- REPRISE trial presented as a late
breaking abstract at American Society of Nephrology (ASN) Kidney
Week 2017
- Tolvaptan reduced the rate of decline
of kidney function by 35 percent over a 12-month period, compared
to placebo, in patients with ADPKD
- ADPKD, the most common type of
polycystic kidney disease, is a progressive disease leading to
kidney failure, diagnosed in 100,000 to 150,000 people in the
U.S.1
Otsuka Pharmaceutical Co., Ltd. (Otsuka) today announced
detailed results from the Phase 3 REPRISE trial of tolvaptan, which
is under investigation in the United States in patients with
autosomal dominant polycystic kidney disease (ADPKD).
According to trial results, tolvaptan showed greater reduction
on the primary endpoint, the rate of change in estimated glomerular
filtration rate (eGFR) compared to placebo. Estimated GFR, the
primary endpoint of the trial, is a key measure of kidney function.
Change in estimated eGFR from pre-treatment baseline to
post-treatment follow-up, adjusted by the duration of the trial for
each patient and expressed per year was -2.34 mL/min/1.73 m2-year
with tolvaptan versus -3.61 mL/min/1.73 m2-year with placebo,
representing a 35% reduction of 1.27 mL/min/1.73 m2-year (95% CI
0.86 to 1.68; P<0.001). These data were presented today as a
late breaking oral abstract at the American Society of Nephrology
(ASN) 2017 Kidney Week in New Orleans,2 and were simultaneously
published online in the New England Journal of Medicine (available
online at NEJM.org).
Polycystic kidney disease (PKD) is a progressive genetic
disorder affecting the kidneys, in which fluid-filled cysts develop
in the kidneys over time, enlarging these organs and inhibiting
their ability to function normally, leading to kidney failure in
most patients.3 Autosomal dominant PKD, known as ADPKD, is the most
common type,3 and is the fourth leading cause of kidney failure.4
By age 57, more than half of people with ADPKD will need dialysis
or a kidney transplant.5
Vicente Torres, MD, PhD, Director of the Mayo Clinic
Translational Polycystic Kidney Disease Center, and lead
investigator on the REPRISE trial, commented, “Tolvaptan slowed the
rate of kidney function decline in this trial. These data represent
a significant milestone in the investigation of this condition, for
which there are currently no approved treatments in the U.S.”
“It is gratifying to see the significance of findings from the
REPRISE trial, which further support the utility of tolvaptan in
patients with ADPKD,” said Robert McQuade, Ph.D., Executive Vice
President and Chief Strategic Officer, Otsuka Pharmaceutical
Development & Commercialization, Inc. “These robust findings
provide evidence that tolvaptan, if approved in the U.S., may be an
important new treatment option with the potential to help patients
with this debilitating disease, and we look forward to discussing
these data with regulatory agencies.”
Along with results from previous pivotal studies, findings from
the REPRISE trial have formed the basis of a response to the
Complete Response Letter (CRL) that FDA issued in August 2013,
which Otsuka has submitted to the U.S. Food and Drug Administration
(FDA) for tolvaptan as a treatment for patients with ADPKD.
Otsuka Pharmaceutical will host a telebriefing for investor and
media on the REPRISE clinical trial results on November 4th at 7:00
pm U.S. Central Standard time. To register, please visit
http://event.on24.com/wcc/r/1534382-1/77E66445B009CE3491DBB035504DCF69.
About the Phase 3 REPRISE Trial
REPRISE was a Phase 3, multi-center, randomized withdrawal,
placebo-controlled, double-blind trial in adult patients with
late-stage 2 to early-stage 4 chronic kidney disease due to ADPKD.
After an 8-week pre-randomization period including sequential
placebo and tolvaptan treatments, 1,370 ADPKD patients were
randomized 1:1 to tolvaptan (90 or 120 mg per day) or placebo and
treated for 12 months. The primary endpoint measured change in
estimated GFR from pre-treatment baseline to post-treatment
follow-up adjusted by the duration of the trial for each patient.
The key secondary endpoint was the estimated GFR slope derived from
the individual slopes in each patient adjusted for the duration of
the observations and expressed per year. This analysis used all
serum creatinine values from placebo run-in, tolvaptan run-in (not
including tolvaptan titration), 12-month double-blind treatment,
and posttreatment follow-up measurements. In the trial, tolvaptan
patients had a significantly smaller decline, of
3.16mL/min/1.73m2/year compared with 4.17 mL/min/1.73m2/year for
placebo treated patients (p<0.0001).
Key safety findings (collected monthly) were generally
consistent with previous pivotal data with the majority of events
across the study. Following randomization, patients who received
tolvaptan experienced more frequent polyuria, nocturia, thirst,
polydipsia, dry mouth, fatigue and diarrhea, whereas those who
received placebo experienced more frequent peripheral edema, renal
pain, and urinary tract infection; most treatment-emergent adverse
events (TEAEs) were mild or moderate in severity. In the
double-blind treatment period, 5.6 percent of patients taking
tolvaptan had significantly abnormal liver blood tests (greater
than 3 times the upper limit of normal), compared with 1.2 percent
of those taking placebo. Transaminase elevations were reversible
after stopping tolvaptan and no patients showed concomitant
bilirubin elevations greater than 2 times the upper limit of
normal. In the study, risk minimization measures consisting of
monthly monitoring of liver parameters helped minimize the risk of
serious liver toxicity.
Otsuka collaborated on the development of the protocol for this
clinical trial with the FDA through the special protocol assessment
process in order to address a CRL issued by the agency for a New
Drug Application (NDA) for tolvaptan in ADPKD in 2013. In the
coming weeks the FDA will acknowledge whether the company’s
response is complete and whether their regulatory review can
proceed.
About Tolvaptan
Tolvaptan is a selective vasopressin V2-receptor antagonist. By
selectively blocking vasopressin at the V2-receptor, tolvaptan has
been shown in preclinical trials to decrease cyst-cell
proliferation and fluid secretion, ultimately reducing cyst
growth.6 In a prior Phase 3 trial, tolvaptan demonstrated a
reduction in kidney growth and a slower decline in kidney function
compared with placebo.7
Tolvaptan is approved for the treatment of adult patients with
ADPKD in Japan, the EU, Canada, South Korea, Switzerland, Hong Kong
and Australia (see local prescribing information for specific
indications in each country).
About Otsuka
Otsuka Pharmaceutical Company is a global healthcare company
with the corporate philosophy: “Otsuka-people creating new products
for better health worldwide.” Otsuka researches, develops,
manufactures and markets innovative products, with a focus on
pharmaceutical products to meet unmet medical needs and
nutraceutical products for the maintenance of everyday health.
In pharmaceuticals, Otsuka is a leader in the challenging area
of mental health and also has research programs on several
under-addressed diseases including tuberculosis, a significant
global public health issue. These commitments illustrate how Otsuka
is a “big venture” company at heart, applying a youthful spirit of
creativity in everything it does.
Otsuka Pharmaceutical Company is a subsidiary of Otsuka Holdings
Co., Ltd. headquartered in Tokyo, Japan. The Otsuka group of
companies employed 45,000 people worldwide and had consolidated
sales of approximately USD 11 billion (€ 9.9 billion) in 2016.
All Otsuka stories start by taking the road less travelled.
Learn more about Otsuka Pharmaceutical Company on its global
website at https://www.otsuka.co.jp/en. Learn more about Otsuka in
the U.S. at www.otsuka-us.com and connect with us on Twitter at
@OtsukaUS.
_________________
1 Descriptive Epidemiology of ADPKD in the United States: Final
Study Report. National Ambulatory Medical Care Survey (NAMCS),
Centers for Disease Control National Center for Health Statistics.
2012-2014.2 Torres V et al. Tolvaptan Slows eGFR Decline in
Later-Stage ADPKD. Abstract # SA-OR121. Presented on Saturday,
November 4, at the American Society of Nephrology (ASN) Kidney Week
2017.3 Polycystic Kidney Disease. Department of Health and Human
Services. Accessed online at
https://ghr.nlm.nih.gov/condition/polycystic-kidney-disease on
October 31, 20174 Chebib F, Torres V et al. Autosomal Dominant
Polycystic Kidney Disease: Core Curriculum 2016. Am J Kidney Dis.
May 2016; 67(5): 792-810.5 Autosomal Dominant Polycystic Kidney
Disease Fact Sheet. NIH Reports. Accessed online at
https://report.nih.gov/NIHfactsheets/ViewFactSheet.aspx?csid=29 on
October 31, 2017.6 Reif, GA, Yamaguchi, T et al. Tolvaptan inhibits
ERK-dependent cell proliferation, Cl – secretion, and in vitro cyst
growth of human ADPKD cells stimulated by vasopressin. Am J Physiol
Renal Physiol; 2011; 301:F1005-F10137 Torres V, Chapman A et al.
Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney
Disease. N Engl J Med; 2012; 367:2407-2418.
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(In Japan)Otsuka Pharmaceutical Co., Ltd.Jeffrey Gilbert,
81-3-6361-7379Leader, Pharmaceutical Public
RelationsGilbert.jeffrey@otsuka.jpor(In the U.S.)Otsuka America
Pharmaceutical, Inc.Melanie Deck, +1-609-535-9032Corporate
Communicationsmelanie.deck-cw@otsuka-us.com