NOX-100

To address the excessive nitric oxide and inflammatory cascade of Acute Respiratory Distress Syndrome (ARDS)

The Medical Need

Acute respiratory distress syndrome (ARDS) is a characteristic response of the lung in reaction to a wide variety of injuries. The condition is characterized by a sudden onset of pulmonary edema and respiratory failure. Accurate diagnosis of ARDS is difficult because it presents in the clinic as a collection of symptoms that can be associated with a wide variety of insults including pneumonia, aspiration of gastric contents, traumatic injury, and smoke inhalation. Each year, 150,000 people in the US are affected by ARDS, which has a 40% mortality rate.

The pathology of ARDS is linked to excessively produced nitric oxide (NO). Clinical studies show that levels of nitrate and nitrite, which are markers of NO metabolism, are elevated in the lungs of ARDS patients. In addition, nitrotyrosine formation, a marker of NO-mediated damage, is also increased in the lung. The high output NO synthase, iNOS, is likely to be the culprit in this pathology because in iNOS knockout mice, lung damage was significantly reduced during experimentally-induced ARDS.

At present there is no drug therapy that is broadly effective in ARDS patients. A recent study showed that delivering smaller versus larger breaths on a mechanical ventilator could reduce mortality by 25%. However, such measures do not address the inflammatory processes that can exacerbate tissue injury and delay the recovery of lung function.

Medinox's Approach

Medinox is developing NOX-100 as a novel two-pronged approach for ARDS. First, as a NO neutralizer, NOX-100 binds and inactivates the excessive NO that causes molecular damage. Second, as an anti-inflammatory agent, NOX-100 inhibits the infammatory cascade that can lead to additional lung injury.

In proof of concept studies, NOX-100 had profound anti-inflammatory effects in lung tissue. In animal models of shock, the compound reduced NFkB gene activation, reduced transcription of TNF-alpha, ICAM, IL-6, IL-6 mRNAs in lung tissue and significantly reduced neutrophil infiltration into the lung.

Medinox has shown that NOX-100 has an excellent safety profile in a previous dose-escalating Phase I/IIa safety study in humans. No drug-related side effects were observed in any dose cohorts up through the highest dose (50 mg/kg).