The Non-Human Primate in Safety Assessment of a Bifunctional Long-Acting Insulin Analogue.

Species selection plays a pivotal part during non-clinical safety assessment in drug development. If possible, use of non-human primates (NHPs) should be avoided due to ethical considerations. However, limiting factors as lack of pharmacologic activity in other species could necessitate use of NHPs. LAI-PCSK9i is a bi-functional molecule combining a long-acting insulin analogue with a PCSK9 inhibitor peptide aiming to provide glycaemic control and to reduce plasma LDL concentrations. The NHP was chosen for the safety assessment of LAI-PCSK9i being the most relevant species with basal levels and plasma lipid composition closest to humans, while the dog and initially also the minipig were deemed irrelevant due to lack of pharmacologic activity on LDL-lowering and biological differences in lipid profiles. An in vivo tolerability and toxicokinetic study of LAI-PCSK9i in NHPs showed recurrent and severe hypoglycaemia at very low doses. Therefore, the minipig was re-evaluated and a follow-up study thoroughly assessing blood glucose and cholesterol levels and clinical signs illustrated that minipigs dosed with LAI-PCSK9i, tolerated the compound and LAI-PCSK9i decreased glucose and LDL over time. This work underlines that careful consideration is required when selecting species during safety assessment in drug development. The tolerability issue in NHPs led to the subsequent selection of the minipig for safety evaluation of LAI-PCSK9i although as a suboptimal alternative, which unexpectedly had a measurable pharmacologic response on LDL lowering. In conclusion, the NHPs may be unsuitable as test species for safety assessment of long-acting insulin analogues due to high sensitivity to recurring hypoglycaemic episodes.

Normal Neurodevelopment and Fertility in Juvenile Male Rats Exposed to Polyethylene Glycol Following Dosing With PEGylated rFIX (Nonacog Beta Pegol, N9-GP): Evidence from a 10-Week Repeat-Dose Toxicity Study.

N9-GP/Rebinyn®/Refixia® is an approved PEGylated (polyethylene glycol-conjugated) recombinant human factor IX intended for prophylactic and/or on-demand treatment in adults and children with haemophilia B. A juvenile neurotoxicity study was conducted in male rats to evaluate effects on neurodevelopment, sexual maturation, and fertility following repeat-dosing of N9-GP. Male rats were dosed twice weekly from Day 21 of age with N9-GP or vehicle for 10 weeks, followed by a dosing-free recovery period for 13 weeks and terminated throughout the dosing and recovery periods. Overall, dosing N9-GP to juvenile rats did not result in any functional or pathological effects, as measured by neurobehavioural/neurocognitive tests, including motor activity, sensory function, learning and memory as well as growth, sexual maturation, and fertility. This was further supported by the extensive histopathologic evaluation of brain tissue. Exposure and distribution of polyethylene glycol was investigated in plasma, choroid plexus, cerebrospinal fluid, and brain sections. PEG did not cross the blood brain barrier and PEG exposure did not result in any effects on neurodevelopment. In conclusion, dosing of N9-GP to juvenile rats did not identify any effects on growth, sexual maturation and fertility, clinical and histological pathology, or neurodevelopment related to PEG exposure and supports the prophylactic use of N9-GP in children.