Phase II Piranga Trial Shows Promise of Xalnesiran Combination for Hepatitis B Treatment

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The Phase II Piranga trial (NCT04225715) found that the combination of the novel hepatitis B drug xalnesiran plus an immunomodulator produced significant hepatitis B surface antigen (HBsAg) loss rates; however, the durability of response and efficacy in patients with high HBsAg-levels remain a challenge, according to the authors of the study, published by The New England Journal of Medicine.^1,2 They added that these findings highlight the need for tailored approaches that target adaptive hepatitis B virus (HBV) immunity.

“Xalnesiran with or without an immunomodulator resulted in substantial reduction in the HBsAg level during treatment, with up to 60% of the participants having an HBsAg level maintained below 100 IU per milliliter at 48 weeks after the end of treatment,” the study authors wrote. “This finding is consistent with results of a previous study and with the long half-life of N-acetyl-d-galactosamine–conjugated small interfering RNA molecules in the liver. However, the addition of an immunomodulator was essential for HBsAg loss.”¹

Background

HBV is classified as a hepaDNA virus, comprised of four distinct genomic regions with a complex mode of replication susceptible to the development of mutant forms of the virus. HBV is typically diagnosed by a HBsAg test to detect active infection.³

Management of HBV typically involves preventive measures that seek to minimize active infection rates. Beyond preventative actions, maintaining antibody levels is also of significant importance. Among patients with active HBV infection, interferon alfa is typically used to directly inactivate viral DNA by inhibiting protein synthesis.

“Standard care, which includes pegylated interferon therapy of finite duration (48 weeks) and lifelong nucleoside or nucleotide analogue (NA) therapy, rarely leads to functional cure, which occurs in only up to 7% of patients after 12 months of treatment,” the study authors wrote. “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.”¹

Xalnesiran, a novel N-acetyl-d-galactosamine–conjugated synthetic double-stranded small interfering RNA molecule, targets the S conserved region of the HBV genome, which the study authors said allows it to silence multiple transcripts. A prior Phase I trial found that the drug achieved substantial and durable decreases in HBsAg levels, indicating it could become the “backbone of finite-duration treatment regimens.”¹

Trial Design

Piranga was a Phase II, multicenter, randomized, controlled, adaptive, open-label platform trial. A total of 159 patients were randomly assigned to one of five groups in a 1:1 ratio, which analyzed 48 weeks of treatment with xalnesiran at a dose of 100 mg in group 1 (n = 30), xalnesiran at a dose of 200 mg in group 2 (n = 30), xalnesiran at a dose of 200 mg plus 150 mg of ruzotolimod in group 3 (n = 34), xalnesiran at a dose of 200 mg plus 180 μg of pegylated interferon alfa-2a in group 4 (n = 30), and monotherapy with a nucleoside or nucleotide analogue (NA) in group 5 ( n = 35) among participants with chronic HBV infection who achieved virologic suppression with NA therapy. The trial’s primary efficacy endpoint was HBsAg loss (HBsAg level, <0.05 IU per milliliter) at 24 weeks following the end of treatment, as well as safety.

Trial Findings

Among the five cohorts, the primary endpoint event was observed in 7% (95% confidence interval [CI], 1 to 22) of patients 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 zero (95% CI, 0 to 10) in group 5. HBsAg seroconversion occurred in 3% in group 1, zero in group 2, 3% in group 3, 20% in group 4, and zero in group 5 at 24 weeks after the end of treatment. HBsAg loss with or without seroconversion was only observed in patients with a screening HBsAg level below 1000 IU per milliliter.

In terms of safety, grade 3 or 4 adverse events (AEs) were reported by 17% of patients in group 1, 10% in group 2, 18% in group 3, 50% in group 4, and 6% in group 5. The most commonly reported AE was elevated alanine aminotransferase level.

“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 study authors concluded. “To address these challenges, a potential approach could be to specifically target adaptive immunity and restore HBV-specific exhausted T cells. Combination regimens containing checkpoint inhibitors are being explored in chronic hepatitis B, including a liver-targeted locked nucleic acid that degrades programmed death ligand 1 expressionand is being evaluated in combination with xalnesiran in other groups of the Piranga platform trial.”¹

References

1. Hou J., et al. Xalnesiran with or without an Immunomodulator in Chronic Hepatitis B. N Engl J Med 2024;391:2098-2109. DOI: 10.1056/NEJMoa2405485. Vol. 391 No. 22.

2. A Trial To Evaluate The Efficacy And Safety Of Multiple Combination Therapies In Participants With Chronic Hepatitis B (Piranga). ClinicalTrials.gov. Updated August 20, 2024. Accessed December 5, 2024. https://clinicaltrials.gov/study/NCT04225715

3. Gregorio, Germana V, et al. Viral Hepatitis. National Center for Biotechnology Information, U.S. National Library of Medicine, 1995, https://www.ncbi.nlm.nih.gov/pmc/. Accessed December 5, 2024.