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

Abstract

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.

Integrated Proteomics Analysis of Baseline Protein Expression in Pig Tissues

“…It is also important to highlight that minipig models are being increasingly used in drug development. Animals are still requested in the safety testing of new drug candidates, and minipigs are a potential nonrodent alternative to the use of nonhuman primates (NHP) due to ethical considerations . The use of alternative in vitro models is still challenging due to complex biological responses in various organ systems following drug treatment.…”

“…Animals are still requested in the safety testing of new drug candidates, and minipigs are a potential nonrodent alternative to the use of nonhuman primates (NHP) due to ethical considerations. 42 The use of alternative in vitro models is still challenging due to complex biological responses in various organ systems following drug treatment. Therefore, it is important to have access to protein expression information in pig organs (and also ideally in mini-pig; there are still very few mini-pig proteomics studies in the public domain) so that comparisons in protein abundance across different organs and species (especially between pig, mini-pig, and human) can be performed.…”

Integrated Proteomics analysis of baseline protein expression in pig tissues

“…It is also important to highlight that mini-pig’s models are being increasingly used in drug development. Animals are still requested in the safety testing of new drug candidates, and minipigs are a potential non-rodent alternative to the use of non-human-primates (NHP), due to ethical considerations [39]. The use of alternative in vitro models is still challenging due to complex biological responses in various organ systems following drug-treatment.…”