Only very few oral peptides have been commercialised to date, these include cyclosporin A (Neoral®) for the treatment of transplantation rejection; desmopressin (DDAVP®) for the treatment of nocturnal enuresis and linaclotide (Linzess®) for the treatment of irritable bowel syndrome with constipation). Each of these is a relatively small biomolecule (< 2K Daltons), each has a cyclic structure which confers stability and in the case of desmopressin is active at very low doses such that the ensuing poor bioavailability is not an issue. To date the challenge of delivering more complex proteins orally has not been met. Crohn’s disease (CD) is a chronic inflammatory condition which can affect any part of the gastro intestinal tract (GIT) but most commonly occurs in the lower part of the ileum and in the colon. This and ulcerative colitis make up the majority of cases of inflammatory bowel disease (IBD). The aetio-pathogenesis of Crohn’s disease is not fully understood but genetic and environmental factors interact to promote an excessive and poorly controlled mucosal inflammatory response against components of the gut micro-floraInhibiting the pro-inflammatory cytokine tumour necrosis factor (TNF) dramatically reduces gut inflammation and thereby restores the gut barrier and promotes healing. Current biologic anti-TNF treatments for Crohn’s disease include adalimumab (Humira®); certolizumab pegol (Cimzia®) and infliximab (Remicade®). All of these have to be administered by injection. VHsquared Ltd has successfully engineered a protease stable domain antibody to TNF (V565, molecular weight 12.6K Daltons) which is the lead compound of the VHsquared Vorabody™ platform technology and has been shown to be effective in neutralising TNF in vitro and inhibiting its effect in biopsies from patients with Crohn’s disease. Unlike existing treatments it has been designed to be administered orally and is currently in Phase 2 clinical trials. Developing an oral protein formulation for the treatment of Crohn’s disease presented a number of challenges: stabilising the protein to resist the proteolytic enzymes present in the upper part of the GIT whilst retaining the anti-TNF binding activity; producing a formulation to protect the protein from the acid in the stomach; minimising the risk of dose dumping and the effect of food; and targeting the appropriate section of the GIT. Details are provided of the nature of the challenges in each of these areas and this poster describes how each of these challenges was tackled and how proof was obtained, using a number of novel in-vitro, in-vivo and ex-vivo approaches, that they have been successfully overcome.
•A better understanding of the challenges in developing an oral protein product. This topic is gaining more and more exposure as the number of biological molecules in development increases
•Formulation designs to provide enteric protection, minimise a food effect and target a specific region of the GIT •Knowledge of in-vitro, in-vivo and ex-vivo approaches to confirm in-vivo protein stability and that the molecule has reached its intended target in the GIT