FREMONT, Calif., March 7, 2019 /PRNewswire/ -- Ardelyx, Inc.
(Nasdaq: ARDX) today announced the publication in the Journal of
the American Society of Nephrology (JASN) of results from the
first of two Phase 3 pivotal trials for tenapanor to treat
hyperphosphatemia in patients with end-stage renal disease (ESRD)
who are on dialysis. During the treatment period, 164 patients
completed treatment in one of three randomized dosing groups (3, 10
and 30 mg titration) of tenapanor twice daily. The data
demonstrated that there were significant decreases in serum
phosphate in all three treatment groups, with mean reduction of
1.0-1.2 mg/dL over 8 weeks (all P < 0.001). Notably, in a
pre-specified secondary analysis of serum phosphate changes in the
randomized withdrawal period, there was a statistically significant
difference in increases of serum phosphate levels between pooled
patients on tenapanor and placebo (n=164; p = 0.003).
"These results, published in one of the most distinguished
journals for nephrology worldwide, strongly support the ability of
tenapanor to reduce phosphate levels in ESRD patients with a simple
regimen of just two small pills twice per day," said chief
development officer, David P.
Rosenbaum, Ph.D. "We look forward to completing our second
monotherapy Phase 3 trial, PHREEDOM, from which we currently expect
to receive results in the fourth quarter of 2019. In
addition, in the second half of this year, we also expect to
receive results from our clinical trial, AMPLIFY, a Phase 3 study
to evaluate a combination regimen of tenapanor with phosphate
binders. We are excited about the progress we've made and the
data that will be forthcoming as we continue to pursue our goal of
providing ESRD patients with a much needed, highly differentiated
therapeutic alternative for lowering phosphorus."
Dr. Glenn Chertow, Division Chief
and Professor of Medicine, Stanford
University, and senior author added, "The results from this
study demonstrate that tenapanor has a clinically meaningful effect
in lowering serum phosphorus in these patients. While ESRD is
associated with high morbidity and mortality, the field has not
seen significant groundbreaking innovation in many years. I
consider tenapanor a major advance in the field, rooted in cutting
edge science. I look forward to the results of both PHREEDOM
and AMPLIFY and the possibility of having tenapanor in my
armamentarium of treatment options for my patients on
dialysis."
Ardelyx's second Phase 3 study, the PHREEDOM trial, is fully
enrolled, and the company expects to report results from this
registration-enabling study in the fourth quarter of this
year. Ardelyx's third Phase 3 study, the AMPLIFY trial,
designed to evaluate expanded use of tenapanor as adjunctive
therapy to phosphate binders, is enrolling patients, and the
company expects to report results in the second half of 2019.
About the Phase 3 Trial
The Phase 3 trial described in the JASN paper was an eight-week,
double-blind, randomized trial, with a four-week,
placebo-controlled, randomized withdrawal period. Ardelyx enrolled
a total of 219 ESRD patients with hyperphosphatemia who are on
dialysis across 41 U.S. sites. Enrolled patients were randomized
evenly into three arms, in which all groups received tenapanor for
eight weeks. Tenapanor was administered at fixed doses of 3 mg or
10 mg twice-daily and in a dose-titration arm starting at 30 mg
twice-daily with the option to down-titrate once a week during the
first four weeks to 20, 15, 10 and 3 mg twice-daily, based on GI
tolerability. After the end of the eight-week treatment period,
patients were re-randomized 1:1 to either remain on their current
tenapanor dose or switch to placebo for a four-week,
placebo-controlled, randomized withdrawal period (RWP). Of
219 patients randomized, 164 (75%) completed treatment. Of
these, 152 (93%) completed the RWP.
The primary endpoint of the trial is the difference in change in
serum phosphorus between the 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. The responder population (n=80 out of
164), which was in the statistical analysis plan reviewed by the
U.S. Food and Drug Administration, is defined as patients who
demonstrate a greater than or equal to 1.2 mg/dL decrease in serum
phosphorus from baseline during the initial eight-week treatment
period. The study demonstrated a statistically significant
difference in serum phosphorus levels from the end of the
eight-week treatment period to the end of the four-week randomized
withdrawal period between the tenapanor-treated group and the
placebo-treated group in the responder patient population (mean
-1.01 mg/dL, median of -1.3 mg/dL) and met its primary endpoint
(95% CI -1.44, -0.21; LSmean -0.82 mg/dL; p=0.01). Notably, in the
responder population there was a mean reduction in serum phosphorus
from baseline to the end of the eight-week treatment period of 2.56
mg/dL, with a reduction of up to 5.7 mg/dL and 33 percent of
patients experiencing a reduction in serum phosphorus of greater
than 3 mg/dL. Only 7.8 percent of patients discontinued treatment
due to gastrointestinal side effects.
The PHREEDOM trial
The PHREEDOM trial, the company's second Phase 3 clinical trial
of tenapanor for the treatment of hyperphosphatemia in ESRD
patients on dialysis, is currently underway. The study's design
includes a 26-week open-label treatment period, with a 12-week
placebo-controlled, randomized withdrawal period followed by an
additional 14 week open-label safety extension. Topline results
from this trial are expected in the fourth quarter of 2019.
The AMPLIFY trial
The AMPLIFY clinical trial is a randomized, double-blind,
placebo-controlled study evaluating tenapanor in combination with
phosphate binders as adjunctive therapy for the treatment of
hyperphosphatemia in patients with ESRD on dialysis.
Approximately 215 patients on a stable phosphate binder regimen
with a serum phosphorus greater than or equal to 5.5 mg/dL and less
than or equal to 10 mg/dL at screening, and after an up to 3-week
run-in period will be randomized into the clinical trial 1:1 to
receive tenapanor or placebo twice daily. Patients will be allowed
to titrate their dose of tenapanor (or placebo) from a starting
dose of 30 mg to 20 mg or 10 mg and then back up to 30 mg
twice-daily, based on GI tolerability and serum phosphorus
levels. The primary endpoint will be the difference in change
of serum phosphate levels between the tenapanor and placebo treated
groups from randomization to the end of the 4-week treatment
period. Results from the AMPLIFY clinical trial are currently
expected in the second half of 2019. If the company's AMPLIFY trial
is successful, tenapanor would, if approved, be the first and only
phosphate lowering therapy to be indicated as adjunctive therapy
for use in combination with binders.
About Hyperphosphatemia
Hyperphosphatemia is a condition resulting in an abnormally
elevated level of phosphorus in the blood that is estimated to
affect more than 745,000 people in major developed countries.
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 Tenapanor
Tenapanor is a minimally absorbed inhibitor of intestinal
sodium/hydrogen exchanger 3 (NHE3) that is being evaluated to
reduce phosphate absorption and lower elevated serum phosphate
concentrations in patients with ESRD on dialysis. A recent
discovery by Ardelyx scientists, in collaboration with global
academic experts, revealed phosphate absorption in humans
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. The effect of tenapanor on phosphate
absorption is mediated by transiently increasing the intracellular
proton concentration in cells lining the gastrointestinal lumen, a
result of NHE3 inhibition, which induces a conformational change in
tight junction proteins, thereby decreasing permeability to
paracellular phosphate transport. Notably, in clinical
trials, tenapanor has not affected the absorption of other ions
(except sodium) or nutrients. A consequence of intestinal NHE3
inhibition is that systemic sodium absorption is reduced leading to
an increase in stool sodium and water content, loosening stool
consistency and increasing bowel movement frequency.
Ardelyx, Inc.
Ardelyx is focused on enhancing the way people with cardiorenal
diseases are treated by developing first-in-class medicines.
Ardelyx's cardiorenal pipeline includes the Phase 3 development of
tenapanor for the treatment of hyperphosphatemia in people with
end-stage renal disease (ESRD) 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 (IBS-C) and submitted a new drug
application, or NDA, to the U.S. Food and Drug Administration, or
FDA, for the treatment of patients with IBS-C which has been
granted a target action date under the Prescription Drug User Fee
Act (PDUFA) of September 12, 2019. 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.
1 KDIGO CKD-MBD Guidelines 2017.
https://kdigo.org/wp-content/uploads/2017/02/2017-KDIGO-CKD-MBD-GL-Update.pdf
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; the potential for
Ardelyx's product candidates to receive approval from the FDA for
marketing for the indications for which they are currently being
developed; Ardelyx's current expectations regarding the timing of
receipt of results from its ongoing Phase 3 clinical trial
evaluating tenapanor for the treatment of hyperphosphatemia in ESRD
patients on dialysis; and Ardelyx's current expectations regarding
the timing of receipt of results from its ongoing Phase 3 clinical
trial evaluating tenapanor in combination with phosphate binders
for the treatment of hyperphosphatemia in ESRD patients 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
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 November 7,
2018, and its future current and periodic reports to be
filed with the Securities and Exchange Commission.
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