also assessed. Among 159 participants (30, 30, 34, 30, and 35 in groups 1 through 5, respectively), the primary end-point event occurred in 7% (95% confidence interval [CI], 1 to 22) of those in group 1, in 3% (95% CI, 0 to 17) of those in group 2, in 12% (95% CI, 3 to 28) of those in group 3, in 23% (95% CI, 10 to 42) of those in group 4, and in none (95% CI, 0 to 10) of those in group 5. In groups 1 through 5, respectively, HBsAg seroconversion occurred in 3%, none, 3%, 20%, and none of the participants at 24 weeks after the end of treatment. HBsAg loss with or without seroconversion occurred only in participants with a screening HBsAg level below 1000 IU per milliliter. In groups 1 through 5, respectively, grade 3 or 4 adverse events occurred in 17%, 10%, 18%, 50%, and 6% of the participants, with the most frequent event being an elevated alanine aminotransferase level. Among participants with chronic HBV infection who had virologic suppression with NA therapy, treatment with xalnesiran plus an immunomodulator resulted in HBsAg loss at 24 weeks after the end of treatment in a substantial percentage of participants. Grade 3 or 4 adverse events were not uncommon. (Funded by F. Hoffmann-La Roche; Piranga ClinicalTrials.gov number, NCT04225715.).
SDGs
Publisher
Massachusetts Medical Society
Type
journal article