FRI0231 Atrosab, a humanized antibody directed against tnf-receptor 1, hold great promises for the treatment of rheumatoid arthritis

Background To date, the five anti-TNFα biologics on the market are firmly established as therapeutics across several inflammatory and autoimmune disorders including rheumatoid arthritis (RA), inflammatory bowel diseases (IBD), psoriatic arthritis, psoriasis, and ankylosing spondylitis. However, by directly neutralizing TNF, they inhibit both TNF receptor 1- and 2-mediated actions. This characteristic has been suggested to underlie the lack of efficacy in certain autoimmune diseases like multiple sclerosis (MS), congestive heart failure (COPD) and may be responsible for some of their side effects, like increased susceptibility to infectious diseases and to demyelinating disorders. Notably, blockade of TNFR2 has been associated with increased sensitivity to viral infections or increased susceptibility to demyelinating disorders. ATROSAB, with its superior specificity to TNF receptor 1, is expected to have a broader therapeutic potential and an improved safety profile. Objectives Evaluation of the first in man (FIM) study of ATROSAB as well as preclinical efficacy and safety studies to demonstrate the potential clinical benefit of a selective blockade of the TNF-receptor 1 for the treatment of inflammatory disease such as RA, IBD and MS. Methods Therapeutic efficacy of ATROSAB was assessed in CIA rhesus monkey model, in the human TNF transgenic/human TNFR1 Knock-in mice model (Tg197/hp55K/i) for arthritis and in human TNFR1 Knock-in mice (hp55K/i) EAE model for MS. The 28 days repeated doses toxicity study with twice weekly intravenous administration of ATROSAB was performed in cynomolgus monkeys. The initiated FIM study involved a total of 35 subjects to provide information on safety, tolerability, pharmacokinetics and pharmacodynamics following single intravenous infusion dosing with ATROSAB. Results In the CIA rhesus monkeys, treatment with ATROSAB showed a significant reduction of the acute-phase C-reactive protein (CRP) and IL-6 in serum, a positive effect on body weight loss, improvement of the clinical arthritis score, delay on the onset of symptoms and inhibition of cartilage degradation. Moreover, therapeutic efficacy of ATROSAB was superior to the comparator drugs Enbrel® and Remicade® in a semi-therapeutic setting in RA mice with significant dose dependent reduction of in-life arthritic pathology and the underlying histopathological lesions. In EAE mice model of MS, ATROSAB abolished the development of paralytic symptoms without affecting the overall health status of the animals. The twice weekly administration of ATROSAB to cynomolgus monkeys showed no adverse signs of toxicity at any dose. The apparent terminal elimination half-life (t1/2) for ATROSAB was 10.5 days. The preliminary safety data of the initiated FIM study following single intravenous infusion dosing with ATROSAB will be presented. Conclusions ATROSAB has been shown to be effective for treatment of inflammatory diseases such as RA and MS in both monkeys and mice in vivo and no adverse events were observed during toxicology studies. ATROSAB is a specific inhibitor of TNF receptor 1 (TNFR1) that clearly distinguishes it from all existing TNF blockers and strongly positions ATROSAB to offer not only efficacy advantages compared to existing TNF inhibitors, but also an improved safety profile with the potential to target new inflammatory disease indications such as MS. Disclosure of Interest : None Declared