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 product, naproxcinod, is in phase 3 development for treating the signs and symptoms of osteoarthritis. The anti-inflammatory agents currently used in the treatment of osteoarthritis (COX-2 inhibitors and non-selective NSAIDs) have long been associated with a range of side effects, including gastrointestinal problems. Furthermore, recent clinical findings have cast significant doubt on their cardiovascular safety, including their association with increased blood pressure.

Naproxcinod is a unique nitric oxide-donating anti-inflammatory and the first of the CINOD class ("COX-Inhibiting Nitric Oxide Donators"). NicOx aims to develop naproxcinod as a powerful anti-inflammatory agent with no detrimental effects on blood pressure and good gastrointestinal tolerability and safety.

Top-line results from the first phase 3 study were successful. This represents an important step towards NicOx’ goal of making naproxcinod the drug-of-choice for osteoarthritis patients.

More on naproxcinod…

In September 2006, NicOx selected NCX 6560 as a new internal development candidate. NCX 6560 is a nitric oxide-donating derivative of a commonly used statin drug, which has the potential for broadened and increased benefit in cardiovascular disease. Statins represent the most effective and best tolerated drugs for lowering abnormally raised cholesterol and have consequently become the world’s best selling class of pharmaceuticals, with combined global sales of $20.1 billion in 2005.

NCX 6560 has the potential to target atherosclerosis and endothelial dysfunction through a multi-pathway approach. The capacity 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.

More on NCX 6560... 

PF-03187207
Glaucoma - Phase 2
Partnered with Pfizer Inc.

Pfizer Inc has entered into clinical development in its collaboration with NicOx, initiated in August 2004, which is focused on the research and development of nitric oxide-donating derivatives of prostaglandin F2-alpha analogs for the treatment of glaucoma. In March 2007, Pfizer initiated the first in a series of planned clinical studies for PF-03187207, the lead candidate selected for development in November 2005. The initiation of this clinical study follows the granting of an Investigational New Drug (IND) approval for the PF-03187207, as a new experimental medicine for the treatement of glaucoma.

The first clinical study is a phase 2, dose-finding trial, which is designed to compare the safety and efficacy of PF-03187207 to latanoprost, a widely used drug for the treatement of glaucoma. The trial will be a 28 day, parallel group, randomized and double-masked study, which is expected to enroll around 150 patients with primary open angle glaucoma, or ocular hypertension, in one or both eyes. The primary endpoint of this study will be the change in diurnal intraocular pressure (IOP, pressure within the eye) at day 28. Secondary endpoints will include: the change in IOP from baseline at the study center visits on day 7, 14, 21 and 28, the proportion of patients at target IOP across all study visits, in addition to safety evaluations.

Based on the very promising preclinical results and on the well-known activities of nitric oxide, PF-03187207 is expected to have an increased capacity to reduce high IOP. The development of abnormally high IOP, due to blockage or malfunction of systems controlling the amount of fluid in the eye, is believed to be one of the principal causes of glaucoma.

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 IOP, which is believed to cause progressive vision impairment. The degree of IOP reduction is believed to be linked to prognosis. 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.

TOPIGEN is currently performing a phase 2 clinical development program initiated in May 2006 for TPI 1020 (formerly NCX 1020) in respiratory disorders. TOPIGEN aims to develop TPI 1020, a novel respiratory anti-inflammatory licensed from NicOx, as a treatment for Chronic Obstructive Pulmonary Disease (COPD) and other respiratory disorders. In November 2007, TOPIGEN dosed the first patients in a phase 2 proof-of-concept study for TPI 1020 in COPD. This study is expected to provide the first assessment of TPI 1020’s potential activity in this disease.

This trial is a 6-week, multi-center, double blind, placebo and active-controlled study, where about 50 patients with COPD are being randomly allocated to three arms. Each arm will receive inhaled doses of TPI 1020 (500μg bid), budesonide (800μg bid), a conventional corticosteroid commonly used in respiratory disorders, or placebo. Eligible patients are smokers or ex smokers between 40 and 80 years old with an established clinical history of mild to moderate COPD, as defined by the Standards for the Diagnosis and Management of patients with COPD. The primary outcome measures of the study are the effect of TPI 1020 and budesonide on the change in sputum neutrophil counts between baseline and day 42 and the safety and tolerability of inhaled TPI 1020 in COPD patients.

The initiation of this new trial follows the announcement of promising top-line results from a phase 2a study in asthmatic smokers, where TPI 1020 showed a good safety and tolerability profile, in addition to certain anti-inflammatory effects which could be potentially beneficial in COPD. This trial was a 21-day, multi-center, double blind study in asthmatic smokers who were randomized to receive repeated and ascending doses of either inhaled TPI 1020 or budesonide. Previously, preclinical models of COPD have suggested that TPI 1020 is more effective than budesonide in protecting against bronchoconstriction and in inhibiting the infiltration and subsequent activation of neutrophils in the lungs (neutrophils are immune cells releasing enzymes that destroy lung tissue).

COPD is characterized by persistent airflow limitation in the lungs and represents the fourth leading cause of death in the United States. The cellular mechanisms that are responsible for COPD pathology are not completely understood. Chronic airflow limitation is believed to be a consequence of an abnormal recruitment of inflammatory cells such as neutrophils and is frequently a response to exposure to cigarette smoke. Smoking is the most important risk factor associated with the development of COPD.

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

NCX 1510 is a nitric oxide-donating drug candidate for the treatment of allergic rhinitis, an extremely common allergic reaction which leads to inflammation of the nasal membrane and associated symptoms such as sneezing or a blocked nose.

A nasal spray formulation of NCX 1510 is currently in phase 2 clinical development and is expected to have equivalent efficacy to existing systemic treatments, in addition to a rapid onset of action.

In June 2004, NCX 1510 reached its primary efficacy endpoint in a phase 2a study in allergic rhinitis. This was a double blind, three way crossover study (NCX 1510 nasal spray, citerizine tablets and placebo) involving 36 patients, which was carried out at Lund University in Sweden. NCX 1510 showed a statistically significant reduction in symptoms (primary endpoint), which were measured as a lower total nasal-symptom score, compared to placebo. NCX 1510 also demonstrated equivalent efficacy to citerizine, the standard systemic treatment.

In February 2005, a second clinical study demonstrated a rapid onset-of-action of only 5-10 minutes. This trial had a randomized, crossover-design, in which 12 healthy volunteers received a single intranasal dose of either NCX 1510, or placebo, followed by histamine challenge to mimic an allergic reaction. NCX 1510 was found to reduce the levels of a protein linked to allergic reactions, in a statistically significant manner compared to placebo, only 5-10 minutes following administration.

Following the completion of a fruitful three year research collaboration, NicOx signed a major exclusive worldwide license agreement with Merck & Co., Inc., in March 2006. This new agreement covers the development of nitric-oxide donating derivatives of several major classes of antihypertensive agents for the treatment of high blood pressure, complications of hypertension, and other cardiovascular and related disorders.

The joint research has generated very good results, particularly in in-vivo validated models of hypertension, suggesting that NicOx‘ proprietary nitric oxide donation technology has the potential to improve the blood pressure lowering activity of antihypertensive agents.

In July 2007, Merck has initiated the first in a series of planned studies in the clinical program for the first selected drug candidate. This first trial is a phase 1, dose-escalating study in healthy volunteers. The primary objective of this trial is to assess the safety, tolerability and pharmacokinetics of single oral doses, in order to select the dose and dosing regimen for further clinical studies. The start of this clinical development program follows the announcement in January 2007 of the companies' selection of the first development candidate and that Merck had started the Good Laboratory Practice (GLP) compliant toxicology studies needed to submit an exploratory IND for this compound. Since the beginning of 2007, NicOx will have been received from Merck a total of €10 million milestone payment. Under the terms of the agreement, Merck is responsible for the funding and performance of the development of this compound going forward.

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.

Moreover, nitric oxide has been found to enhance the effects of gabapentin, which has become a reference drug for the treatment of neuropathic pain. Thus, a prototypic compound NCX 8001 is effective in models of neuropathic pain with a profile superior to that of gabapentin. These data have been of stimulus to focus  further on the potential of nitric oxide-donating drugs for the treatment of neuropathic pain, an area of still high medical need.