Biotech Values

[DonShimoda]

XOMA and Servier to develop anti-IL-1ß antibody for inflammatory diseases

Nature Reviews Drug Discovery 10, 166 (March 2011)

BIOBUSINESS BRIEFS: Deal watch: XOMA and Servier to develop anti-IL-1ß antibody for inflammatory diseases
XOMA and Servier have agreed to jointly develop and commercialize the interleukin-1ß (IL-1ß)-targeted monoclonal antibody gevokizumab (XOMA 052) for the treatment of multiple inflammatory disorders. Following recent positive Phase II trial results, XOMA 052 has been granted orphan drug status by the US Food and Drug Administration (FDA) for Behçet's disease (BD), and the agent is currently undergoing Phase II trials in type 2 diabetes and cardiovascular disease.

Under the terms of the agreement, XOMA will retain development and commercialization rights for BD, as well as other indications, in the United States and Japan, whereas Servier will receive similar rights in the rest of the world. Servier will also gain worldwide rights for diabetes and cardiovascular disease indications. In return, XOMA will receive upfront and milestone payments potentially totalling over US$500 million.

BD is a multisystem, relapsing chronic vasculitic disorder, and its underlying cause remains unknown. Characteristic disease manifestations include recurrent oral ulcers, genital ulcers and vision-threatening uveitis (ocular inflammation). Symptoms are typically treated by corticosteroids or immunosuppressive drugs, although these agents can induce significant side effects.

The inflammatory cytokine tumour necrosis factor (TNF) has been implicated in the pathogenesis of BD, and targeting TNF has emerged as an alternative therapeutic approach, but this is not the answer for all patients. “Although the TNF-targeted monoclonal antibody infliximab [Remicade; Centocor] has proved to be highly effective for most patients, it is contraindicated in some patients and ineffective in others,” explains James Rosenbaum, from the Oregon Health & Science University, Portland, USA. He adds: “XOMA 052 is an innovative potential alternative.” Charles Dinarello, from the University of Colorado School of Medicine, Denver, USA, explains further: “In patients with BD, IL-1ß blockade with agents such as XOMA 052 could have a substantially better safety profile than TNF inhibition, particularly in regions where reactivation of tuberculosis infection could be a major concern.”

By binding to the pro-inflammatory cytokine IL-1ß, XOMA 052 inhibits IL-1 receptor activation and prevents downstream signalling events that mediate inflammatory processes in BD. In June 2010, XOMA reported that all seven participants in a Phase II trial displayed a rapid reduction in intraocular inflammation and improvement in visual acuity after a single treatment. These patients were suffering from vision-threatening disease exacerbations despite taking maximal doses of immunosuppressive agents. In addition, five patients who were re-treated with XOMA 052 — owing to recurring uveitis — responded to the antibody again and maintained their response for several months. According to the report, there were no drug-related adverse events.

As elevated IL-1ß activity is characteristic of inflammatory diseases, XOMA 052 is likely to have multiple applications. It is currently undergoing Phase II trials in type 2 diabetes and cardiovascular disease and is also being investigated in myeloma models. Several other agents that target IL-1ß activity are also in development for various indications, with three already approved by the FDA (see Supplementary information S1 (table)). “Rheumatoid arthritis, gout, pseudogout and several rare autoinflammatory diseases such as cryopyrin-associated periodic syndromes are effectively treated by inhibition of IL-1ß,” notes Rosenbaum. “The potential uses for blocking IL-1ß in inflammatory diseases continue to expand,” adds Dinarello. “These also include diabetes, heart failure after myocardial infarction, smouldering myeloma and stroke. In addition, IL-1ß is highly pro-angiogenic and the time has come to add anti-IL-1ß to cancer treatments,” he proposes.

Importantly, targeting IL-1ß appears to be well-tolerated and safe: “To date, this strategy has an excellent safety profile and has superior efficacy for selected syndromes,” concludes Rosenbaum.
http://www.nature.com/nrd/journal/v10/n3/full/nrd3390.html