Beyond naproxcinod and the pre-clinical candidate, NCX 6560, which are being developed in NicOx’ core therapeutic areas of inflammatory and cardio-metabolic disorders, the company has a broader pipeline of molecules in other therapeutic areas, many of which are the subject of partnership agreements :

NicOx' most advanced investigational drug, naproxcinod, has successfully completed a regulatory phase 3 program in patients with osteoarthritis of the knee and hip. Anti-inflammatory agents currently used in the treatment of osteoarthritis (traditional NSAIDs and COX-2 inhibitors) have long been associated with a range of side effects, including gastrointestinal problems. Furthermore, clinical findings continue to cast significant doubt on their cardiovascular safety, including their association with increased blood pressure.

Naproxcinod is a unique nitric oxide-donating anti-inflammatory compound and the first CINOD (Cyclooxygenase-Inhibiting Nitric Oxide Donator) in late-phase development. NicOx aims to demonstrate that naproxcinod is an anti-inflammatory agent with no detrimental effect on blood pressure and good gastrointestinal tolerability and safety.

NicOx has completed a regulatory phase 3 program for naproxcinod in patients with OA of the knee (the 301 and 302 studies) and hip (the 303 study), with all three studies achieving highly statistically significant results on all three co-primary efficacy endpoints. NicOx plans to submit a New Drug Application (NDA) for naproxcinod to the US Food and Drug Administration (FDA) in mid-2009.

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In March 2009, NicOx announced the initiation of clinical development for NCX 6560, a novel, nitric oxide-donating compound which could become an improved drug for serious cardiovascular diseases. The first-in-man study will enroll both healthy male volunteers and those with abnormally raised cholesterol and will compare NCX 6560 to placebo and atorvastatin (Lipitor^®), with a preliminary evaluation of activity, safety and tolerability. The initiation of this study follows the selection of NCX 6560 as a new internal development candidate in September 2006 and promising pre-clinical results which suggest NCX 6560 could inhibit multiple steps in the development of atherosclerosis, a key dysfunction underlying cardiovascular disorders.

The objective of this phase 1 proof-of-principle study is to assess the safety, tolerability, pharmacokinetic and pharmacodynamic profile of single and repeated escalating doses of NCX 6560. The trial will also follow a biomarker relevant to cardiovascular disorders, in order to provide the first evaluation of the compound’s activity in man and guide its future development. 

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PF-03187207
Glaucoma - Phase 2
Partnered with Pfizer Inc

It is estimated that over 3 million people in the United States suffer from glaucoma and 120,000 are believed to have lost their vision as a result of the disease. Current drug therapy is focused on reducing intraocular pressure (IOP), which is believed to cause progressive vision impairment. The degree of IOP reduction is believed to be linked to prognosis (i.e. the greater the reduction in IOP the slower the progression towards vision loss and eventually blindness).

Xalatan® (latanoprost) is a proprietary Pfizer product and the leader in worldwide glaucoma sales, with approximately $1.6 billion of franchise sales in 2007. However, despite recent advances in glaucoma treatment, research shows that around 10% of patients who receive proper care still experience vision loss, demonstrating the strong necessity for improved drugs.

In 2008, NicOx announced the results of two dose-ranging phase 2 studies conducted with PF-03187207 in glaucoma patients by its partner Pfizer Inc., in the United States and in Japan. PF-03187207 is a nitric oxide-donating prostaglandin analog. These studies were designed to compare the safety and efficacy of several doses of PF-03187207 to Xalatan® and enrolled an overall number of 327 patients with primary open angle glaucoma or ocular hypertension.

On the primary endpoint of both studies at 28 days, the highest doses of PF 03187207 showed an improvement over Xalatan® 0.005% of up to 12%, in terms of the reduction in diurnal IOP compared to baseline, although this did not reach statistical significance. PF 03187207 appeared to be safe and well tolerated, with adverse events being mild.

In both the Japanese and U.S. studies, PF-03187207 showed a 20% greater reduction in IOP at 20 hours post-dose compared to Xalatan® 0.005%, which reached statistical significance in the U.S. study, suggesting a more sustained IOP lowering effect.

Following the results of these phase 2 studies, Pfizer decided not to launch a phase 3 program for PF-03187207. NicOx and Pfizer are currently in discussions regarding the worldwide rights to PF-03187207, to allow its potential continued development and commercialization. PF-03187207 is covered by the companies’ August 2004 agreement.

TPI 1020 is a novel anti-inflammatory drug-candidate licensed from NicOx to Topigen Inc. for respiratory indications. In December 2008, the results of a phase 2a study in 61 patients with Chronic Obstructive Pulmonary Disease (COPD) were announced. COPD is a very prevalent respiratory disorder characterized by persistent airflow limitation in the lungs. COPD is very difficult to treat and there are no drugs available that can slow the progressive decline in lung function.

In the phase 2a study, TPI 1020 showed good overall safety and tolerability, although its activity profile was not significantly different from budesonide, a conventional corticosteroid commonly used in respiratory disorders. Nevertheless, TPI 1020 did show a numerical reduction in the sputum neutrophil count in the airways between baseline and day 42, as compared to budesonide which increased them (p=0.095). Neutrophils are inflammatory cells which are directly implicated in the pathology of COPD. In light of the efficacy results of this study, Topigen and NicOx have decided to discontinue the development of TPI 1020 in COPD and are currently exploring potential opportunities for this compound in other indications, under the ongoing collaboration agreement.
 

NCX 1510 (NLA)
Allergic rhinitis - Phase 2
Partnered with Orexo AB

In the United States, nearly one person in three suffers from hypertension (high blood pressure). This chronic disorder is a leading cause of mortality and morbidity, as it increases the risk of stroke, heart failure, cardiovascular disease and renal disease. It is estimated that more than 190 million people suffer from high blood pressure in the seven leading pharmaceutical markets, and researchers have predicted that there will be a relative increase of 24% in the prevalence of hypertension in developed countries from 2000 to 2025, due to an aging population and the increased rate of diabetes and obesity. The global market for antihypertensive drugs totaled $53.1 billion in 2007, which represents the largest indication for prescription pharmaceuticals worldwide.

Despite the numerous different classes of antihypertensive therapies available to physicians, less than one third of treated patients are believed to achieve established blood pressure goals, highlighting the pressing need for new drugs. NicOx and Merck & Co., Inc. are collaborating on the development of new antihypertensive drugs using NicOx’ proprietary nitric-oxide donating technology, which has the potential to meet this need. 

In May 2008, Merck initiated the first in a series of planned clinical studies, in volunteers with mild to moderate hypertension. Merck plans to conduct a number of clinical studies in this population, involving single and multiple ascending dosing, prior to the selection of a compound to be advanced into phase 2. The main objectives of these studies are to assess the efficacy, safety, tolerability and pharmacokinetics of single ascending doses of these candidates. Subsequent studies will assess multiple ascending doses. 

A previous series of planned clinical trials had been initiated in 2007 in healthy volunteers. The first of those trials was a phase 1, dose-ranging study, the primary objective of which was to assess the safety, tolerability and pharmacokinetics of single oral doses of the drug-candidate. 

Endothelial nitric oxide is believed to play an important role in the regulation of blood pressure. Very promising preclinical results were presented in 2006 at the American Heart Association for a prototype compound, a nitric oxide-donating derivative of a commonly used antihypertensive drug. These results suggest that NicOx’ proprietary technology has the potential to improve the blood pressure lowering activity of existing antihypertensive agents.

The clinical program for developing new nitric oxide-donating antihypertensive drugs is being funded and managed by Merck & Co., Inc., following the signature of the companies’ 2006 exclusive worldwide agreement.

The new compounds, while maintaining lipid lowering properties, show marked NO-mediated effects in predictive models of cardiovascular disorders such as myocardial infarction or peripheral vascular diseases, with an activity superior to that of reference compounds. Thus, nitric oxide-donating derivatives of atorvastatin or pravastatin, for instance, represent an attractive generation of drugs for the treatment of atherosclerosis and other cardiometabolic disorders. 

Previous research efforts have clearly demonstrated the value of nitric oxide-donation in enhancing anti-inflammatory properties of commonly used drugs, e.g. NSAIDs or glucocorticoids. Given the interesting clinical results obtained with the most advanced compound, naproxcinod, an additional effort is ongoing to identify other NO-donating NSAIDs (CINODs) which can combine effective anti-inflammatory properties with gastrointestinal and cardiovascular safety.