Pegcetacoplan is a symmetrical molecule comprised of two identical pentadecapeptides covalently bound to the ends of a linear 40-kDa PEG molecule. The peptide moieties bind to complement C3 and exert a broad inhibition of the complement cascade. The 40-kDa PEG moiety imparts improved solubility and longer residence time in the body after administration of the medicinal product.
Pegcetacoplan binds to complement protein C3 and its activation fragment C3b with high affinity, thereby regulating the cleavage of C3 and the generation of downstream effectors of complement activation. In PNH, extravascular haemolysis (EVH) is facilitated by C3b opsonisation while intravascular haemolysis (IVH) is mediated by the downstream membrane attack complex (MAC). Pegcetacoplan exerts broad regulation of the complement cascade by acting proximal to both C3b and MAC formation, thereby controlling the mechanisms that lead to EVH and IVH.
In Study APL2-302, the mean C3 concentration increased from 0.94 g/L at baseline to 3.83 g/L at Week 16 in the pegcetacoplan group and sustained through Week 48. In Study APL2-308, the mean C3 concentration increased from 0.95 g/L at baseline to 3.56 g/L at Week 26.
In Study APL2-302, the mean percentage of PNH Type II + III RBCs increased from 66.80% at baseline, to 93.85% at Week 16 and sustained through Week 48. In Study APL2-308, the mean percentage of PNH Type II + III RBCs increased from 42.4% at baseline to 90.0% at Week 26.
In Study APL2-302, the mean percentage of PNH Type II + III RBCs with C3 deposition was decreased from 17.73% at baseline to 0.20% at Week 16 and sustained through Week 48. In Study APL2-308, the mean percentage of PNH Type II + III RBCs with C3 deposition decreased from 2.85% at baseline to 0.09% at Week 26.
Pegcetacoplan is administered by subcutaneous infusion and gradually absorbed into the systemic circulation with a median Tmax between 108 and 144 hours (4.5 to 6.0 days) following a single subcutaneous dose to healthy volunteers. Steady-state serum concentrations following twice weekly dosing at 1 080 mg in patients with PNH were achieved approximately 4 to 6 weeks following the first dose. In complement inhibitor-experienced patients (Study APL2-302) the geometric mean (CV) steady-state serum concentrations ranged between 655 (18.6) and 706 (15.1%) µg/mL in patients treated for 16 weeks. Steady-state concentrations in the patients (n=22) that continued to receive pegcetacoplan up to Week 48 were 623 µg/mL (39.7%), indicating sustainable therapeutic concentrations of pegcetacoplan through Week 48. In complement inhibitor-naïve patients (Study APL2-308) the geometric mean (CV) steady-state serum concentration at Week 26 was 744 µg/mL (25.5) with twice weekly dosing. The bioavailability of a subcutaneous dose of pegcetacoplan is estimated to be 76% based on population PK analysis.
The mean (CV) volume of distribution of pegcetacoplan is approximately 3.98 L (32) in patients with PNH based on population PK analysis.
Based on its PEGylated peptide structure, the metabolism of pegcetacoplan is expected to occur via catabolic pathways and be degraded into small peptides, amino acids, and PEG. Results of a radiolabelled study in cynomolgus monkeys suggest the primary route of elimination of the labelled peptide moiety is via urinary excretion. Although the elimination of PEG was not studied, it is known to undergo renal excretion.
Pegcetacoplan showed no inhibition or induction of the CYP enzyme isoforms tested as demonstrated from the results of in vitro studies. Pegcetacoplan was neither a substrate nor an inhibitor of the human uptake or efflux transporters.
Following multiple subcutaneous dosing of pegcetacoplan in patients with PNH, the mean (CV) clearance is 0.015 L/h (30) and median effective half-life of elimination (t1/2) is 8.6 days as estimated by the population PK analysis.
Exposure of pegcetacoplan increases in a dose proportional manner from 45 to 1 440 mg.
No impact on the pharmacokinetics of pegcetacoplan was identified with age (19-81 years), race or sex based on the results of population PK analysis.
Compared with a reference 70 kg patient, the steady-state average concentration is predicted to be approximately 20% higher in patients with a body weight of 50 kg. Patients weighing 40 kg are predicted to have a 45% higher average concentration. Minimal data are available on the safety profile of pegcetacoplan for patients with a body weight below 50 kg.
Although there were no apparent age-related differences observed in these studies, the number of patients aged 65 years and over is not sufficient to determine whether they respond differently from younger patients.
In a study of 8 patients with severe renal impairment, defined as creatinine clearance (CrCl) less than 30 mL/min using the Cockcroft-Gault formula (with 4 patients with values less than 20 mL/min), renal impairment had no effect on the pharmacokinetics of a single 270-mg dose of pegcetacoplan. There are minimal data on patients with PNH with renal impairment who have been administered the clinical dose of 1 080 mg twice weekly. There are no available clinical data for the use of pegcetacoplan in patients with ESRD requiring haemodialysis.
In vitro and in vivo toxicology data reveal no toxicity of special concern for humans. Effects observed in animals at exposure levels similar to clinical exposure levels are described below. These effects were not observed in clinical studies.
Pegcetacoplan treatment of pregnant cynomolgus monkeys at a subcutaneous dose of 28 mg/kg/day (2.9 times the human steady-state Cmax) from the gestation period through parturition resulted in a statistically significant increase in abortions or stillbirths. No maternal toxicity or teratogenic effects were observed in offspring delivered at term. Additionally, no developmental effects were observed in infants up to 6 months postpartum. Systemic exposure to pegcetacoplan was detected in foetuses from monkeys treated with 28 mg/kg/day from the period of organogenesis through the second trimester, but the exposure was minimal (less than 1%, not pharmacologically significant).
Long term animal carcinogenicity studies of pegcetacoplan have not been conducted.
Pegcetacoplan was not mutagenic when tested in in vitro bacterial reverse mutation (Ames) assays and was not genotoxic in an in vitro assay in human TK6 cells or in an in vivo micronucleus assay in mice.
Repeat-dose studies were conducted in rabbits and cynomolgus monkeys with daily subcutaneous doses of pegcetacoplan up to 7 times the human dose (1 080 mg twice weekly). Histologic findings in both species included dose-dependent epithelial vacuolation and infiltrates of vacuolated macrophages in multiple tissues. These findings have been associated with large cumulative doses of long-chain PEG in other marketed PEGylated drugs, were without clinical consequence, and were not considered adverse. Reversibility was not demonstrated in the pegcetacoplan animal studies after one month and was not evaluated for a longer duration. Data from literature suggest reversibility of PEG vacuoles.
Renal tubular degeneration was observed microscopically in both species at exposures (Cmax and AUC) less than or comparable to those for the human dose and was minimal and nonprogressive between 4 weeks and 9 months of daily administration of pegcetacoplan. Although no overt signs of renal dysfunction were observed in animals, the clinical significance and functional consequence of these findings are unknown.
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