siRNA JNJ-73763989 decreases HBsAg and HDV RNA in NA-treated hepatitis D patients but may cause ALT flares.

Summary

In a phase 2 double-blind RCT (n=22), HBsAg-targeting siRNA (JNJ-3989) reduced HDV RNA and HBsAg in chronic hepatitis D patients on background nucleos(t)ide analogs. However, ALT elevations were frequent, leading to treatment discontinuation in many participants, particularly those with high baseline HBsAg.

Key Findings

• Primary endpoint (≥2 log10 decline in HDV RNA) achieved in 4/17 (24%) in the active arm and 0/5 in controls.
• ALT elevations led to treatment discontinuation in 12/17 (71%) participants receiving JNJ-3989.
• Unexpected ALT elevations occurred in 14/21 (67%) participants ever exposed to JNJ-3989 (immediate or deferred), with return to baseline after discontinuation.
• HBsAg and HDV RNA declines were observed during treatment in participants on JNJ-3989.

Clinical Implications

JNJ-3989 shows antiviral activity against HDV via HBsAg reduction but requires stringent liver enzyme monitoring and careful patient selection; it is not yet practice-changing pending larger studies and safety optimization.

Limitations

• Small sample size and high discontinuation rate due to ALT flares
• Incomplete treatment exposure for many participants; limited generalizability

Future Directions

Larger, stratified RCTs with refined dosing, baseline HBsAg thresholds, and immune-monitoring are needed to balance efficacy and hepatotoxicity; mechanistic studies to elucidate ALT flare biology.