Pozelimab

Pozelimab-bbfg is a human, monoclonal immunoglobulin G4^P (IgG4^P) antibody directed against the terminal complement protein C5 that inhibits terminal complement activation by blocking cleavage of C5 into C5a (anaphylatoxin) and C5b, thereby blocking the formation of the membrane-attack complex (C5b-C9, a structure mediating cell lysis).

The effect of pozelimab-bbfg on complement activity was measured by total complement hemolytic activity test (CH50). The magnitude and duration of reduction from baseline in CH50 by pozelimab-bbfg was dose dependent.

In healthy subjects receiving a single dose of pozelimab 30 mg/kg administered as an intravenous infusion over approximately one hour, the complete inhibition of CH50 was achieved at the end of infusion in all subjects, was maintained for 28 days, and returned to baseline 84 days post-dose. After a single dose of pozelimab administered as a 600 mg subcutaneous injection, the maximum reduction from baseline in CH50 was achieved 7 days post-dose in most subjects (range: 3 to 14 days), corresponding to T_max, and returned to baseline 56 days post-dose.

In patients with CD55-deficient PLE receiving a single 30 mg/kg dose administered as an intravenous infusion over approximately one hour followed by a weight-tiered subcutaneous injection once weekly starting at Week 1, CH50 was completely inhibited by Week 1 for most subjects and by Week 12 for all patients.

In the same study of patients with CD55-deficient PLE, serum albumin concentrations increased as early as Week 1 and reached the normal range (≥3.5 g/dL) by Week 4 for most subjects and by Week 12 for all subjects. The serum albumin concentrations were maintained within the normal range for the duration of treatment. Endogenous serum IgG concentrations were also increased from baseline at Week 1 in all patients with CD55-deficient PLE and reached a stable concentration around Week 16.

In healthy subjects, single intravenous infusions of pozelimab over approximately one hour resulted in dose proportional increases in mean C_max, but greater than proportional increases in mean AUC_inf (>16-fold) for total pozelimab concentrations in serum between 3 mg/kg and 30 mg/kg. The mean AUC_inf increased by 3.5-fold between 10 mg/kg and 30 mg/kg. In healthy subjects, single subcutaneous injections of pozelimab resulted in approximately 1.5-fold increase in mean C_max and 2.2-fold increase in mean AUC_inf between 300 mg and 600 mg.

In patients with CD55-deficient PLE, a single dose of pozelimab 30 mg/kg administered as an intravenous infusion over approximately one hour resulted in median (range) total pozelimab trough concentration of 180 (52.8, 268) mg/L at Week 1. The predicted mean (SD) trough concentrations of total pozelimab at steady state are 330 (94.2) mg/L and 385 (112) mg/L for pozelimab 10 mg/kg or 12 mg/kg (up to a maximum 800 mg) once weekly via subcutaneous injection(s), respectively, following the intravenous loading dose.

Absorption

In healthy subjects, following subcutaneous injection of 600 mg, the bioavailability of pozelimab-bbfg is estimated as 51%. The median (range) time to reach peak concentration was 7 (3 to 7) days following a single subcutaneous injection of 300 mg or 600 mg in healthy subjects.

Distribution

In healthy adult subjects with a mean body weight of 70 kg, the mean (SD) volume of distribution following a single intravenous dose of 30 mg/kg was 3.3 (0.4) L. The mean (SD) apparent volume of distribution following a single subcutaneous injection of 300 mg and 600 mg was 6.0 (0.9) L and 8.6 (2.7) L, respectively.

Elimination

Pozelimab-bbfg is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG. Pozelimab-bbfg elimination is mediated via linear and non-linear pathways. At higher concentrations, pozelimab-bbfg elimination is primarily through the linear non-saturable proteolytic pathway, whereas at lower concentrations, the non-linear, saturable C5 target-mediated elimination predominates.

In healthy adult subjects, the median (range) terminal half-life of total pozelimab in serum was 13.5 (10.0, 17.2) days following a single 30 mg/kg dose administered as an intravenous infusion. The median (range) terminal half-life was 14.1 (8.6, 17.3) days following a single 600 mg subcutaneous injection.

In patients with CD55-deficient PLE, steady-state total pozelimab concentrations were reached at approximately 20 weeks following subcutaneous injection once weekly.

Specific Populations

Body Weight

Body weight was a significant covariate on the pharmacokinetics of pozelimab-bbfg.

Renal and Hepatic Impairment

Pozelimab-bbfg, a monoclonal antibody, is not likely to undergo renal or hepatic excretion.

Drug Interaction Studies

Drug interaction studies have not been conducted. Intravenous Immunoglobulin (IVIg) may interfere with the endosomal neonatal Fc receptor (FcRn) recycling mechanism of monoclonal antibodies such as pozelimab-bbfg, which may decrease serum pozelimab concentrations.