Chronic HBV treatment with xalnesiran plus immunomodulator confers highest HBsAg loss
Key takeaways:
- The highest percentages of patients with HBsAg loss were observed in the groups that received xalnesiran plus an immunomodulator.
- The most frequent grade 3 or 4 adverse event was elevated ALT.
Treatment with xalnesiran, a small interfering RNA molecule, plus an immunomodulator resulted in hepatitis B surface antigen loss among adults with chronic HBV infection, according to a study published in The New England Journal of Medicine.
“Functional cure — defined as a sustained loss of HBsAg and undetectable HBV DNA at 24 weeks after finite-duration therapy — is a desired treatment outcome that is associated with significantly reduced risks of hepatocellular carcinoma, cirrhosis, liver decompensation and death from any cause,” Jinlin Hou, MD, director and professor of the hepatology unit and department of infectious diseases at Nanfang Hospital of Southern Medical University in Guangzhou, China, and colleagues wrote.
“Standard care, which includes pegylated interferon therapy of finite duration — 48 weeks — and lifelong nucleoside or nucleotide analogue therapy, rarely leads to functional cure, which occurs in only up to 7% of patients after 12 months of treatment,” they added. “To improve functional cure rates, an emerging strategy involves combining new antiviral agents to reduce the antigenic load with immunomodulators to restore the dysregulated immune response.”
In the phase 2, multicenter, randomized, controlled, adaptive, open-label platform Piranga trial, Hou and colleagues evaluated the efficacy and safety of xalnesiran (Roche) regimens with and without immunomodulators ruzotolimod (Roche) or peginterferon alfa-2a (Pegasys, Genentech) for the treatment of chronic HBV infection.
The researchers enrolled 159 adults aged 18 to 65 years (82.6% men; 94% Asian) who had virologic suppression with nucleotide analogue therapy and randomly assigned them to one of five groups:
- group 1 (n = 30), which received 100 mg of xalnesiran subcutaneously every 4 weeks for 48 weeks;
- group 2 (n = 30), which received 200 mg of xalnesiran at the same schedule;
- group 3 (n = 34), which received 200 mg of xalnesiran plus 150 mg of ruzotolimod orally every other day from weeks 13 to 24 and weeks 37 to 48;
- group 4 (n = 30), which received 200 mg of xalnesiran plus 180 µg of PEG-IFN a-2a subcutaneously weekly for 48 weeks; or
- group 5 (n = 35), which received daily nucleotide analogue therapy alone.
The primary efficacy endpoint was HBsAg loss — defined as an HBsAg level below 0.05 IU/mL — at 24 weeks after the end of the 48-week treatment period. Secondary endpoints included HBsAg loss at additional time points, HBsAg seroconversion and safety.
At 24 weeks, the highest percentage of participants with HBsAg loss was observed in group 4, at 23% (95% CI, 10-42), followed by group 3, at 12% (95% CI, 3-28).
HBsAg loss also was achieved in 7% (95% CI, 1-22) of participants in group 1 and 3% (95% CI, 0-17) of those in group 2, but none of those in group 5, according to the researchers.
Group 4 had the highest percentage of participants with HBsAg seroconversion at 24 weeks, at 20%, followed by 3% of participants each in groups 1 and 3. HBsAg seroconversion did not occur in groups 2 or 5.
Additionally, the researchers found that HBsAg loss with or without seroconversion only occurred in participants with an HBsAg level below 1,000 IU/mL at screening.
“These results are consistent with the hypothesis that a low pretreatment HBsAg level is prognostic for HBsAg loss, a situation that highlights the challenge of obtaining a functional cure in patients with high HBsAg,” the researchers wrote.
Grade 3 or 4 adverse events occurred among 17% of participants in group 1, 10% of those in group 2, 18% of those in group 3, 50% of those in group 4 and 6% of those in group 5, the most frequent of which was elevated alanine aminotransferase.
“This phase 2 trial showed that treatment with xalnesiran plus an immunomodulator led to substantial percentages of participants with HBsAg loss, while identifying challenges in durability of HBsAg loss and efficacy in participants with high HBsAg levels,” the researchers wrote. “To address these challenges, a potential approach could be to specifically target adaptive immunity and restore HBV-specific exhausted T cells.”
Hou and colleagues acknowledged several limitations to the trial, including their inability to formally compare outcomes among the treatment groups because it did not include groups treated with immunomodulators alone, as well as the overrepresentation of men and Asian participants.
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