IRL201805 (‘1805)

‘1805 is a first-in-class compound and is a modified analogue of the endogenous immuno-regulatory protein (Binding Immunoglobulin Protein, BiP), and has been shown to exert long term, marked anti-inflammatory and immunomodulatory effects in human cell and tissue explants, as well as in preclinical studies of disease.

‘1805 has a very short circulating half-life in blood (around 6h), but preclinical in vivo studies have shown that a single dose of ‘1805 can prevent the development of arthritis in mice (transgenic and collagen-induced arthritis, models for human rheumatoid arthritis) and delay the onset and reduce the severity of arthritis for many weeks. Additionally, adoptive cell transfer experiments have shown that immune cells from ‘1805-treated mice are able to prevent arthritis in untreated mice, supporting the hypothesis that ‘1805 is able to ‘reset the immune system’ to induce disease remission.

Consistently, ‘1805 increases the number and function of Treg cells and significantly reduces key markers of inflammation and joint destruction, as well as increasing the production of anti-inflammatory cytokines IL-10, IL-4, IL-5 and IL-10, for up to 7-8 weeks following a single dose. In addition, in both human and animal models, ‘1805 has demonstrated a reduction in the number of osteoclasts and in their ability to resorb bone. [data on file]

A Phase 1/2A dose range finding study in patients with active rheumatoid arthritis who had failed one or more standard therapies, ‘1805 given intravenously as a single dose, showed a good tolerability profile, with no drug-related toxicities. Clinical responses and remissions of disease was achieved in some patients, which correlated to early reductions in a number of inflammatory biomarkers, in those patients that had been given ‘1805. Activity of ‘1805 appeared to be durable, with effects on biomarkers and clinical changes lasting for up to 12 weeks. Interestingly, clinical responses in the treated patients was associated with an induction of Treg cells. This study may represent early proof of concept for ‘1805 as a safe and effective immunomodulating treatment for rheumatoid arthritis.

A Phase 2 clinical study with ‘1805 is planned in patients with moderate to severe RA to further assess remission rates and longevity of action.