FREMONT, Calif., Aug. 29, 2018 /PRNewswire/ -- Ardelyx, Inc.
(Nasdaq: ARDX), today announced that the novel mechanism of action
for tenapanor for the treatment of hyperphosphatemia, or elevated
serum phosphorus, has been published in the peer-reviewed journal
Science Translational Medicine. Tenapanor, Ardelyx's lead
product candidate, is a sodium/hydrogen exchanger 3 (NHE3)
inhibitor currently being evaluated in a second, Phase 3
registration trial, the PHREEDOM trial, for the treatment of
hyperphosphatemia in patients with end-stage renal disease (ESRD)
who are on dialysis. The paper, titled "Inhibition of
sodium/hydrogen exchanger 3 in the gastrointestinal tract by
tenapanor reduces paracellular phosphate permeability," can be
accessed in the current online edition of the publication.
"The elucidation of tenapanor's mechanism is a landmark
discovery in our field causing us to completely rethink our
understanding of phosphate transport and absorption," said
Geoff Block, M.D., director of
clinical research at Denver Nephrology Research, and a PHREEDOM
trial investigator. "Nearly all patients with ESRD have elevated
serum phosphorus, a problem that if not managed properly through
diet changes and prescription medication, can lead to an increase
in morbidity and mortality in patients. Today, our only therapeutic
option is to use phosphate binders, which are inadequate in
reducing serum phosphorus in the majority of patients and
associated with a number of challenges, including low rates of
compliance because of the large number of pills that must be taken
each day, significant tolerability issues and long-term concerns
related to the safety of our patients. I believe tenapanor could
shift our treatment approach and offer a significant benefit to
patients, who absolutely need better options."
Ardelyx scientists, in collaboration with global academic
experts, established the mechanism by which tenapanor reduces
gastrointestinal phosphate absorption using in
vivo studies in rodents, as well as Ardelyx's human stem
cell-based translational technology called the Ardelyx Primary
Enterocyte and Colonocyte Culture System (APECCS). In the past, the
literature has described two pathways of phosphate absorption in
the gut: active transcellular transport directly through
the cells lining the gut and passive paracellular flux
through tight junction protein pores between cells. Historically,
the science has focused almost exclusively on the transcellular
transport pathway where specific transporter proteins bring
phosphate into and through intestinal cells and into the blood.
Ardelyx's discoveries conclude that phosphate absorption in humans
actually occurs primarily through a dynamically regulated
paracellular pathway. This pathway of phosphate flux is inhibited
by tenapanor in a manner that appears largely specific for
phosphate, whereas the overall absorption of other ions and large
molecules appear not to be affected. Tenapanor's phosphate
mechanism is due to its direct action on NHE3, which exchanges
sodium from the lumen of the gut for an intracellular proton.
Inhibition of NHE3 by tenapanor results in proton retention in the
cell, which modulates tight junction proteins to decrease
permeability to phosphate, reducing paracellular phosphate
absorption. Dynamic regulation of the permeability characteristics
of the tight junction pore has only very recently been recognized,
and tenapanor is the first agent to demonstrate this dynamic
regulation of paracellular phosphate permeability.
Tenapanor's novel mechanism of action has translated into
meaningful reductions in serum phosphorus in humans, as reported in
the findings from Ardelyx's first Phase 3 clinical study evaluating
tenapanor for the treatment of hyperphosphatemia in ESRD patients
on dialysis. That trial met its primary endpoint, demonstrating a
statistically significant difference in change in serum phosphorus
between pooled tenapanor-treated patients and placebo-treated
patients from the end of the eight-week treatment period to the end
of the four-week randomized withdrawal period, in the responder
population. Tenapanor was also well-tolerated in the trial, with
limited discontinuations due to GI-related adverse events in the
treatment period and no discontinuations related to GI events in
the randomized withdrawal period.
"Tenapanor's dynamic mechanism of lowering phosphate by tight
junction modulation with just two small pills has the potential to
offer a first-of-its-kind approach to treating this large and
growing patient population," commented David Rosenbaum, Ph.D., chief development
officer of Ardelyx. "This important publication showcases our
commitment to scientific innovation, unique insights into the
biology of the gut and chemistry capabilities that enable us to
design and optimize gut-restricted compounds. Tenapanor, if
approved, would offer an entirely new way of treating ESRD patients
who need a convenient, effective and tolerable medicine for
managing phosphorus."
Ardelyx's Phase 3 PHREEDOM trial is enrolling patients, and the
company expects to report results from this registration study in
2019.
About Hyperphosphatemia
Phosphorus, a vital element
required for most cellular processes, is present in almost every
food in the Western diet, and, in individuals with normal kidney
function, excess dietary phosphorus is efficiently removed by the
kidneys and excreted in urine. In adults with functioning kidneys,
normal serum phosphorus levels are 2.5 to 4.5 mg/dL. With kidney
failure, elevated phosphorus becomes harmful and is diagnosed as
hyperphosphatemia when serum phosphorus levels are greater than 4.5
mg/dL, according to KDIGO guidelines1.
Although patients with end-stage renal disease
(ESRD) rely on dialysis to eliminate harmful agents, these patients
cannot adequately handle a typical daily phosphate intake and other
means of managing phosphorus levels must be employed. In addition
to dialysis, ESRD patients are put on restrictive low phosphorus
diets and are currently prescribed medications called phosphate
binders, the only interventions currently marketed for the
treatment of hyperphosphatemia.
About Ardelyx, Inc.
Ardelyx is focused on
enhancing the way people with renal diseases are treated by
developing first-in-class medicines. Ardelyx's renal
pipeline includes the Phase 3 development of tenapanor for the
treatment of hyperphosphatemia in people with end-stage renal
disease who are on dialysis and RDX013, a potassium secretagogue
program for the potential treatment of high potassium, or
hyperkalemia, a problem among certain patients with kidney and/or
heart disease. In addition, Ardelyx has completed Phase 3
development of tenapanor for the treatment of irritable bowel
syndrome with constipation and anticipates submitting a New Drug
Application to the U.S. Food and Drug Administration for
this indication early in the fourth quarter of 2018. To efficiently
bring its treatments to market, Ardelyx is pursuing
strategic collaborations for tenapanor for IBS-C and
hyperphosphatemia in certain territories. Ardelyx has established
agreements with Kyowa Hakko Kirin in Japan, Fosun
Pharma in China and Knight
Therapeutics in Canada. For more information, please
visit http://www.ardelyx.com/ and connect with us on
Twitter @Ardelyx.
Forward Looking Statements
To the extent that
statements contained in this press release are not descriptions of
historical facts regarding Ardelyx, they are forward-looking
statements reflecting the current beliefs and expectations of
management made pursuant to the safe harbor of the Private
Securities Reform Act of 1995, including the potential for
Ardelyx's product candidates in treating the diseases and
conditions for which they are being developed; Ardelyx's expected
timing for the filing of its NDA for tenapanor for the treatment of
IBS-C, and Ardelyx's expected timing to report topline data for its
Phase 3 PHREEDOM clinical trial of tenapanor for the treatment of
hyperphosphatemia in patients with end-stage renal disease who are
on dialysis. Such forward-looking statements involve substantial
risks and uncertainties that could cause the development of
Ardelyx's product candidates or Ardelyx's future results,
performance or achievements to differ significantly from those
expressed or implied by the forward-looking statements. Such risks
and uncertainties include, among others, the uncertainties inherent
in research and the clinical development process, including the
regulatory approval process. Ardelyx undertakes no obligation to
update or revise any forward-looking statements. For a further
description of the risks and uncertainties that could cause actual
results to differ from those expressed in these forward-looking
statements, as well as risks relating to Ardelyx's business in
general, please refer to Ardelyx's Quarterly Report on Form 10-Q
filed with the Securities and Exchange Commission on August 7, 2018, and its future current and
periodic reports to be filed with the Securities and Exchange
Commission.
1 KDIGO CKD-MBD Guidelines 2017.
https://kdigo.org/wp-content/uploads/2017/02/2017-KDIGO-CKD-MBD-GL-Update.pdf
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