A yes for NO?

C&I Issue 19, 2007

In just over ten years, French biotech firm NicOx has become a global leader in nitric oxide (NO) drug technology. This involves taking a known drug and grafting an NO-donating moiety to it, improving the drug’s efficacy and safety profile. The company’s most advanced compound, naproxcinod, is in Phase III development for treating the signs and symptoms of osteoarthritis. This is a lucrative $12bn market for which there are few available treatment options following the recent withdrawal of several COX-2 inhibitors including Vioxx and Bextra, and the failure of Arcoxia to gain US approval.

NicOx’s chairman and ceo Michele Garufi believes his relatively small company is nurturing a blockbuster in a market completely turned upside down by the Vioxx and Bextra withdrawals. ‘The market, the doctors and the patients are waiting for a new drug in which they can have greater confidence in terms of cardiovascular safety,’ he says. ‘We may have a great advantage considering the blood pressure data we have for naproxcinod.’

Naproxcinod’s most interesting feature is that, in addition to its efficacy in treating osteoarthritis, it doesn’t have the negative effect of raising blood pressure. Other treatment options for osteo-arthritis include non-selective non-steroidal anti-inflammatory drugs (NSAIDs) and the COX-2 inhibitor, Celebrex, but these can also raise blood pressure, a side effect that increases risk for many patients because some 40% of osteoarthritis patients also have high blood pressure. A rise in blood pressure associated with some COX-2 inhibitors may also have been part of their undoing as this precipitated cardiovascular events.

‘Based on these effects on blood pressure, naproxcinod will have a niche in the market in osteoarthritis patients with hypertension, according to Datamonitor’s report Commercial Insight: Osteoarthritis –- Market sees steady growth.

CINODs – a new class of drug

Naproxcinod is a first in a new class of anti-inflammatory agents: Cox Inhibiting Nitric Oxide Donators (CINODs), classified by the World Health Organisation. Clinical trials to date have demonstrated that the compound is equivalent to the non-selective NSAIDs and COX-2 inhibitors in terms of efficacy, and NicOx claims it seems to have no detrimental effect on blood pressure. It also appears to have an improved safety and tolerability profile compared to the non-selective NSAIDs. However, experts at the Arthritis Research Campaign (ARC) caution: ‘It is difficult without trial data and the complete toxicity profile from all studies, especially to see if there are any new unexpected side effects.’

According to Garufi, the company’s technology is not just a drug delivery system. ‘Our drugs are new chemical entities, which couple the property of the drug with the slow release and long term effect of nitric oxide.’ The drug molecule cleaves from the linker molecule first, and the NO is released slowly over several hours as it dissociates from the linker molecule by an enzymatic mechanism.

Nitric oxide has been used for many years to treat angina in nitro-glycerine-based preparations, which offer a quick hit of NO. The molecule is also well known for its action on blood vessels in erectile tissues, and impotence drugs such as Viagra trigger its production. The compound is made by nerve cells, and plays a role in signalling in the nervous system. When it is produced by the innermost cell layer of the arteries, the endothelium, nitric oxide spreads through cell membranes to underlying muscle cells, where it prevents their contraction. This is how NO dilates arteries, and can control blood pressure and distribution.

NicOx is focused on cardiovascular, metabolic and inflammatory diseases, and aims to become a marketing company in these therapeutic areas. ‘We don’t intend to go straight into marketing alone to the mass of general practitioners, but to co-promote naproxcinod with partners to specialist physicians, for example, rheumatologists and also targeted high prescribing GPs,’ explains the company’s corporate relations and market analysis manager Karl Hanks.

Rather than just offering a platform technology, like many other biotech companies, NicOx is taking the bold step of developing drugs, which it hopes to play a part in marketing. ‘The transition from being a research and development company to being a marketing one is challenging,’ Hanks admits.

The company’s scientists take an existing drug, which could be a generic drug or a drug that is still under patent protection. ‘We then make a covalent linkage with a spacer molecule and a nitrate group,’ Hanks says. It is the nitrate group that then donates nitric oxide. ‘In a way the secret of the technology is in the linker.’ Organic nitrates are available, but have a number of drawbacks. The main difficulty is that they release NO immediately – if you give them to hypertensive patients the result would be a large short-lived drop in blood pressure and, quite often, dizziness and fainting.

The company aims to submit a new drug application (NDA) for naproxcinod to the US Food and Drug Administration (FDA) as well as to European authorities early in 2009. To market the product to general practitioners, the company may need a partner to help with the pre-launch and marketing costs. NicOx is talking to a number of potential suitors for naproxcinod, but also wants to retain co-marketing and promotion rights to the product. ‘We’re asking quite a lot,’ Hanks says.

Between 1998 and 2003, development of naproxcinod was partnered with the Anglo-Swedish pharmaceuticals group AstraZeneca, which invested in large Phase II trials for the product. AstraZeneca also ran a trial comparing naproxcinod’s gastro-intestinal (GI) side effect profile to naproxen, which showed a GI advantage for naproxcinod over naproxen but did not reach statistical significance on its GI-based primary endpoint. AstraZeneca returned the naproxcinod rights to NicOx in August 2003.

‘You have to remember that at that time the COX-2 inhibitors had taken the anti-inflammatory market by storm on the back of their improved GI profiles compared to traditional non-selective NSAIDs’, says Garufi. ‘The results suggested naproxcinod was better on GI than non-selective NSAIDs but not as good as COX-2 inhibitors. There was not widespread concern about the blood pressure and cardiovascular safety at that time, although a few experts were voicing concerns, and therefore the very promising blood pressure data from these Phase II trials was overlooked.’ A year later Vioxx was withdrawn.

However, analysts caution that the success of naproxcinod is very much dependent on NicOx successfully attracting a suitor to take naproxcinod to the market. And although big pharma is hungry for blockbusters, Garufi says that the big investment required to launch the drug makes them cautious.  ‘People in big pharma are becoming more risk averse. We have to do the right deal for us – this will be the transformational event for NicOx to become an integrated pharma company.’

Potential developments

There is potential to use NO technology to treat a number of other conditions outside of its core areas of inflammatory and cardiometabolic diseases, including Alzheimer’s disease and osteoporosis.

Nitric oxide is a messenger molecule that is present throughout the body in tissues and organ systems, and plays several roles in allowing communication between cells. ‘Lots of different diseases are due to a lack of nitric oxide, so NO donating drugs could be beneficial,’ Hanks says. At present, however, showing a clinical benefit in clinical trials for these conditions is very difficult. ‘We’ve focused our pipeline on where we can show a benefit in clinical trials,’ says Hanks.

Aside from naproxcinod, NicOx has a number of other NO-based products in development. ‘You cannot develop a company in the long term based on only one product, even if it is a fantastic one like naproxcinod,’ Garufi says. The company is working on a new statin product. ‘Our compound has a very strong rationale, because in addition to cholesterol lowering, nitric oxide release is a key mechanism by which statins work. Statins improve cardiovascular outcomes because they increase the endogenous NO production of the vessel, so the vessel works better.’

The new NO-donating statin is showing advantages in animal tests, and has not yet made it into human trials. But Garufi believes a statin-based NO compound could be a potentially even bigger blockbuster than naproxcinod.

The company has licensing deals for its technology for ophthalmic drugs with Pfizer and for antihypertensive compounds with Merck. Pfizer currently has a leading prostaglandin product, latanoprost, for glaucoma and intraocular pressure, soon to go off patent. ‘They need a successor,’ says Garufi, adding that Pfizer saw the advantage of developing an NO derivative of a prostaglandin analogue using NicOx technology.

The company is currently opening a commercial and development office in New Jersey, US, which it plans to use in future for marketing and sales. NicOx’s future success very much depends on finding a suitable partner to bring its blockbuster, and future blockbusters, to fruition.

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