Innovative NSAID on home straight

03/07/2007 - NicOx's innovative arthritis drug is on the home straight towards approval, having started its third and final Phase III trial.

The French company's lead drug candidate, naproxcinod, takes a non-steroidal anti-inflammatory drug (NSAID) molecule and adds a nitric oxide (NO) donating part to it, in order to make the NSAID safer while losing none of the efficacy. The drug's name is a combination of naproxen, the well-established NSAID it contains, and an in-house term: 'COX inhibiting nitric oxide-donating drug' (CINOD).

NSAIDs themselves are a widely used class of drugs that reduce pain, fever and inflammation. Annual sales are estimated to be around $18bn (€13.24bn) for pain treatment alone.

However, their use is limited due to the prevalence of side effects, whether they block cyclooxygenase 1 and 2 (COX-1/COX-2) non-specifically or only COX-2. These effects include gastrointestinal bleeding and also serious cardiovascular events, such as heart attack and stroke.

The risk of these latter problems is exacerbated if the patient has coexisting risk factors, such as high blood pressure, which represents around 40 per cent of osteoarthritis sufferers. It is well known that NO could overcome this as it reduces inflammation and dilates blood vessels. However, as NicOx's Karl Hanks explained to DrugResearcher.com, the problem with giving an NSAID plus a separate NO-donating compound is that the NO is used up too fast.

To overcome this, Hanks said that the firm decided the best approach was to chemically attach the NO donating group (actually ONO2) to the end of an NSAID using a 'spacer', such as a butyl group. Once the drug is administered, the NSAID is released very quickly meaning its effectiveness is maintained but, because of the spacer, the NO-donating part circulates around the body and the NO is released over several hours, through enzymatic processes.

"The spacer is the secret of the technology," said Hanks. "If the make-up of this group changes, it affects the release of the drug and NO."

He admitted that there is some trial and error concerning the best spacer to use but the results of naproxcinod clinical trials have been very promising so far. The final study is in hip osteoarthritis patients and follows on from two knee osteoarthritis trials, one completed and one ongoing. NicOx expects to file the drug for approval in the US in the first quarter of 2009.

The name naproxcinod is a combination of the NSAID it contains, the well-established naproxen, and an in-house term 'COX inhibiting nitric oxide-donating drug' (CINOD).

Once NicOx had demonstrated to regulators that naproxcinod as a whole didn't interact with either COX1 or COX2 (although obviously its naproxen derivative does), the US Food and Drug Administration (FDA) decided that there was no need for the company to do a cardiovascular safety study. As Hanks explained, this is because naproxen itself has been on the market for decades and is seen as one of the safest NSAIDs in terms of blood pressure effects.

The results for one Phase III trial have already been released by the company and show the drug to have a comparable safety profile to placebo and a better one that normal naproxen, in terms of blood pressure. This is because NO reduces vascular inflammation and dilates blood vessels. NicOx also said that it inhibits pro-inflammatory cytokines and reduces oxidative stress.

Speaking about the latest trial, Maarten Beekman, vice president of clinical development at NicOx said: "[It] will provide the final data for a predefined pooled analysis on the blood pressure measurements from the full Phase III program.

"We believe that confirming naproxcinod's improved blood pressure profile over current treatments will be a key differentiating factor in the current anti-inflammatory market."

The gastrointestinal effects have also been analysed in clinical trials with naproxcinod shown to reduce the occurrence of ulcers by 30 per cent compared to naproxen. Hanks said that these positive effects are thought to be because NO protects the gastrointestinal lining, which is eroded by COX1 inhibition. The preclinical data for naproxcinod showed that it was as safe as COX2-specific drugs (developed specifically to avoid this side-effect) and although this impressive statistic wasn't maintained through the clinical trials, it remains better than non-specific NSAIDs.

New management could tackle one possible hitch at NicOx

NicOx has also announced this week that Dr Pascal Pfister has been appointed as the company's chief scientific officer. Dr. Pfister's previous management career includes 19 years at Novartis and its subsidiary Sandoz Pharmaceuticals.

His experience at launching new drugs will undoubtedly prove useful to NicOx and could also come in handy regarding one potential fly in the ointment at the company - its diabetes drug NCX 4016. Although this drug has shown good results in Phase II trials, a small academic trial - actually looking at the drug as a possible anticancer treatment - was recently suspended after other in vitro test on a potential metabolite of NCX 4016 showed some genotoxicity. This contradicted NicOx's in vivo data for both NCX 4016 and its metabolite but the company still decided to put the drug on hold pending more genotoxicity tests.

It hopes these will be finished soon and the trials can start again in the third quarter of this year, said Hanks but the timeframe essentially depends on when the FDA are happy. He also pointed out that no other drugs in NicOx's pipeline are affected and genotoxicity tests are known to give false positives sometimes.

NCX 4016 is an NO-donating version of aspirin (acetyl-salicylic acid), which NicOx believe could be used to treat Type II diabetes, thanks to aspirin's ability to improve glucose metabolism at high doses. Also, dysfunctional NO signalling is thought to be involved in the disease. Normally, such high doses of aspirin would not be viable, but the addition of NO could make it safe. The NO also had a therapeutic effect as it has been shown to inhibit IKK-beta, NF-kappa-B and cytokines that stimulate IKK-beta, which leads to an improvement in insulin sensitivity and better utilisation of glucose. This latter effect is caused by NO promoting the movement of the glucose transporter to the cell surface and improving glucose supply through increasing blood flow.

By Mike Nagle

Source : Outsourcing Pharma (provided by DrugResearcher.com)