Viral Hepatitis HBV/HBV Cure [AASLD 2023] Roche releases positive interim off-treatment results from their Ph2 PIRANGA trial testing xalnesiran (siRNA) combinations in chronic hepatitis B (CHB)

On November 13^th, 2023, Roche released positive interim results from their Ph2 PIRANGA trial (N=160) testing xalnesiran (siRNA) combinations in CHB patients. This data was released as a late breaker at AASLD 2023.

Key Details:

• The Ph2 PIRANGA study (N=160) consists of 9 trial arms which explore combinations of siRNA, CAM, TLR7, PegIFN, and PDL1. An arm with NUC is used as an active comparator.
  • About 50% of patients enrolled in this trial demonstrate a low baseline HBsAg level of <1000 IU/ml
• Interim 48-wk off-treatment results were presented for 5/9 arms where patients received xalnesiran (siRNA, 200 mg SC Q4W) in combination with NUC with/without pegIFN (180μg SC QW) or ruzotolimod (TLR7, 150mg PO every other day during wks 13-24 and wks 37-48)
  • All xalnisiran combinations for 48-weeks were generally well-tolerated. SAEs observed were not associated with xalnesiran and/or ruzotolimod
• 30% of patients who received a combination of xalnesiran and pegIFN achieved HBsAg negativity at the end of therapy and 23.3% demonstrated a sustained virologic response at 24 wks after end of treatment (SVR 24)
  • All pts who achieved SVR24 had a baseline HBsAg level <1000 IU/mL
  • Patients that received xalnesiran and ruzotolimod only achieved a SVR24 of 11.8%

Assessment:

• While this is the highest SVR 24 we’ve seen thus far in HBVCure, cautious interpretation of these Ph2 data is warranted given the small sample size, the fact that HBsAg loss occurred only with low baseline HBsAg, and the high response rate to pegIFN alone observed in patients with similarly low baseline HBsAg.
  • During the Q&A following the presentation KOLs highlighted the lack of a pegIFN comparator arm and questioned the additive benefit of xalnesiran
  • Recall, VIR’s combination of VIR-2218 (siRNA) + peg-IFN had a SVR24 of 16.1% and  GSK’s bepirovirsen monotherapy had a SVR24 of ~9%
• If Roche continues to develop the xalnisiran + PEG-IFNα combination, an approval by 2H 2031 would be possible following the successful completion of a Ph3 study

Additional details: 

Efficacy Data from Roche’s Ph2 PIRANGA Trial and Ph2 PIRANGA Study Design and Details

• Phase: Ph2
• Status: Active, Not Recruiting
• Treatment: Xalnesiran (siRNA)
• Population: N=280 (Inclusion criteria specifies HBV DNA must be below the lower LLOQ or < 20 IU/mL for > 6 months prior to screening and confirmed at screening)
• Timing: PCD August 2024, SCD January 2025
• Dosing Arms:
  • Active comparator (NUC)
  • TLR7 + CAM + NUC
  • siRNA + NUC
  • siRNA + pegIFN + NUC
  • siRNA + CAM + NUC
  • siRNA + TLR7 + NUC
  • siRNA + PD-L1 + NUC
• Assets: siRNA (RO7445482, Xalnesiran), CpAM (RO7049389), TLR7 (RO7445482), PD-L1 LNA (RO791863)
• Primary Endpoint: Percentage of Participants with Hepatitis B Surface Antigen (HBsAg) loss at 24 weeks post-EOT

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