NicOx' second lead product, NCX 4016, is being developed as a novel insulin sensitizing agent for the treatment of type 2 diabetes.

The prevalence of type 2 diabetes is rapidly increasing in the developed world and there is a clear need for a new class of oral treatments which could counteract insulin resistance through an alternative mechanism of action.

Encouraging results have previously been observed in type 2 diabetes patients that were treated with NCX 4016 during several phase 2 studies in the cardiometabolic setting. NCX 4016 has also demonstrated a good safety and tolerability profile in long-term treatment.

NCX 4016 is a nitric oxide-donating derivative of acetyl-salicylic acid (or aspirin), which NicOx is developing as a novel insulin sensitizing agent for the treatment of type 2 diabetes.

Diabetes affects millions of people and represents a major threat to global public health that is rapidly growing. The disease has its greatest impact on adults of working age in developed countries. It affects around 190 million people worldwide today and this figure is expected to reach 330 million by 2030. Type 2 diabetes (or non insulin-dependent diabetes) is the most prevalent form of the disease and is a metabolic disorder caused by insulin resistance, increased glucose production by the liver and an impaired ability to secrete insulin. The disease leads to the damage and function impairment of many organs, most importantly in the cardiovascular system.

Improved control of blood sugar levels has been shown to reduce the incidence of diabetic complications and lowers overall health-care costs associated with diabetes management. The rapidly increasing prevalence of type 2 diabetes indicates a clear medical need for effective drugs aimed at preventing and treating this very serious disease.

NicOx plans to initiate two phase 2 studies for NCX 4016 in type 2 diabetes which will have the goal of confirming the mechanism of action of NCX 4016 as an insulin sensitizer and demonstrating a clinical benefit in the treatment of type 2 diabetes. The first study is projected to be a single-center, cross-over trial designed to confirm the mechanism of action of NCX 4016 as an insulin sensitizing agent using a hyperinsulinemic euglycemic clamp, a technique which has been used in previous clinical trials for NCX 4016 (see below). The second trial is projected to be a placebo and active controlled, double blind, parallel study, aiming to demonstrate a clinical benefit for NCX 4016 through the measurement of HbA1c (glycosylated hemoglobin, the gold standard test for glycemic control in diabetics) and blood glucose in the fasting state and after meals.

The start of these two planned studies has been delayed, as a precautionary measure, pending completion of additional testing on NCX 4015 which is a potential, specific metabolite of NCX 4016. This decision follows some results from in-vitro genotoxicity tests on NCX 4015. NicOx has previously successfully completed the full range of in-vitro and in-vivo genotoxicity tests, recommended by international guidelines on NCX 4016.

The metabolism of NCX 4016 in the body generates sustained levels of salicylate and a nitric oxide donating moiety. It has been known for a number of years that high dose aspirin treatment, through the release of salicylate, can have a beneficial effect in diabetes management by lowering plasma glucose levels. This has been shown to be due to improved insulin sensitivity and decreased insulin clearance. However, high dose aspirin or salicylate can not be used chronically for the treatment of type 2 diabetes due to safety and tolerability issues.

The results of previous clinical trials suggest that the salicylate released from NCX 4016 may have a beneficial effect in type 2 diabetes patients at a lower concentration than when salicylate or aspirin are administered alone. This could be due to a possible synergistic effect with nitric oxide. Furthermore, there is considerable scientific evidence suggesting that salicylate and nitric oxide may have synergistic effects in improving insulin sensitivity. In particular, both of these compounds exert a direct effect on IKK beta, a signaling molecule which regulates intracellular glucose uptake and therefore insulin sensitivity. Furthermore, nitric oxide has been shown to be involved in regulating blood flow and insulin secretion and inhibiting pro-inflammatory signaling molecules, all of which are believed to become dysfunctional in type 2 diabetes.

In contrast to what is seen with high dose aspirin and salicylate treatment, the salicylate levels generated by NCX 4016 have not caused tolerability issues in clinical studies to date.

In November 2005, NicOx presented the results of a 13-patient, exploratory phase 2a study in patients with type 2 diabetes and early nephropathy at the 2005 American Heart Association (AHA). They showed a statistically significant increase in insulin sensitivity (glucose disposal rate measured by hyperinsulinemic euglycemic clamp) following treatment with NCX 4016, as compared to baseline.  

Furthermore, in September 2006 NicOx announced the results of a sub-study in a trial concerning 40 type 2 diabetes patients. It aimed to study the effects of NCX 4016 on patients’ insulin levels and glucose utilization. The results revealed that during the last 30 minutes of the clamp, insulin plasma levels were approximately 40% higher in the two groups that received NCX 4016, when compared to the groups which received aspirin only and placebo, most probably due to decreased insulin clearance. During the clamp, glucose was infused at a variable rate in order to maintain plasma glucose levels at a steady state. The results indicate that the glucose infusion rate during the last 30 minutes of the clamp was approximately 50-60% higher in the two NCX 4016 treated groups, compared to the groups treated with aspirin alone and placebo, indicating increased glucose utilization.

Insulin resistance is often seen in people with obesity and NCX 4016 may have potential in preventing the development of type 2 diabetes in insulin resistant patients. This has been shown in another study, in 12 healthy subjects with obesity which demonstrated a highly significant improvement in glucose uptake after 2-weeks of treatment with NCX 4016.

Positive results seen in a sub-group of diabetic patients with peripheral arterial obstructive disease (PAOD):

In November 2005, NicOx announced results of a phase 2 trial for NCX 4016 in Peripheral Arterial Obstructive (PAOD). Although the primary endpoint of this trial based on maximum walking distance, was not met in the overall patient population, a statistically significant advantage was observed for NCX 4016 in a predefined sub-group of patients with type 2 diabetes.

NCX 4016 may be more effective than aspirin at inhibiting platelet activation in diabetics:

In March 2005, NicOx announced data from a phase 2a study in 40 patients with type 2 diabetes. These suggested that NCX 4016 may be more effective than aspirin at inhibiting platelet activation induced by acute hyperglycemia in diabetic patients.