TOP1890 is our lead candidate for the treatment of ulcerative colitis (UC), a chronic, relapsing inflammatory condition effecting over 2 million people worldwide. It usually manifests with bloody diarrhoea and abdominal pain while in the long-term it increases the risk of developing colorectal cancer. First-line therapy fails in an estimated 50% of patients and despite current treatments, approximately 15% of patients end up requiring a partial or total colectomy (surgical removal of the colon). Please see our Disease Focus section for more information on this disease.
Better by design
Our approach has been to develop TOP1890, a relatively large ‘small molecule’ which targets several important kinases (P38, Src family kinases (Src & Lck) and Syk) involved in the signalling cascade in inflammatory diseases. TOP1890 has demonstrated an excellent preclinical activity profile in vitro and in vivo, including in models of human disease, and it has been shown to synergistically inhibit key pathways involved in innate and adaptive immunity.
Through its specific structural properties, TOP1890 has been designed to act locally in the gastrointestinal (GI) tract when given orally, with only limited systemic absorption. This means that the body’s exposure to the drug is minimized, thereby avoiding or reducing the side-effects seen with currently available treatments. As a result, we anticipate that the product could be can used both in the short-term to achieve disease emission and also in the long term as a maintenance therapy.
UC provides an ideal opportunity for the delivery of topical treatments to the site of the disease, as agents can be administered either by rectal or oral delivery although the latter has much greater patient acceptance and convenience.
An oral formulation of TOP1890 will enter a Phase 1 study Q4 2018. Employing an innovative trial design, individual subjects will receive serial sigmoidoscopies so that multiple colon biopsies can be obtained to allow the direct measurement of tissue drug concentrations, as well as markers of target engagement and pharmacodynamic responses, from colon tissue. This trial design has been validated by our pioneering compound in UC, TOP1288 which reported very positive oral phase 1 results with both drug levels and pharmacodynamics effects being detected up to 36 hours after last dose.
For more information on the studies, please visit https://clinicaltrials.gov/