Nonclinical evaluation of immunological safety in Göttingen Minipigs: The CONFIRM initiative.

There is a growing need to consider non-rodent species for the immunological safety evaluation of drug candidates. The EU Framework-6 RETHINK Project demonstrated that the Göttingen Minipig is a relevant animal model for regulatory toxicology studies. Extensive knowledge on the immune system of domestic pigs is available and fewer differences from humans have been identified as compared to other species, such as mice or non-human primates. Minipig data are too scarce to allow for claiming full immunological comparability with domestic pigs. Another gap limiting minipig use for immunological safety evaluation is the lack of a qualified and validated database. However, available data lend support to the use of minipigs. The need for a COllaborative Network For Immunological safety Research in Minipigs (the CONFIRM Initiative) was obvious. It is intended to trigger immunological safety research in Göttingen Minipigs, to assist and synergize fundamental, translational and regulatory investigative efforts relevant to the immunological safety evaluation of pharmaceuticals and biologics, and to spread current knowledge and new findings to the scientific and regulatory toxicology community.

Pre-clinical safety evaluation of the synthetic human milk, nature-identical, oligosaccharide 2'-O-Fucosyllactose (2'FL).

In order to match the composition of human breast milk more closely, it is now possible to supplement commercial infant formula (IF) with synthesised oligosaccharides that are chemically identical to human milk oligosaccharides. The safety data generated on a new human-identical milk oligosaccharide (HiMO), 2'-O-Fucosyllactose (2'FL), are presented. Standard in vitro genotoxicity tests were performed. To investigate the toxicological profile in a model representative of the intended target population, 2'FL was administered via gavage in a juvenile adapted sub-chronic rat study at dose levels of 0, 2000, 5000 and 6000 mg/kgbw/day. Fructooligosaccharide (FOS), currently acknowledged as safe and approved for use in IF, was used as a reference high-dose control at 6000 mg/kgbw/day. 2'FL was non-mutagenic in the in vitro assays. Oral administration up to 5000 mg/kgbw/day to rats over 90 days was not associated with any adverse effects based on clinical observations, body weight gain, food consumption, ophthalmoscopy, clinical pathology, organ weights and histopathology findings. Based on this 90-day study, a No Observed Adverse Effect Level (NOAEL) of 5000 mg/kgbw/day for both male and female rats was established for 2'FL. These findings support the safety of synthetic 2'FL for possible use in infant food.