Molecular mass: 3,562.229 g/mol PubChem compound: 133083018
Zilucoplan is a 15 amino acid, synthetic macrocyclic peptide that inhibits the effects of the complement protein C5 through a dual mechanism of action. It specifically binds to C5, thereby inhibiting its cleavage by the C5 convertase to C5a and C5b, which results in a downregulation of the assembly and cytolytic activity of the membrane attack complex (MAC). Additionally, by binding to the C5b moiety of C5, zilucoplan sterically hinders binding of C5b to C6, which prevents the subsequent assembly and activity of the MAC, should any C5b be formed.
The pharmacodynamic effect of zilucoplan was analysed through the ability of inhibiting ex vivo, complement-induced sheep red blood cell (sRBC) lysis.
Data from the phase 2 and phase 3 studies demonstrate rapid, complete (>95%) and sustained complement inhibition with zilucoplan.
Following single and multiple daily subcutaneous administration of the zilucoplan recommended dose (Table 1) in healthy subjects, zilucoplan reached peak plasma concentration generally between 3 to 6 hours post-dose.
In study MG0010 in patients with gMG, after daily repeated subcutaneous administration of the zilucoplan recommended dose (Table 1), plasma concentrations of zilucoplan were consistent, with steady state trough concentrations being reached by week 4 and maintained through week 12. Exposures after subcutaneous administration of single zilucoplan doses in the abdomen, thigh, or upper arm were comparable.
Zilucoplan and the active (RA103488) and major inactive (RA102758) circulating metabolites are highly bound to plasma proteins (>99%). The mean volume of distribution for zilucoplan (Vc/F) using a population pharmacokinetic analysis is 3.51 L. Zilucoplan is not a substrate for common drug transporters.
Zilucoplan is not a substrate of major CYP enzymes. In plasma, 2 metabolites, the active (RA103488) and major inactive metabolite (RA102758) were detected. The formation of RA103488 is mainly due to cytochrome CYP450 4F2. RA103488 has pharmacological activity similar to zilucoplan but is present at a much lower concentration compared to zilucoplan. The contribution of RA103488 to pharmacological activity is low. Further, as a peptide, zilucoplan is expected to be degraded into smaller peptides and amino acids via catabolic pathways.
Zilucoplan inhibits MRP3 in vitro at therapeutic concentrations; the clinical relevance of this inhibition is unknown.
As a peptide, zilucoplan is expected to be degraded into smaller peptides and amino acids via catabolic pathways. The mean plasma terminal elimination half-life was approximately 172 hours (7-8 days). The half-life was 220 hours and 96 hours respectively for the active (RA103488) and major inactive metabolite (RA102758). The excretion of zilucoplan and its metabolites (RA103488 and RA102758) measured in both urine and faeces was negligible. The pegylated part of zilucoplan is anticipated to be excreted mainly via the kidneys and the main degradation of fatty acid part is via β-oxidation to acetyl-CoA.
In the population pharmacokinetic analysis (doses corresponding to 0.05 to 0.6 mg/kg), zilucoplan pharmacokinetics is characterised by target dependent drug disposition with less than dose proportional increase in exposure with increasing doses, and after multiple doses compared to single dose.
The incidences of ADA and anti-PEG antibodies in the phase 3 study in patients with gMG were comparable between the zilucoplan treatment group and the placebo treatment group. The ADA and anti-PEG antibody status of patients treated with zilucoplan did not affect zilucoplan concentrations.
Population pharmacokinetic analysis on data collected across studies in gMG showed that body weight significantly influences the pharmacokinetics of zilucoplan. Zilucoplan dosing is based on body weight categories, no further dose adjustment is needed.
Based on population pharmacokinetic analysis, age did not influence the pharmacokinetics of zilucoplan. No dose adjustment is required.
The effect of renal impairment on the pharmacokinetics of zilucoplan and its metabolites was studied in an open-label phase 1 study, where a single-dose of the zilucoplan recommended dose (Table 1) was administered to healthy subjects and subjects with severe renal impairment (creatinine clearance between 15 and <30 mL/min).
Systemic exposure to zilucoplan and the major inactive metabolite RA102758 was not different in subjects with severe renal impairment compared to subjects with normal renal function. The exposure to the active metabolite RA103488 was approximately 1.5-fold higher in subjects with severe renal impairment compared to subjects with normal renal function.
Based on the pharmacokinetic results, no dose adjustment is required in patients with renal impairment.
The effects of moderate hepatic impairment (as defined by a Child-Pugh score between 7 and 9) on the pharmacokinetics of zilucoplan and its metabolites were studied in an open-label phase 1 study, where a single dose of the zilucoplan recommended dose (Table 1) was administered to healthy subjects and subjects with moderate hepatic impairment.
Systemic exposure to zilucoplan was 24% lower in subjects with moderate impaired liver function compared to healthy subjects, which was in line with a higher systemic and peak exposures of both metabolites in subjects with hepatic impairment compared to healthy subjects. Zilucoplan peak exposure as well as terminal half-life were comparable between both groups. Further pharmacodynamic analysis did not identify meaningful differences in complement levels or inhibition of complement activity between both groups. Based on these results, no dose adjustment is required in patients with mild and moderate hepatic impairment.
In a phase 1 clinical study in healthy Caucasian and Japanese subjects, the pharmacokinetic profile of zilucoplan and its two metabolites (RA102758 and RA103488) was compared following a single dose (Table 1) and after multiple dosing for 14 days. Results were generally similar between both groups. The population pharmacokinetic analysis for zilucoplan showed that there are no differences between the different race categories (Black/African American, Asian/Japanese, and Caucasians). No dose adjustment is required.
In the population pharmacokinetic analysis, no difference in pharmacokinetics between genders was observed. No dose adjustment is required.
In repeat-dose toxicity studies performed in non-human primates, there were vesicular degeneration/hyperplasia of epithelial cells and mononuclear cell infiltrates in various tissues at clinically relevant exposure. In the pancreas, this sometimes manifested as pancreatic acinar cell degeneration, some with fibrosis and ductal degeneration/regeneration and was accompanied with increased plasma concentrations of amylase and lipase. In female reproductive organs (vagina, cervix, uterus), mononuclear cell infiltrates with epithelial degeneration and cervical squamous metaplasia were seen. In a monkey male fertility study, minimal to slight germ line degeneration/depletion was observed at clinically relevant exposures but severity did not increase with dose. No impact on spermatogenesis was observed.The findings in non-human primates are of uncertain clinical relevance and some are possibly related to infections secondary to the pharmacological effect of zilucoplan, but other mechanisms cannot be excluded. The findings did not correlate with any effects on embryofetal development or pregnancy outcomes (pregnancy loss, parturition, pregnancy outcomes, or infant postnatal development) in non-human primates at similar dose levels.
No carcinogenicity studies were conducted with zilucoplan.
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