ORE1001 Overview
ORE1001 is a novel, potent, and highly selective inhibitor of Angiotensin Converting Enzyme 2 (ACE2). The molecule possesses a desirable therapeutic and commercial profile, including:
- First-in-class small molecule
- Orally administered
- Well tolerated in human subjects
- Excellent preclinical safety profile
- PK consistent with once- or twice-daily dosing
- Efficient, simple 4-step chemical synthesis
- Potential therapeutic use in a number of high-need gastrointestinal indications, including ulcerative colitis, Crohn’s disease, radiation enteritis, non-ulcer dyspepsia, gastric ulcer, esophagitis, and chronic pancreatitis.
ORE1001 Development
ORE1001 is a nanomolar inhibitor of the ACE2 enzyme, whose substrates include products of angiotensinogen and apelin, which is involved in intestinal epithelium repair in colitis. Ore broadly analyzed ORE1001’s action in vivo and in vitro as well as its disease-specific expression in over 20,000 human tissue samples.
ACE2 is highly expressed in the gastrointestinal tract. Of more than 400 diverse disease states examined, ACE2 was modulated in only two conditions: chronic gastritis and chronic pancreatitis. In vivo animal data demonstrated that ORE1001 inhibited NF-ĸB pathway activity in some GI organs, suggesting tissue-specific anti-inflammatory activity. In vivo models provided compelling evidence that ORE1001 reduces signs of injury and inflammation in experimental colitis, gastritis and gastric ulcer. In the mouse dextran sodium sulfate (DSS) model, for example, ORE1001 dose-dependently reduced signs of disease activity, reduced severity of histological lesions, and achieved high concentrations selectively in the tissues of the colon. ORE1001 reduced gastric damage scores and myeloperoxidase activity in rat models of injury induced by non-steroidal anti-inflammatory drugs. Additional preclinical testing is ongoing.
ORE1001 was initially tested in a blinded, placebo-controlled, single ascending dose Phase I clinical study in 63 healthy volunteers in the United Kingdom. Results of that clinical trial indicated that the drug candidate was well-tolerated up to the highest dose tested, with no serious adverse events observed. In June 2008, Ore filed an investigational new drug (“IND”) application with the U.S. Food and Drug Administration (“FDA”) for ORE1001. Following clearance of the IND, Ore commenced clinical testing of ORE1001 in September 2008 in a blinded, placebo-controlled, multiple ascending dose Phase I clinical trial in 32 healthy volunteers to evaluate the drug candidate’s safety profile in human subjects. In this study, the drug candidate was orally administered for a period of 14 days. Results of the trial showed that ORE1001 was well tolerated by human subjects, with no serious adverse events observed. In total, 71 human subjects have received ORE1001, with no serious adverse events observed.
We initiated a Phase Ib/IIa clinical trial in ulcerative colitis patients in the fourth quarter of 2009. This trial is designed to further evaluate the safety and tolerability of ORE1001 as well as provide some initial evidence of its effectiveness in treating ulcerative colitis.
Intellectual Property
Ore has an exclusive license to ORE1001 composition-of-matter (COM) patents, which were issued in the U.S. in 2003 and 2006. The patent estate is fortified by recent patent applications claiming methods of use for gastrointestinal disease indications and an exclusive license to related target patents useful for the expanded development of ORE1001.