therapeutic mission________________

ulcerative colitis, toll-like receptors and PRV-300

Ulcerative colitis (UC) is an IBD that causes long-lasting inflammation and ulceration in the digestive tract. UC affects the innermost lining of the colon and symptoms occur over time, rather than sudden onset. While current treatments for UC can reduce symptoms and bring about long-term remission in a subset of patients, there is no cure. A majority of patients experience debilitating relapses which can potentially be life-threatening.

Toll-Like Receptors (TLRs) function as the body’s “alarm system” by detecting a broad range of pathogens and initiating responses from the immune system. Increasing evidence suggests that TLR3 plays an important role in the pathology of emerging viral infections and the excessive immune response viruses can trigger. Additionally and importantly, TLR3 is believed to also play a key role in chronic inflammation triggered by non-virally derived endogenous RNA and double stranded RNA (dsRNA).  Human biomarker and animal model studies show that TLR3 appears to be involved in the pathogenesis of UC.

PRV-300, in-licensed from Janssen, is a first-in-class, anti-TLR3 human monoclonal antibody that blocks TLR3 on cell surfaces and in endosomes.  Based on the connection between TLR3 and inflammation, we are planning to initiate a Phase 1/2 proof-of-concept and proof-of-mechanism study of PRV-300 in 32 UC patients. The study will be a randomized, placebo-controlled, double-blinded study of intravenous anti-TLR3 administered for 12-weeks to patients with moderate to severe UC. The primary endpoint will be safety, and secondary and exploratory endpoints will include endoscopic and histologic findings, and mucosal mRNA signature.

Although UC is the initial target indication, PRV-300 offers attractive life-cycle expansion opportunities, including high risk influenza infection in the hospitalized setting, as well as emerging viral diseases.