Genkyotex, the leading developer of NOX enzyme inhibitors, announced today that a group of collaborators have discovered a link between the enzyme NOX4 and development of osteoporosis. These results, published online in the Journal of Clinical Investigation doi:10.1172/JCI67603), indicate that inhibitors of NOX4, such as GKT137831 developed by Genkyotex could lead to a novel way of treating patients with osteoporosis. GKT137831, the first in class NOX1 and 4 inhibitor, has shown favorable safety and pharmacokinetic profiles in Phase I studies, and following a recently FDA approved IND will enter a Phase II trial in patients with diabetic nephropathy.
"Osteoporosis is a common disease of bone that causes fractures and pain in almost one in three women," said Prof. Katrin Schröder, Institute of Cardiovascular Physiology, Faculty of Medicine at the Goethe University, Frankfurt. "Data from our studies clearly indicate that NOX4 plays a role in osteoclast generation, which triggers bone resorption and loss. In our studies we found that NOX4 was induced in human osteoporosis, and inhibiting NOX4 could reduce bone loss in mice."
Dr. Ursula Ney, CEO of Genkyotex commented: "The data from these studies provide compelling evidence for a role of NOX4 in the development of osteoporosis and builds on the growing evidence of the NOX enzymatic pathway in a number of common and often difficult to treat diseases, as well as confirming the therapeutic potential for our small molecule NOX inhibitors. Genkyotex will continue to assess the therapeutic potential of NOX4 inhibition in bone loss, including in patients with chronic kidney disease."
Details of the Studies
Initially, researchers conducted a series of studies using mice lacking NOX4 (knock-out) and found that bone of NOX4 knock-out mice had wider, thicker trabeculae that had also 30% greater density compared to wild type mice. Importantly, this effect was specific for NOX4, as genetic deletion of NOX2 or NOX1 had no effect.
The rate of bone formation through osteoblast activity was found not to be altered by genetic deletion of NOX4. In contrast, NOX4 was found to participate in the maturation and activation of osteoclasts, the cells responsible for bone resorption. Importantly, a single nucleotide polymorphism in the NOX4 gene was associated with elevated circulating markers of bone turnover and reduced bone density in women. Furthermore, human bone obtained from patients with increased osteoclast activity (osteoporosis and Paget disease) exhibited increased NOX4 expression.
In a mouse model of osteoporosis, acute NOX4 deletion or treatment with the Genkyotex's NOX4 inhibitor significantly attenuated bone loss. The breaking strength of bone from treated mice was also significantly higher than that of mice receiving control.
Also, in a PIT formation assay, Genkyotex's NOX4 inhibitor GKT137831 dose-dependently prevented the degradation of the extracellular matrix, a major feature of osteoclasts maturation, which suggests that NOX4 is essentially involved in osteoclastogenesis in human cells.
Overall, these very comprehensive studies indicate that NOX4 inhibition has significant therapeutic potential in diseases where increased osteoclast activity results in bone loss. Such diseases include osteoporosis, Paget disease, and possibly the development of bone metastasis and their complications. The data also suggests that GKT137831 may attenuate bone loss in patients with chronic kidney disease.