Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Swedish Orphan Biovitrum AB (publ), SE-112 76 Stockholm, Sweden
Pharmacotherapeutic group: Immunosuppressants, Selective immunosuppressants
ATC code: L04AA54
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 opsonization 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, mean C3 concentration increased from 0.94 g/L at baseline to 3.83 g/L at Week 16 in the pegcetacoplan group. The baseline percentage of PNH Type II + III RBCs was 66.80%, which then increased to 93.85% at Week 16. The mean percentage of PNH Type II + III RBCs with C3 deposition was 17.73% at baseline and this decreased to 0.20% at Week 16.
The efficacy and safety of ASPAVELI in patients with PNH was assessed in an open-label, randomised, active-comparator controlled 16-week Phase 3 study (APL2-302). This study enrolled patients with PNH who had been treated with a stable dose of eculizumab for at least the previous 3 months and with haemoglobin levels <10.5 g/dL.
The dose of ASPAVELI was 1 080 mg twice weekly. Eligible patients entered a 4-week run-in period during which they received ASPAVELI 1 080 mg subcutaneously twice weekly in addition to their current dose of eculizumab. Patients were then randomised in a 1:1 ratio to receive either 1 080 mg of ASPAVELI twice weekly or their current dose of eculizumab through the duration of the 16-week RCP. If required, the dose of ASPAVELI could be adjusted to 1 080 mg every 3 days. Randomisation was stratified based on the number of packed red blood cell (PRBC) transfusions within the 12 months prior to Day -28 (<4; ≥4) and platelet count at screening (<100 000/mm³; ≥100 000/mm³).
The primary efficacy endpoint was change from Baseline to Week 16 (during RCP) in haemoglobin level. Baseline was defined as the average of measurements prior to the first dose of pegcetacoplan (at the beginning of the run-in period). Key secondary efficacy endpoints were transfusion avoidance, defined as the proportion of patients who did not require a transfusion during the RCP, and change from Baseline to Week 16 in absolute reticulocyte count (ARC), LDH level, and FACIT-Fatigue scale score.
A total of 80 patients entered the run-in period. At the end of the run-in period, all 80 were randomised, 41 to ASPAVELI and 39 to eculizumab. Demographics and baseline disease characteristics were generally well balanced between treatment groups (see Table 2). A total of 38 patients in the group treated with ASPAVELI and 39 patients in the eculizumab group completed the 16-week RCP and continued into the 32-week open-label period. Because of adverse reactions of haemolysis, 3 patients were discontinued from the ASPAVELI group during the RCP. Two out of 41 patients in the ASPAVELI group needed the dose adjustment to 1 080 mg every 3 days.
Table 2. Patient baseline demographics and characteristics in Study APL2-302:
| Parameter | Statistics | ASPAVELI (N=41) | Eculizumab (N=39) |
|---|---|---|---|
| Age (years) 18-64 years ≥65 years | Mean (SD) n (%) n (%) | 50.2 (16.3) 31 (75.6) 10 (24.4) | 47.3 (15.8) 32 (82.1) 7 (17.9) |
| Dose level of eculizumab at baseline Every 2 weeks IV 900 mg Every 11 days IV 900 mg Every 2 weeks IV 1.200 mg Every 2 weeks IV 1.500 mg | n (%) n (%) n (%) n (%) | 26 (63.4) 1 (2,4) 12 (29,3) 2 (4.9) | 30 (76.9) 0 9 (23.1) 0 |
| Female | n (%) | 27 (65.9) | 22 (56.4) |
| Time since diagnosis of PNH (years) to Day -28 | Mean (SD) | 8.7 (7.4) | 11.7 (9.6) |
| Haemoglobin level (g/dl) | Mean (SD) | 8.7 (1.1) | 8.7 (0.9) |
| Reticulocyte count (109/l) | Mean (SD) | 218 (75.0) | 216 (69.1) |
| LDH level (U/l) | Mean (SD) | 257.5 (97.7) | 308.6 (284.8) |
| Total FACIT-Fatigue* | Mean (SD) | 32.2 (11.4) | 31.6 (12.5) |
| Number of transfusions in last 12 months prior to Day -28 <4 ≥4 | Mean (SD) | 6.1 (7.3) | 6.9 (7.7) |
| n (%) | 20 (48.8) | 16 (41.0) | |
| n (%) | 21 (51.2) | 23 (59.0) | |
| Platelet count at screening (count/mm³) | Mean (SD) | 167 (98.3) | 147 (68.8) |
| <100 000 | n (%) | 12 (29.3) | 9 (23.1) |
| ≥100 000 | n (%) | 29 (70.7) | 30 (76.9) |
| History of aplastic anaemia | n (%) | 11 (26.8) | 9 (23.1) |
| History of myelodysplastic syndrome | n (%) | 1 (2.4) | 2 (5.1) |
* FACIT-Fatigue is measured on a scale of 0-52, with higher values indicating less fatigue.
ASPAVELI was superior to eculizumab for the primary endpoint of the haemoglobin change from baseline (P<0.0001).
Figure 1. Adjusted mean change in haemoglobin (g/dL) from baseline to Week 16:
Non-inferiority was demonstrated in key secondary endpoints of transfusion avoidance and change from baseline in ARC.
Non-inferiority was not met in change from baseline in LDH.
Due to hierarchical testing, statistical testing for change from baseline for FACIT-Fatigue score was not formally tested.
The adjusted means, treatment difference, confidence intervals, and statistical analyses performed for the key secondary endpoints are shown in Figure 2.
Figure 2. Key secondary endpoints analysis:
Results were consistent across all supportive analyses of the primary and key secondary endpoints, including all observed data with post transfusion data included.
Haemoglobin normalization was achieved in 34% of patients in the ASPAVELI group versus 0% in the eculizumab group at Week 16. LDH normalization was achieved in 71% of patients in the group treated with ASPAVELI versus 15% in the eculizumab group.
The European Medicines Agency has deferred the obligation to submit the results of studies with ASPAVELI in one or more subsets of the paediatric population in paroxysmal nocturnal haemoglobinuria (see section 4.2 for information on paediatric use).
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 and mean (CV) steady-state serum concentrations ranged between 655 (18.6) to 706 (15.1%) µg/mL in patients treated for 16 weeks. The bioavailability of a subcutaneous dose of pegcetacoplan is estimated to be 77% based on population PK analysis.
The mean (CV) volume of distribution of pegcetacoplan is approximately 3.9 L (35) 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) of clearance is 0.015 (28) L/h and median effective half-life of elimination (t1/2) is 8.0 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) and sex based on the results of population PK analysis. Race was also shown not to have an impact; however, data are limited and therefore not considered conclusive.
Patients with a body weight below 50 kg are predicted to have up to 34% higher average exposure at steady state compared to a 70-kg subject, based on population PK analysis. 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. See section 4.2.
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. See section 4.2.
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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