Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Ultragenyx Germany GmbH, Rahel-Hirsch-Str. 10, 10557 Berlin, Germany
Pharmacotherapeutic group: Other lipid modifying agents
ATC code: not yet assigned
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.
This was a multicentre, double-blind, randomised, placebo-controlled trial evaluating the efficacy and safety of evinacumab compared to placebo in 65 patients with HoFH. The trial consisted of a 24-week double-blind treatment period and a 24-week open-label treatment period. In the double-blind treatment period, 43 patients were randomised to receive evinacumab 15 mg/kg IV every 4 weeks and 22 patients to receive placebo. Patients were on a background of other lipid-lowering therapies (e.g. statins, ezetimibe, PCSK9 inhibitor antibodies, lomitapide, and lipoprotein apheresis). The diagnosis of HoFH was determined by genetic testing or by the presence of the following clinical criteria: history of an untreated TC >500 mg/dl (13 mmol/l) together with either xanthoma before 10 years of age or evidence of TC >250 mg/dl (6.47 mmol/l) in both parents. Patients regardless of mutation status were included in the trial. Patients were defined as having null/null or negative/negative variants if the variations resulted in little to no residual LDLR function; null/null variants were defined as having <15% LDLR function based on in vitro assays and negative/negative variants were defined as having premature termination codons, splice site variations, frame shifts, insertion/deletions or copy number variations. In this trial, 32.3% (21 of 65) of patients had null/null variants and 18.5% (12 of 65) of patients had negative/negative variants.
The mean LDL-C at baseline was 255.1 mg/dl (6.61 mmol/l) and in the subset of patients with null/null variants was 311.5 mg/dl (8.07 mmol/l) and with negative/negative variants was 289.4 mg/dl (7.50 mmol/l). At baseline, 93.8% of patients were on statins, 75.4% on ezetimibe, 76.9% on a PCSK9 inhibitor antibodies, 21.5% on lomitapide, and 33.8% were receiving lipoprotein apheresis. The mean age at baseline was 42 years (range 12 to 75) with 12.3% ≥65 years old; 53.8% women, 73.8% White, 15.4% Asian, 3.1% Black and 7.7% Other or not reported.
The primary efficacy end-point was percent change in LDL-C from baseline to week 24. At week 24, the LS mean treatment difference between evinacumab and placebo in mean percent change in LDL-C from baseline, was -49.0% (95% CI: -65.0% to -33.1%; p <0.0001). For efficacy results see Table 2.
Table 2. Effect of evinacumab on lipid parameters in patients with HoFH in study ELIPSE-HoFH:
| Baseline (mean), mmol/l (N=65) | LS mean percent change or change from baseline at week 24 | Difference from placebo (95% CI) | P-value | ||
|---|---|---|---|---|---|
| evinacumab (N = 43) | placebo (N = 22) | ||||
| LDL-C (percent change) | 6.6 | -47.1% | +1.9% | -49% (-65.0 to -33.1) | <0.0001 |
| LDL-C (absolute change)(mmol/l) | 6.6 | -3.5 | -0.1 | -3.4 (-4.5 to -2.3) | <0.0001 |
| ApoB (g/l) | 1.7 | -41.4% | -4.5% | -36.9% (-48.6 to -25.2) | <0.0001 |
| Non-HDL-C | 7.2 | -49.7% | +2.0% | -51.7% (-64.8 to -38.5) | <0.0001 |
| TC | 8.3 | -47.4% | +1.0% | -48.4% (-58.7 to -38.1) | <0.0001 |
| TG | 1.4 | -55.0% | -4.6% | -50.4% (-65.6 to -35.2) | <0.0001a |
| HDL-Cb | 1.2 | -29.6% | +0.8% | - | - |
a nominal p-value since TG is not a key secondary endpoint
b Mean percent change at week 24 results are presented based on the actual treatment received in safety population (evinacumab, n=44; placebo, n=20); there is no formal statistical testing in safety population
After the double-blind treatment period, 64 of the 65 randomised patients who entered the open-label treatment period received evinacumab. The mean percent change in LDL-C from baseline to week 48 ranged from -42.7% to -55.8%. Figure 1 shows the LDL-C mean percent change from baseline for the double-blind and observed mean percent change for the open-label treatment periods across patients who were on evinacumab or placebo during the double-blind treatment period.
Figure 1. Calculated LDL-C LS mean percent change from baseline over time through week 24, and observed mean percent change from week 28 through week 48 in study ELIPSE-HoFH:
At Week 24, the observed reduction in LDL-C with evinacumab was similar across predefined subgroups, including age, sex, null/null or negative/negative variants, concomitant treatment with lipoprotein apheresis, and concomitant background lipid-lowering medications (statins, ezetimibe, PCSK9 inhibitor antibodies, and lomitapide). The effect of evinacumab on cardiovascular morbidity and mortality has not been determined.
In an ongoing multicentre, open-label extension study 81 patients with HoFH showed a 43% decrease in LDL-C at 24 weeks of exposure following evinacumab treatment 15 mg/kg IV every 4 weeks on top of other lipid-lowering therapies (e.g., statins, ezetimibe, PCSK9 inhibitor antibodies, lomitapide, and lipoprotein apheresis). Patients regardless of mutation status were included in the trial, including patients with null/null or negative/negative variants.
In ELIPSE-HoFH, 1 adolescent patient received 15 mg/kg IV of evinacumab every 4 weeks and 1 adolescent patient received placebo, as an adjunct to other lipid-lowering therapies (e.g. statins, ezetimibe, PCSK9 inhibitor antibodies and lipoprotein apheresis). Both adolescent patients had null/null variants in the LDLR. At week 24, the percent change in LDL-C with evinacumab was -73.3% and with placebo +60%.
In ELIPSE-OLE, 13 adolescent patients received 15 mg/kg IV of evinacumab every 4 weeks as an adjunct to other lipid-lowering therapies (e.g. statins, ezetimibe, PCSK9 inhibitor antibodies and lipoprotein apheresis). Two patients entered after completing the ELIPSE-HoFH study and 11 patients were evinacumab-naïve. The mean baseline LDL-C in these adolescent patients was 310.3 mg/dl (8.04 mmol). The mean age was 14 years (range: 12 to 17 years), with 61.5% males and 38.5% females. At baseline, all patients were on a statin, 69.2% on ezetimibe, 46.2% on PCSK9 inhibitor, and 61.5% were receiving lipoprotein apheresis. Four (30.8%) patients had null/null variants and 4 (30.8%) patients had negative/negative variants for LDLR mutations. At week 24, the percent change in LDL-C with evinacumab was -52.4% (n=9).
The European Medicines Agency has deferred the obligation to submit the results of studies with evinacumab in one or more subsets of the paediatric population in the treatment of homozygous familial hypercholesterolaemia (see section 4.2 for information on paediatric use).
This medicine has been authorised under ‘exceptional circumstances’. This means that due to the rarity of the disease it has not been possible to obtain complete information on this medicinal product. The European Medicines Agency will review any new information which may become available every year and this SmPC will be updated as necessary.
Evinacumab is administered intravenously to patients with HoFH. Based on population PK modelling, at the end of infusion at steady-state, Cmax is 689 ± 157 mg/l following a dose of 15 mg/kg every 4 weeks. The accumulation ratio is 2. Mean steady-state trough concentration is 241 ± 96.5 mg/l.
The total volume of distribution estimated by population PK analysis in a typical individual weighing 74.1 kg was approximately 4.8 L and scales with body weight, 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 subjects and 95 patients with HoFH, suggests that the following factors have no clinically significant effect on the exposure of evinacumab: age (12 to 75 years), gender, body weight (42 to 152 kg), race. Apheresis did not appear to substantially influence the pharmacokinetics of evinacumab.
There were 2 patients age 12 to 17 years with HoFH receiving evinacumab at 15 mg/kg IV every 4 weeks, steady-state trough and end of infusion concentrations were within the range observed in adult patients. The pharmacokinetics of evinacumab in paediatric patients less than 12 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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