Table 3. Pharmacokinetic and Safety Profile Comparison across Different Chemical Modalities.

chemical modality	excretion	Cl (clearance)	DDI risk	immunogenicity	toxicity risk (off-target selectivity)	PD duration
small molecule (SM)	primarily excreted in bile and urine	often linear Cl	high	no	high	generally short
bRo5 SM	primarily excreted in bile and urine	often rapid plasma Cl	variable	no	medium	variable
bRo5 cyclopeptides/macrocycles	primarily excreted in bile and urine	often rapid plasma Cl	variable	no	medium	variable
large peptides	primarily excreted in urine	rapid plasma Cl	low	no	low	longer than SM
oligonucleotide ASO	primarily excreted in urine	rapid plasma Cl due to distribution to tissues; slow Cl from tissues	very low	yes	low	long
oligonucleotide siRNA	primarily excreted in urine	more rapid Cl than ASO	very low	yes	low	long
biologics (antibodies)	very limited	slow Cl	uncommon	yes (high risk of impacting PK and PD)	uncommon	long