FDA Approves Phase 2 Trial of Potential IPF Therapy GKT831

The U.S. Food and Drug Administration (FDA) will allow the start of a Phase 2 clinical trial of treatment candidate GKT831 for idiopathic pulmonary fibrosis (IPF).

GKT831 is an orally available inhibitor of the NOX1 and NOX4 enzymes, and has been explored for the treatment of liver and kidney fibrosis. NOX enzymes are known to help generate reactive oxygen species (ROS), and high levels of ROS have been associated with tissue damage.

In July 2018, the National Institutes of Health (NIH) awarded an $8.9 million grant to Victor Thannickal, MD, a professor at the University of Alabama at Birmingham, to fund a multi-year research program focusing on the effect of NOX enzymes in IPF.

The FDA’s approval of the investigational new drug (IND) application submitted by Genkyotex clears the way for the third Phase 2 trial of GKT831, this time focused on lung fibrosis as potential indication for this therapy. The double-blind Phase 2 study of GKT831 is the core component of the IPF program.

“We congratulate Professor Victor Thannickal and his colleagues for obtaining FDA approval for this important trial,” Philippe Wiesel, Genkyotex’s chief medical officer, said in a press release.

The study in IPF will assess the safety and effectiveness of GKT831 in 60 patients on standard of care treatment, comparing the potential therapy to placebo. Participants will receive 400 mg of  GKT831 twice a day, a dose that showed anti-fibrotic and anti-inflammatory activity and had an excellent safety profile in a Phase 2 trial (NCT03226067) in patients with the liver disease primary biliary cholangitis (PBC), Genkyotex said.

The primary goal of the 24-week trial will be to assess the change in plasma levels of o,o’-dityrosine — an oxidized modification of residues of tyrosine amino acid — which can be a marker of pulmonary oxidative stress and is often increased in patients with interstitial lung disease.

Researchers also will evaluate changes in exercise capacity and lung function through the 6-minute walk distance (6MWD) test and forced vital capacity assessment.

“The clear efficacy, excellent safety, and quality of life improvement achieved by GKT831 in our recently reported PBC trial suggest that GKT831 may provide important therapeutic benefits in patients with IPF,” Wiesel said.

Of note, GKT831 also is being tested in a Phase 2 study in patients with diabetes and kidney disease (NCT02010242).

Preclinical studies conducted on mice by Thannickal and his team identified NOX4 as a key driver of lung fibrosis as it triggered the differentiation of fibroblasts into myofibroblasts, and was involved in the production of extracellular matrix, which provides support to cells and accumulates in IPF patients.

Researchers also demonstrated that levels of NOX-4 are increased in people with IPF, and that suppressing NOX1/4 with GKT831 had anti-fibrotic effects and extended the survival of aged mice with lung fibrosis. In turn, several models of lung disease identified NOX1 as a driver of vascular remodeling, which, along with secondary right heart disease, was reduced after treatment with GKT831.

“This is an important step forward in translating seminal preclinical discoveries to patients with fibrotic lung disease,” Thannickal said.  “NOX1/4 inhibition may have profound disease modifying effects on the fibrotic and vascular remodeling, which drives disease progression in IPF.”

“We believe GKT831 has the potential to be an effective treatment in IPF,” he added.