A new and better type of COX-inhibitor?

HCT 3012 (formerly AZD3582) is the first in a new class of analgesic and anti-inflammatory drugs called COX-inhibiting nitric oxide donators (CINODs). It was first developed by French pharmaceutical company NicOx SA and as already undergone a few trials and ultimately delivered promising results. NicOX expects phase III trials to complete before the end of 2005.

The inhibition of cyclo-oxygenase (COX) enzymes is the basic mode of approach of the non-steroidal anti-inflammatory drugs (NSAIDs). Until early COX-inhibitors, HCT 3012 is an entirely new chemical which provides balanced inhibition of COX enzymes while also supplying nitric oxide (NO) at sites of inflammation. NO is known to exert a relaxing effect on internal epithelial cells. Donation of NO may also have a protective effect on the gastrointestinal tract and other organs. This is a serious departure from NSAIDs which are known to cause damage to the gastrointestinal tract.

Early data that established the efficacy and safety of HCT 3012 were first presented at Digestive Diseases Week in May 2002. Results from the phase I double-blind, crossover study indicated treatment with HCT 3012 750mg produced significantly fewer stomach and duodenal (post-stomach) ulcers than twice-daily conventional NSAID 500mg (specifically naproxen). Intestinal permeability also increased in the naproxen treatment, whereas no change occurred with HCT 3012.

Despite these data, results from a subsequent phase II placebo-controlled endoscopic trial released in early 2003 showed that HCT 3012 failed to reach its primary endpoint in terms of reduced frequency of gastrointestinal ulcers. A subsequent review of all phase II data by the US Clinical Consultant Advisory Board (CAB) suggested that HCT 3012 merited further development for the pain relief in conditions such as osteoarthritis. Based on data from 2,709 patients in five separate phase II clinical trials, the CAB judged HCT 3012 375mg twice-daily an effective analgesic for patients with osteoarthritis. Analgesic efficacy was considered equivalent to both NSAIDs and selective COX-2 inhibitors, while HCT 3012 had an improved gastrointestinal safety profile compared with NSAIDs.

In addition to gastrointestinal safety, HCT 3012 also showed no evidence of increasing blood pressure. This was in contrast to the NSAID rofecoxib, which at equivalent doses was associated with a significant increase in systolic blood pressure. It has been suggested that, via NO release, CINODs may be able to counteract the detrimental effects of COX inhibition on blood pressure.

Article References
HCT 3012--COX-Inhibiting Nitric Oxide-Donator (CINOD) for Relief of Pain and Inflammation, site accessed on 09/20/05

NicOx to proceed with phase III development of lead CINOD HCT 3012 following positive end phase II meeting with FDA, site accessed on 09/20/05