Lerodalcibep

Lerodalcibep is a recombinant fusion protein that binds PCSK9 with picomolar affinity. PCSK9 binds to low-density lipoprotein receptor (LDLR) on the surface of hepatocytes to promote LDLR degradation within the liver. By inhibiting the binding of PCSK9 to LDLR, lerodalcibep increases the number of LDLRs available to clear LDL-C from the blood, thereby lowering LDL-C levels.

After subcutaneous administration of 300 mg lerodalcibep every month, greater than 90% suppression of PCSK9 occurs within 24 hours after dosing and is maintained throughout the dosing interval, returning toward baseline during the last 7 to 10 days of the monthly dosing period.

Following a single subcutaneous administration, exposure to lerodalcibep increased in a dose proportional manner over the dose range 75 to 300 mg of lerodalcibep.

Lerodalcibep pharmacokinetics were observed at steady state in patients at the approved recommended dosage and are presented as mean (SD), unless otherwise specified. Lerodalcibep maximum concentration (C_max) is 31.4 (10.2) mcg/mL, and total systemic exposure (AUC_0-tau) is 12,600 (5,190) (hrs*mcg/mL) following subcutaneous dose of lerodalcibep 300 mg once every four weeks. Lerodalcibep steady-state is reached following 2 to 3 doses. Lerodalcibep accumulation is approximately 30% at the approved recommended dosage.

Absorption

The median (min, max) estimated subcutaneous bioavailability of lerodalcibep is 83% (66%, 89%). The median (min, max) time to maximum plasma concentration (T_max) is 6 days (2, 9 days) at steady state.

Distribution

Lerodalcibep does not extensively distribute into tissues; the apparent volume of distribution is 5.3 L.

Elimination

As a protein, lerodalcibep is expected to degrade to small peptides and amino acids. Clearance of free lerodalcibep (CV%) is 0.36 L/day (30%) with an estimated half-life of approximately 10 days. The estimated elimination rate of lerodalcibep (CV%) bound to PCSK9 is 0.47 L/day (22%) which corresponds to a half-life of approximately 1.5 days.

Specific Populations

No clinically significant differences in the pharmacokinetics of lerodalcibep were observed based on age (21 to 78 years), body weight, sex, race, mild (eGFR 60 to 89 mL/min) or moderate (eGFR 30 to 59 mL/min) renal impairment, or mild (total bilirubin 1.0 to 1.5 upper limit of normal or aspartate aminotransaminase greater than the upper limit of normal) or moderate (total bilirubin 1.5 to 3.0 upper limit of normal) hepatic impairment. The effect of severe renal impairment (eGFR less than 30 mL/min) or severe hepatic impairment on lerodalcibep pharmacokinetics is unknown.

Drug Interaction Studies

No formal clinical drug interaction studies have been performed.