Arrowhead Pharmaceuticals(US:ARWR)2025-07-09 11:34ARC-520 Tolerability and Mechanism - ARC-520 has been very well tolerated in 84 humans with single doses, showing no serious or severe adverse events or discontinuations due to AEs[15, 16] - Chimpanzee studies showed that ARC-520 leads to deep HBsAg reduction, with HBeAg(+) chimps showing a mean peak knockdown of 99% (2 log) and HBeAg(-) chimps showing 81% (0.7 log)[17] - The DPC platform is potent and consistent, de-risking ARC-520 and future candidates built on the same DPC, with HBeAg knockdown in HBeAg(+) patients reaching 92% (1.2 log) mean max KD and 98% (1.7 log) max KD after a single 4mg/kg dose[19] ARC-520 Efficacy and Target Population - ARC-520 achieved a 99% (1.9 log) maximum knockdown of HBsAg after a single dose, the highest ever reported in a human using RNAi[20] - In NUC-naïve HBeAg(+) patients, ARC-520 administration resulted in a mean max HBsAg knockdown of 1.05 log, with a maximum knockdown of 99% (1.9 log) through Day 15[21] - In the US, 95% of estimated CHB patients are NUC-naïve, with approximately 50% estimated to be HBeAg(+), making them an important target population for ARC-520[25] - In Western Europe, 90% of estimated CHB patients are NUC-naïve, with approximately 33% estimated to be HBeAg(+)[25] Integrated DNA and ARC-521 - Integrated DNA becomes an increasingly important source of HBsAg as cccDNA is reduced, influencing the response to ARC-520[19] - Two HBeAg neg chimps treated with siRNA targeting integrated DNA showed a mean nadir of HBsAg reduction of 99.8% after switching from ARC-520, representing an additional 2 log decline[77] - The company nominated an additional candidate, ARC-521, optimized to include integrant KD, with an IND or equivalent expected by mid-year 2016[29, 30]