BioWorld International Correspondent

PARIS - NicOx SA unveiled details of its Phase III development program for naproxcinod (HCT 3012) in treating the signs and symptoms of arthritis.

The company plans to conduct three Phase III trials to test the drug's efficacy, the first of which is under way in the U.S. on patients suffering from arthritis of the knee. A second trial in arthritis of the knee is to be initiated in the first quarter of 2007, while a third on patients with arthritis of the hip is scheduled to begin in the third quarter of next year.

NicOx, of Sophia Antipolis, France, has not disclosed where the second two trials will take place, indicating only that they will be located either in Western Europe or the U.S.

HCT 3012 is the first of a new class of anti-inflammatory drugs, with no negative effects on blood pressure and good gastric tolerance, NicOx said, giving it the potential to become a "reference treatment for patients suffering from arthritis."

The first trial got under way in early 2006 and, as planned, 820 patients were quickly enrolled. However, at the behest of the investigators, an additional 98 subjects were recruited later. The results are due in the fourth quarter.

The second trial will begin in the first quarter of 2007, and the results would be available in the first quarter of 2008. It will be similar to the first in size. It will be a double-blind study against placebo and naproxene. The results of the third trial similarly will be available a year after it is initiated in the third quarter of 2007.

The first two trials are to be followed by long-term extensions that would provide tolerance data over 12 months or more, yielding a quantity of data that will considerably exceed the recommendations of the International Conference on Harmonization (ICH). All the data are due to be available by the last quarter of 2008.

NicOx said its program for HCT 3012 was drawn up following discussions with the FDA in the U.S. and with the British and Swedish regulatory authorities, so it should satisfy the current demands of both the FDA and the European Medicines Evaluation Agency (EMEA).

In particular, the company says it was informed by the European regulators that the safety of naproxcinod should be evaluated in accordance with standard IHC recommendations, implying that a long-term study of its cardiovascular tolerability was not required for regulatory approval in Europe. On the other hand, it still is waiting for a ruling from the FDA on long-term safety data, and also for its comments on a scientific dossier on naproxcinod and COX inhibition that NicOx submitted to the agency in August.

NicOx believes that the preclinical and clinical studies it has carried out to date have established the superiority of naproxcinod in terms of control over blood pressure and gastrointestinal tolerance relative to existing non-steroid anti-inflammatory drugs (NSAIDs), thanks to its release of nitric oxide. The Phase III trials should yield further evidence of that, while two additional studies are to be carried out to provide corroboration of its cardiovascular and gastrointestinal merits.

The company hopes to file HCT 3012 with the regulatory authorities in the U.S. and Europe in the first quarter of 2009. In Japan, NicOx plans to agree a development plan for the product with the Japanese authorities in the first quarter of 2007.

NicOx Plans Development Of NO-Donating Statin

NicOx SA also has decided to move NCX 6560, its nitric oxide-donating derivative of a leading statin, into clinical development on the strength of preclinical studies indicating both broader and enhanced clinical benefit in validated models of common cardiovascular disorders.

NicOx declined to give any indication as to the development timetable for NCX 6560, saying only that it was keen to initiate a Phase I trial as soon as possible.

The company's vice president of research, Ennio Ongini, explained the merits of NCX 6560 as follows: "Restoring deficient nitric oxide signaling is known to reduce endothelial dysfunction, atherosclerosis and thrombosis, which represent the key processes underlying the most common cardiovascular diseases. We have demonstrated that nitric oxide donation can boost the non-lipid activities of statins in preclinical studies, suggesting that NCX 6560 could be suitable for the preventive treatment of high-risk cardiovascular patients."

NicOx stressed the multi-pathway approach of NCX 6560, maintaining that "the ability of the nitric oxide-donating moiety to counteract vascular inflammation and endothelial dysfunction should act in concert with the cholesterol-lowering activity of the statin portion to favorably influence the composition, structure and stability of atherosclerotic plaques." It added that "the nitric oxide released from NCX 6560 appears to markedly increase the non-cholesterol lowering activities of statins."

In preclinical tests comparing NCX 6560 with a widely used statin, NicOx said its drug demonstrated superior efficacy in four areas: anti-platelet and anti-thrombotic activity, anti-inflammatory activity, improved endothelial function and gold standard cholesterol-lowering activity.

In other news, the company reported preliminary results from two Phase IIa trials to evaluate NCX 4016 as a potential insulin-sensitizing agent for the treatment of Type II diabetes. In the first trial, NCX 4016 demonstrated increased glucose uptake after two weeks of treatment. In the second trial, conducted on 12 healthy but obese volunteers, there was improvement in glucose uptake, also after two weeks of treatment.