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Xalnesiran Plus Immunomodulator Results in HBsAg Loss Among Patients With Chronic Hepatitis B

Key Takeaways

  • Xalnesiran targets HBV genome regions, silencing multiple transcripts, and shows potential efficacy in chronic HBV treatment.
  • The phase 2 trial involved 159 patients, assessing xalnesiran alone and with immunomodulators, focusing on HBsAg loss.
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Despite the reductions in hepatitis B surface antigen (HBsAg), grade 3 and 4 adverse events were not uncommon.

Among clinical trial participants who had chronic hepatitis B virus infection (HBV) and had virologic suppression with nucleotide analogue (NA), xalnesiran (Roche, Dicerna Pharmaceuticals) alongside an immunomodulator resulted in hepatitis B surface antigen (HBsAg) loss at 24 weeks after the end of treatment. The clinical trial results, which were published in The New England Journal of Medicine in December 2024, also show that adverse events (AEs), particularly grades 3 or 4, were not uncommon.1

Blood sample testing for hepatitis B virus -- Image credit: gamjai | stock.adobe.com

Image credit: gamjai | stock.adobe.com

Xalnesiran is a small interfering RNA molecule that targets a conserved region of the HBV genome, which silences multiple HBV transcripts. According to the investigators, it may have efficacy when used to treat patients with chronic HBV, whether used with or without an immunomodulator.1 Its safety, tolerability, and efficacy when used as a combination therapy with other treatments was assessed in a phase 2 trial (NCT04225715) that enrolled patients with chronic HBV with preserved liver function and without significant fibrosis or cirrhosis. Additionally, all participants had virologic suppression with NA therapy.2

The multicenter, randomized, adaptive, open-label, controlled platform phase 2 trial evaluated xalnesiran with other agents and therapies. A total of 159 patients were randomly assigned into 1 of 5 arms, all of which consist of a screening phase (up to 8 weeks), treatment phase (up to 48 weeks), and post-treatment follow-up phase (48 weeks). The arms received xalnesiran alone at a dose of 100 mg (group 1; n = 30); xalnesiran alone at a dose of 200 mg (group 2; n = 30); xalnesiran at a dose of 200 mg in combination with 150 mg of subcutaneous ruzotolimod (RO7191863, Roche; group 3; n = 34); xalnesiran at a dose of 200 mg in combination with 180 μg of pegylated interferon alfa-2a (group 4; n = 30); or a nucleoside or NA alone (group 5; n = 35).1,2

About the Trial

Trial Name: A Trial To Evaluate The Efficacy And Safety Of Multiple Combination Therapies In Participants With Chronic Hepatitis B (Piranga)

ClinicalTrials.gov ID: NCT04225715

Sponsor: Hoffmann-La Roche

Completion Date: July 19, 2024

The trial’s primary end point was the percentage of participants with HBsAg loss at 24 weeks following the end of treatment. Additionally, secondary end points included percentage of patients with HBsAg seroconversion, patients with hepatitis B early antigen (HBeAg) loss, and patients with HBV DNA lower than the limit of quantification (LLOQ), all of which were assessed up to 96 weeks. Other end points included pharmacokinetic and safety outcome measures, which were primarily assessed up to 48 weeks.1,2

According to the trial findings, the primary end point event occurred in approximately 7% of patients (95% confidence interval [CI], 1 to 22) in group 1, 3% (95% CI, 0 to 17) in group 2, 12% (95% CI, 3 to 28) in group 3, 23% (95% CI, 10 to 42) in group 4, and none (95% CI, 0 to 10) in group 5. Additionally, seroconversion occurred in approximately 3%, none, 3%, 20%, and none of the participants in each respective group at 24 weeks following the end of treatment. Further, HBsAg loss with or without seroconversion occurred only in participants who had a screening HBsAg level below 1000 IU/mL.1

Additionally, the findings demonstrated that grades 3 or 4 AEs were not uncommon. These AEs were most frequent in group 4 (50%), followed by group 3 (18%), group 1 (17%), group 2 (10%), and group 5 (6%).1

REFERENCES
1. Hou J, Zhang W, Xie Q, et al. Xalnesiran with or without an Immunomodulator in Chronic Hepatitis B. NEJM. 2024;391(22):2098-2109. doi:10.1056/NEJMoa2405485
2. A Trial To Evaluate The Efficacy And Safety Of Multiple Combination Therapies In Participants With Chronic Hepatitis B (Piranga). ClinicalTrials.gov identifier: NCT04225715. Updated August 20, 2024. Accessed January 14, 2025. https://clinicaltrials.gov/study/NCT04225715
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