Evinacumab is a recombinant human monoclonal antibody, which specifically binds to and inhibits ANGPTL3. ANGPTL3 is a member of the angiopoietin-like protein family that is expressed primarily in the liver and plays a role in the regulation of lipid metabolism by inhibiting lipoprotein lipase (LPL) and endothelial lipase (EL).
Evinacumab blockade of ANGPTL3 lowers TG and HDL-C by releasing LPL and EL activities from ANGPTL3 inhibition, respectively. Evinacumab reduces LDL-C independent of the presence of LDL receptor (LDLR) by promoting very low-density lipoprotein (VLDL) processing and VLDL remnants clearance upstream of LDL formation through EL-dependent mechanism.
Evinacumab is administered intravenously to patients with HoFH. Based on population PK modelling, at the end of infusion at steady-state, mean ± SD Cmax is 681 ± 185 mg/l in adult patients following a dose of 15 mg/kg every 4 weeks. The accumulation ratio is approximately 2. The mean ± SD steady-state trough concentration is 230 ± 81.3 mg/l in adult patients.
The steady-state volume of distribution estimated by population PK analysis in a typical individual weighing 72 kg was approximately 4.9 L in adult patients, indicating that evinacumab is distributed primarily in the vascular system.
The specific metabolism studies were not conducted because evinacumab is a protein. As a human monoclonal IgG4 antibody, evinacumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.
Evinacumab elimination is mediated by parallel linear and nonlinear pathways. At higher concentrations, evinacumab elimination is primarily through a non-saturable proteolytic pathway, while at lower concentrations, the non-linear saturable ANGPTL3 target-mediated elimination predominates. Elimination half-life is a function of evinacumab concentrations in serum and is not a constant.
After the last steady-state dose of 15 mg/kg IV every 4 weeks, the median time for evinacumab concentrations to decrease below the lower limit of detection (78 ng/ml) is 19 weeks.
Due to nonlinear clearance, a slightly greater than dose proportional increase was observed, with a 4.3-fold increase in area under the concentration-time curve at steady-state (AUCtau.ss) for a 3-fold increase in dose from 5 mg/kg to 15 mg/kg IV every 4 weeks.
The pharmacodynamic effect of evinacumab in lowering LDL-C is indirect, and mediated through the binding to ANGPTL3. Concentration of total ANGPTL3 increases from baseline upon administration of evinacumab and the increases plateau when target saturation is approached. When target is saturated, further increase in evinacumab concentrations is not expected to result in a further LDL-C reduction.
A population PK analysis conducted on data from 183 healthy adult participants and 139 patients with HoFH, suggests that the following factors have no clinically significant effect on the exposure of evinacumab: age (5 to 75 years), gender, body weight (19.7 to 152 kg), race. Apheresis did not appear to substantially influence the pharmacokinetics of evinacumab.
There were 14 patients aged 12 to 17 years with HoFH receiving evinacumab at 15 mg/kg IV every 4 weeks, steady-state trough and maximum concentrations were generally within the range of those in adult patients. The mean steady-state Cmax was 566 ± 206 mg/l in patients aged 12 to <18 years with HoFH.
For the 20 patients aged 5 to 11 years with HoFH receiving evinacumab at 15 mg/kg IV every 4 weeks, the mean (SD) steady-state trough evinacumab concentration based on population PK analyses was 160 ± 57.6 mg/l and the mean (SD) steady-state Cmax was 419 ± 99.4 mg/l in patients aged 5 to 11 years with HoFH.
The pharmacokinetics of evinacumab in paediatric patients less than 5 years of age with HoFH have not been established.
Evinacumab is not expected to undergo significant renal elimination. Observed trough concentrations at steady-state were comparable between patients with mild or moderate renal impairment and patients with normal renal function. No data are available in patients with severe renal impairment.
Evinacumab is not expected to undergo significant hepatic elimination. No data are available in patients with hepatic impairment.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and repeated dose toxicity.
Carcinogenicity and genotoxicity studies have not been conducted with evinacumab. Monoclonal antibodies are not expected to alter DNA or chromosomes.
No effects on surrogate markers of fertility in male and female reproductive organs were observed in a 6-month chronic toxicology study with sexually mature cynomolgus monkeys. In animal reproduction studies, evinacumab was administered subcutaneously to pregnant rabbits every 3 days from gestation day 7 until gestation day 19 during organogenesis. Maternal toxicity (premature neonatal death, foetal loss and/or premature delivery) was observed at all doses and foetal findings (soft tissues and skeletal malformations) were observed at all but the lowest dose (1 mg/kg). Mean systemic exposure measured during the gestation period in rabbits was below that measured at maximum recommended human dose (MRHD) of 15 mg/kg every 4 weeks. Because the lipid profile of rabbits differs significantly from that of humans, particularly during pregnancy, the clinical relevance of these results is uncertain.
There were no effects on embryo-foetal development when rats were subcutaneously administered evinacumab every 3 days from gestation day 6 to gestation day 18 during organogenesis. Mean systemic exposure measured during the gestation period in rats was below that measured at MRHD of 15 mg/kg every 4 weeks.
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