NIH-Funded Consortium Will Conduct Phase 2 Trial to Assess Role of NOX Enzymes in IPF

Do NOX enzymes play a pivotal role in idiopathic pulmonary fibrosis (IPF)? This is the question researchers hope to answer with a newly funded research program evaluating the role of NOX enzymes.

Genkyotex, a company focused on developing therapies for chronic diseases, recently announced that the U.S. National Institutes of Health (NIH) has awarded an $8.9 million grant to Victor Thannickal, MD,  professor at the University of Alabama at Birmingham (UAB), to create an academic consortium to lead the multi-year research program.

The central investigative component of the program will be a 24-week Phase 2 clinical trial of the company’s lead product candidate, GKT831, in patients with IPF.

The Phase 2 trial will be a placebo-controlled, double-blind study to investigate the effectiveness and safety of oral GKT831 in patients with IPF receiving current standard of care treatments. The trial will recruit 60 patients and will begin enrollment during in 2019.

The trial’s goals will be assessed over a 24-week period. The primary goal will evaluate the change in blood plasma levels of o,o’-dityrosine, a marker of pulmonary oxidative stress that can cause damage. This marker is elevated in patients with interstitial lung diseases, such as IPF.

NOX enzymes are involved in the generation of reactive oxygen species (ROS), and high levels of ROS have been associated with tissue damage.

The secondary goal of the study is the assessment of post-treatment change in 6-minute walk distance (a measure of exercise capacity), forced vital capacity (a measure of lung function), and high-resolution computed tomography (CT) scan.

The newly funded consortium will be led by principle investigator Thannickal, and its members include researchers who previously have published data on the potential role of NOX enzymes in IPF.

Studies published by the consortium members include “NADPH Oxidase-4 Mediates Myofibroblast Activation and Fibrogenic Responses to Lung Injury,” published in the journal Nature Medicine, in which researchers identified NOX4 as a central driver of lung fibrosis.

Another important finding was published in the journal Science Translational Medicine. In the article “Reversal of persistent fibrosis in aging by targeting Nox4-Nrf2 redox imbalance,” researchers demonstrated that blocking NOX1/4 with GKT831 achieved marked anti-fibrotic effects and prolonged survival in a mouse model of lung fibrosis.

In two additional studies, “Nox4 Is Expressed In Pulmonary Artery Adventitia And Contributes To Hypertensive Vascular Remodeling” and “The nox4 inhibitor, gkt137831, attenuates hypoxia-induced pulmonary vascular cell proliferation,” NOX1 was shown to drive vascular tissue remodeling, an important factor contributing to disease progression in IPF, in several preclinical models of lung disease. In these preclinical models, GKT831 reduced vascular remodeling and secondary right heart disease.

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“We are pleased to advance our research on NOX enzymes to the clinical stage. Importantly, NOX1/4 inhibition may have profound disease modifying effects by addressing the fibrotic and vascular remodeling, which drives disease progression,” Thannickal said in a press release.

“Based on the preclinical data generated to date, we believe GKT831 has the potential to be an effective treatment in IPF. GKT831 has previously shown marked anti-fibrotic activity in preclinical models, and we now look forward to further evaluating this promising candidate in a Phase 2 clinical trial,” Thannickal added.

GKT831 also is being evaluated in patients with liver and kidney fibrosis in two separate Phase 2 clinical trials.

“We are very excited about this planned investigator-initiated Phase 2 trial, which expands the clinical evaluation of GKT831 into an additional fibrotic disorder,” said Philippe Wiesel, MD, chief medical officer of Genkyotex.