|[October 21, 2013]
Genkyotex Collaborators Elucidate Role of NOX4 in Osteoporosis
GENEVA & ARCHAMPS, France --(Business Wire)--
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
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
Genkyotex is developing first in class, small molecule therapeutics that
specifically and selectively inhibit the NOX family of enzymes. Using a
unique screening platform, Genkyotex has identified novel NOX inhibitors
with the potential to treat disease areas with a high clinical need and
large market potential. The company's lead product, GKT137831, is now
entering Phase II clinical studies in patients with diabetic nephropathy
and has shown promise in several other disease models, including
atherosclerosis, idiopathic pulmonary fibrosis, liver fibrosis and
models of angiogenesis. Genkyotex was founded in 2006 by scientists from
Switzerland, the USA and Japan, with backing from Geneva incubator
Eclosion. Leading global investors Edmond de Rothschild Investment
Partners, Vesalius BioCapital and MP Healthcare Venture Management have
joined Eclosion in providing significant investment to Genkyotex.
Further information can be found at: www.genkyotex.com.
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