Plasma Polyethylene Glycol (PEG) Levels Reach Steady State Following Repeated Treatment with N8-GP (Turoctocog Alfa Pegol; Esperoct®)

Abstract

Background Extended half-life (EHL) factor VIII (FVIII)-replacement therapies enable patients with haemophilia A to maintain higher activity levels with fewer injections. N8-GP (turoctocog alfa pegol; Esperoct ®) is an EHL product derived from conjugation of polyethylene glycol (PEG) to a recombinant FVIII protein. Upon activation, PEG is released from the active protein and excreted in urine and faeces. While PEG levels are expected to reach steady state with repeated dosing, there has been some discussion regarding whether abnormal accumulation of PEG in plasma and tissues may occur. Objective Our objective was to examine plasma PEG concentrations in rats and humans repeatedly treated with N8-GP for periods of up to 5 years. Methods PEG levels were measured using liquid chromatography-tandem mass spectrometry in plasma samples from rats treated with N8-GP as part of a 52-week toxicity study. Human plasma samples from children, adolescents and adults treated with N8-GP as part of the pathfinder programme were also examined (NCT01731600; NCT01480180). These data were compared with steady-state PEG levels predicted by pharmacokinetic modelling of single-dose rat data. Results PEG levels reached steady state in plasma in both rats and humans after repeated dosing. The timing and degree of PEG increase to steady state were in line with or below model predictions, confirming the utility of the pharmacokinetic model and indicating that rat data can be used to estimate human plasma PEG levels. Conclusion Steady-state PEG levels were reached in plasma from rats and humans repeatedly treated with N8-GP. No unexpected increase in PEG was observed.

PEGylated Recombinant Human Growth Hormone Jintrolong® Exhibits Good Long-Term Safety in Cynomolgus Monkeys and Human Pediatric Growth Hormone Deficiency Patients

“…A follow-up study of the Phase IV with treatment time as long as 3 years in 644 patients was also investigated, and no obvious differences in the incidence of ARs and CNS-related ARs between the treatment groups were found. These data are consistent with other PEG-conjugated drug clinical trials, such as those conducted for 40 kDa PEG N9-GP (50,54,55) and 60 kDa PEG BAY 94-9027 (56). In a long-term safety study of N9-GP administered for at least 5 years in 25 children with hemophilia B from 17 sites in 8 countries, the mean PEG plasma reached a steady state after 6 months, and no new abnormal findings in neurological examinations were observed in the study (55).…”

“…The calibration ranged from 0.1 to 10 mg/L in urine after a single intravenous administration of the PEGylated drug. LC-MS/MS was also applied to analyze the 40 kDa PEGylated drug N8-GP in rats and humans (50). Further exploration of Jintrolong ® is still needed to detect intact PEG and lower doses or metabolites of PEG.…”

An overview of the pathfinder clinical trials program: Long‐term efficacy and safety of N8‐GP in patients with hemophilia A

“…However, hypothetical concerns have been raised regarding long‐term exposure to PEGylated drugs and the potential for PEG to accumulate beyond steady‐state levels in some tissues 27 . Recently, a study conducted by Novo Nordisk examined the plasma concentration of PEG in children, adolescents, and adults receiving long‐term prophylactic treatment with N8‐GP as part of the pathfinder program 28 . This study demonstrated that PEG levels reach steady state in plasma and do not accumulate further beyond expected steady‐state levels.…”

N8‐GP: A new extended half‐life recombinant factor VIII product for hemophilia A

“…8,9 Interestingly, a closer examination of PEG exposure in patients treated with N8-GP for periods up to 5 years showed that plasma PEG levels rapidly achieved a steady state, with no unexpected increase above steady-state levels, even with long-term treatment. 10 PEG is ubiquitous and is used extensively in various consumer products, including commercial medicines. The attainment of a steady state is reassuring, as it demonstrates the ability of the body to excrete this moiety, confirming the long-term safety observed with other PEG molecules used in patients with chronic conditions.…”