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Otsuka's JYNARQUE™ (tolvaptan) Approved by U.S. FDA as the First Treatment to Slow Kidney Function Decline in Adults at Risk of Rapidly Progressing Autosomal Dominant Polycystic Kidney Disease (ADPKD)

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  • ADPKD, the fourth leading cause of end-stage renal disease,1,2
    is a progressively debilitating genetic disease characterized by the
    development of fluid-filled cysts in the kidneys3
  • Data from two phase 3 clinical trials showed that JYNARQUE™
    (tolvaptan) slowed kidney function decline in adults at risk of
    rapidly progressing ADPKD
  • JYNARQUE can cause serious and potentially fatal liver injury. Due to
    elevations of liver enzymes in the blood associated with JYNARQUE,
    this medication will be available only through a restricted
    distribution program and patients will need to be monitored for
    elevations in these enzyme levels. Please see IMPORTANT SAFETY
    INFORMATION below for more detailed risk information

Otsuka
Pharmaceutical Co., Ltd.
(Otsuka) announces that the U.S. Food and
Drug Administration (FDA) has approved JYNARQUE (tolvaptan)
as the first drug treatment to slow kidney function decline in adults at
risk of rapidly progressing autosomal dominant polycystic kidney disease
(ADPKD).

This press release features multimedia. View the full release here:
https://www.businesswire.com/news/home/20180424006422/en/

ADPKD Infographic (Graphic: Business Wire)

ADPKD Infographic (Graphic: Business Wire)

ADPKD is a genetic disease with consequences that can lead to dialysis
or kidney transplantation. It is a progressively debilitating and often
painful disorder in which fluid-filled cysts develop in the kidneys over
time. These cysts enlarge the kidneys and impair their ability to
function normally, leading to kidney failure in most patients.3
ADPKD is diagnosed in approximately 140,000 people in the U.S.,4,5
and impacts families across multiple generations, since a parent with
ADPKD has a 50 percent chance of passing the disease on to each of their
children.6,7

The efficacy of tolvaptan was demonstrated in two pivotal trials,
lasting one year and three years, respectively. In the one-year REPRISE
study, the primary endpoint was the treatment difference in the change
of eGFR from pretreatment baseline to post-treatment follow-up,
annualized by dividing by each subject's treatment duration. In the
randomized period, the change of eGFR from pretreatment baseline to
post-treatment follow-up was −2.3 mL/min/1.73 m2/year
with tolvaptan as compared with −3.6 mL/min/1.73 m2/year
with placebo, corresponding to a treatment effect of 1.3 mL/min/1.73 m2/year
(p <0.0001). In the three-year TEMPO 3:4 study, tolvaptan reduced the
rate of decline in eGFR by 1.0 mL /min /1.73m2 /year (95
% confidence interval of 0.6 to 1.4) as compared to placebo in patients
with earlier stages of ADPKD. In the extension trial, eGFR differences
produced by the third year of the TEMPO 3:4 trial were maintained over
the next 2 years of JYNARQUE treatment.

The primary endpoint in TEMPO 3:4 study was the intergroup difference
for rate of change of total kidney volume (TKV) normalized as a
percentage. The trial met its pre-specified primary endpoint of 3-year
change in TKV (p<0.0001). The difference in TKV between treatment groups
mostly developed within the first year, the earliest assessment, with
little further difference in years two and three. In years 4 and 5
during the TEMPO 3:4 extension trial, both groups received JYNARQUE and
the difference between the groups in TKV was not maintained. Tolvaptan
has little effect on kidney size beyond what accrues during the first
year of treatment. The key secondary composite endpoint (ADPKD
progression) was time to multiple clinical progression events of: 1)
worsening kidney function (defined as a persistent 25% reduction in
reciprocal serum creatinine during treatment (from end of titration to
last on-drug visit); 2) medically significant kidney pain (defined as
requiring prescribed leave, last-resort analgesics, narcotic and
anti-nociceptive, radiologic or surgical interventions); 3) worsening
hypertension (defined as a persistent increase in blood pressure
category or an increased anti-hypertensive prescription); 4) worsening
albuminuria (defined as a persistent increase in albumin/creatinine
ratio category). The relative rate of ADPKD-related events was decreased
by 13.5% in tolvaptan-treated patients, (44 vs. 50 events per
100 person-years; hazard ratio, 0.87; 95% CI, 0.78 to 0.97; p=0.0095).
As shown in the table below, the result of the key secondary composite
endpoint was driven by effects on worsening kidney function and kidney
pain events. In contrast, there was no effect of tolvaptan on either
progression of hypertension or albuminuria. Few subjects in either arm
required a radiologic or surgical intervention for kidney pain. Most
kidney pain events reflected use of a medication to treat pain such as
use of paracetamol, tricyclic antidepressants, narcotics and other
non-narcotic agents.

JYNARQUE can cause serious and potentially fatal liver injury, and acute
liver failure requiring liver transplantation has been reported. JYNARQUE
has been associated with elevations of blood alanine and aspartate
aminotransferases (ALT and AST), with infrequent cases of concomitant
elevations in bilirubin-total (BT). To ensure the safety of patients
taking JYNARQUE, it is necessary to measure ALT, AST and bilirubin
before initiating treatment, at 2 weeks and 4 weeks after initiation,
then monthly for 18 months and every 3 months thereafter, for as long as
the patient is on JYNARQUE (tolvaptan) treatment. Because of the risks
of serious liver injury, JYNARQUE is available only through a restricted
distribution program supported by a Risk Evaluation and Mitigation
Strategy (REMS) Program approved by the FDA. For more information about
JYNARQUE, please visit www.JYNARQUE.com.

"The progressive nature of ADPKD means that kidney function gets worse
over time, eventually leading to end-stage renal
disease. This progression happens more rapidly for some patients than
others." said Michal Mrug, M.D., Associate Professor at the University
of Alabama at Birmingham and investigator on the REPRISE trial. "Today's
approval is great news for adults at risk of rapidly progressing ADPKD
because by slowing the decline in kidney function, this therapy may give
them more time before kidney transplant or dialysis."

Andy Betts, CEO of the PKD Foundation, observed, "Today is an historic
day in providing hope to patients with autosomal dominant polycystic
kidney disease, and we are thrilled to be a part of this first milestone
in treatment. For the past 35 years, our goal has been to walk with PKD
patients every step of the way. It is gratifying to play a part in the
inception of the discovery of this treatment, and to see it come to
fruition. We hope that this is just the beginning of a new chapter for
adults at risk of rapidly progressing ADPKD who suffer from the disease."

Also, Tatsuo Higuchi, president and representative director of Otsuka
Pharmaceutical Co., Ltd., commented, "This approval is important news
for many adults at risk of rapidly progressing ADPKD in the U.S., who
have had no therapeutic alternatives to delay the eventual end-stage
interventions of dialysis or kidney transplantation. We are humbled to
be able to offer an earlier, proactive course of action to slow the
progression of this disease, which we know means so much to patients,
their families and healthcare providers. Simultaneously, we are grateful
to the patients and researchers who through their continued commitment
made this milestone possible."

About ADPKD

ADPKD is a progressively debilitating and often painful genetic disorder
in which fluid-filled cysts develop in the kidneys over time. These
cysts enlarge the kidneys and impair their ability to function normally,
leading to kidney failure in most patients. ADPKD can impact quality of
life, and is also associated with cardiovascular complications that can
cause death.3 ADPKD is diagnosed in approximately 140,000
people in the U.S.,4,5 and is the fourth leading cause of
end-stage renal disease.1,2

ADPKD impacts families across multiple generations, since a parent with
ADPKD has a 50 percent chance of passing the disease on to each of their
children.6,7 Risk factors for rapid disease progression
include having a greater TKV than expected for age,8,9 family
history of end-stage renal disease before 58 years of age,10
high blood pressure before 35 years of age,11 certain
urologic events before 35 years of age,12 a historical
decline in eGFR of ≥5 mL/min/1.73 m2 within 1 year,10
certain inherited genetic profiles,12 or male sex.12
Visit https://pkdcure.org/what-is-pkd/adpkd/
for more information about ADPKD.

About JYNARQUE (tolvaptan)

JYNARQUE is a selective vasopressin V2-receptor antagonist
indicated to slow kidney function decline in adults at risk of rapidly
progressing ADPKD. The medication has been approved as a treatment for
adults with ADPKD in Japan, the EU, Canada, South Korea, Switzerland,
Hong Kong, Australia, Turkey and Taiwan. See local prescribing
information for specific indications in each country.

The FDA approval of JYNARQUE is supported by data from the TEMPO 3:4
(Tolvaptan Efficacy and Safety in Management of Autosomal Dominant
Polycystic Kidney Disease and Its Outcomes) and REPRISE (Replicating
Evidence of Preserved Renal Function: an Investigation of Tolvaptan
Safety and Efficacy in ADPKD) clinical trials published in the New
England Journal of Medicine in November
2012
and November
2017
, respectively.

JYNARQUE will be sold in a 28-day treatment pack at a wholesale
acquisition cost of $13,041.10.

More information for U.S. Healthcare Providers can be found at www.JYNARQUEhcp.com.

INDICATION and IMPORTANT SAFETY INFORMATION for JYNARQUETM
(tolvaptan)

INDICATION:

JYNARQUE is indicated to slow kidney function decline in adults at risk
of rapidly progressing autosomal dominant polycystic kidney disease
(ADPKD).

IMPORTANT SAFETY INFORMATION:

WARNING: RISK OF SERIOUS LIVER INJURY

  • JYNARQUE (tolvaptan) can cause serious and potentially fatal liver
    injury. Acute liver failure requiring liver transplantation has been
    reported
  • Measure transaminases (ALT, AST) and bilirubin before initiating
    treatment, at 2 weeks and 4 weeks after initiation, then monthly for
    the first 18 months and every 3 months thereafter. Prompt action in
    response to laboratory abnormalities, signs, or symptoms indicative of
    hepatic injury can mitigate, but not eliminate, the risk of serious
    hepatotoxicity.
  • Because of the risks of serious liver injury, JYNARQUE is available
    only through a Risk Evaluation and Mitigation Strategy program called
    the JYNARQUE REMS Program

CONTRAINDICATIONS:

  • History, signs or symptoms of significant liver impairment or injury.
    This contraindication does not apply to uncomplicated polycystic liver
    disease
  • Taking strong CYP3A inhibitors
  • With uncorrected abnormal blood sodium concentrations
  • Unable to sense or respond to thirst
  • Hypovolemia
  • Hypersensitivity (e.g., anaphylaxis, rash) to JYNARQUE or any
    component of the product
  • Uncorrected urinary outflow obstruction
  • Anuria

Serious Liver Injury: JYNARQUE can cause serious and potentially
fatal liver injury. Acute liver failure requiring liver transplantation
has been reported in the post-marketing ADPKD experience.
Discontinuation in response to laboratory abnormalities or signs or
symptoms of liver injury (such as fatigue, anorexia, nausea, right upper
abdominal discomfort, vomiting, fever, rash, pruritus, icterus, dark
urine or jaundice) can reduce the risk of severe hepatotoxicity. To
reduce the risk of significant or irreversible liver injury, assess ALT,
AST and bilirubin prior to initiating JYNARQUE, at 2 weeks and 4 weeks
after initiation, then monthly for 18 months and every 3 months
thereafter.

Hypernatremia, Dehydration and Hypovolemia: JYNARQUE therapy
increases free water clearance which can lead to dehydration,
hypovolemia and hypernatremia. Instruct patients to drink water when
thirsty, and throughout the day and night if awake. Monitor for weight
loss, tachycardia and hypotension because they may signal dehydration.
Ensure abnormalities in sodium concentrations are corrected before
initiating therapy. If serum sodium increases above normal or the
patient becomes hypovolemic or dehydrated and fluid intake cannot be
increased, suspend JYNARQUE until serum sodium, hydration status and
volume status parameters are within the normal range.

Inhibitors of CYP3A: Concomitant use of JYNARQUE with drugs that
are moderate or strong CYP3A inhibitors (e.g., ketoconazole,
itraconazole, lopinavir/ritonavir, indinavir/ritonavir, ritonavir, and
conivaptan) increases tolvaptan exposure. Use with strong CYP3A
inhibitors is contraindicated; dose reduction of JYNARQUE is recommended
for patients taking moderate CYP3A inhibitors. Patients should avoid
grapefruit juice beverages while taking JYNARQUE.

Adverse Reactions: Most common observed adverse reactions with
JYNARQUE (incidence >10% and at least twice that for placebo) were
thirst, polyuria, nocturia, pollakiuria and polydipsia.

Other Drug Interactions:

  • Strong CYP3A Inducers: Co-administration with strong CYP3A
    inducers reduces exposure to JYNARQUE. Avoid concomitant use of
    JYNARQUE with strong CYP3A inducers
  • OATP1B1/3 and OAT3 Transporter Substrates: Caution should be
    used in patients who take JYNARQUE and OATP1B1/B3 and OAT3 substrates
    (e.g., statins, bosentan, glyburide, nateglinide, repaglinide,
    methotrexate, furosemide), as the plasma concentrations of these
    substrates may be increased.
  • BCRP Transporter Substrates: Tolvaptan is an inhibitor of BCRP.
    Patients who take JYNARQUE, should avoid concomitant use with BCRP
    substrates (e.g., rosuvastatin)
  • V2-Receptor Agonist: Tolvaptan
    interferes with the V2-agonist activity of desmopressin
    (dDAVP). Avoid concomitant use of JYNARQUE with a V2-agonist.

Pregnancy and Lactation: Based on animal data, JYNARQUE may cause
fetal harm. In general, JYNARQUE should be discontinued during
pregnancy. Advise women not to breastfeed during treatment with JYNARQUE.

To report SUSPECTED ADVERSE REACTIONS, contact Otsuka America
Pharmaceutical, Inc. at 1-800-438-9927 or FDA at 1-800-FDA-1088 (www.fda.gov/medwatch).

Please see FULL
PRESCRIBING INFORMATION
, including BOXED WARNING.

Otsuka, maker of JYNARQUE (tolvaptan), is committed to helping
patients access the medications they need.

Otsuka is committed to helping adults at risk of rapidly progressing
ADPKD and will work closely with these patients, providers and payers to
ensure JYNARQUE is broadly accessible. Otsuka offers a number of support
programs for eligible patients, including the JYNARQUE Copay Savings
program, which ensures that eligible commercially insured patients do
not pay more than $10 per prescription for JYNARQUE. Further details
about program limitations and legally required exclusions are available
at www.JYNARQUE.com/Copay-Savings.
The Otsuka Patient Assistance Foundation (OPAF), a separate and
independent entity, provides support for eligible patients who are
unable to afford their medication. OPAF's mission is to eliminate
financial barriers to drug therapies for uninsured or underinsured
patients. For more information, please visit www.otsukapatientassistance.com.

About Otsuka

Otsuka Pharmaceutical Co., Ltd. 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 R&D programs in areas including nephrology and
cardiology. 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 46,000 people worldwide and had consolidated sales of
approximately USD 11.1 billion in 2017.

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 United States Renal Data System. National Institutes of
Health, National Institute of Diabetes and Digestive and Kidney
Diseases, Bethesda, MD, 2016. Available at: https://www.usrds.org/2016/download/v2_ESRD_16.pdf
(accessed August 8, 2017).

2 Lentine, K. L. (2015). Renal Function and Healthcare Costs
in Patients with Polycystic Kidney Disease. Clinical Journal of the
American Society of Nephrology, 5, 1471-1479.

3 Chebib F, Torres V et al. Autosomal dominant polycystic
kidney disease: core curriculum 2016. Am J Kidney Dis. May 2016; 67(5):
792-810.

4 Data on file. Otsuka America Pharmaceutical, Inc., 2018

5 Willey, CJ et al. Epidemiology of Autosomal Dominant
Polycystic Kidney Disease in the United States. Poster presented at
American Society of Nephrology Kidney Week; 2013 Nov 5-10; Atlanta, GA

6 Autosomal Dominant Polycystic Kidney Disease Fact Sheet.
NIH Reports. Accessed online on March 30 2018 at https://report.nih.gov/NIHfactsheets/ViewFactSheet.aspx?csid=29&key=A#A\

7 Torres VE, Grantham JJ. Cystic diseases of the kidney. In:
Taal MW, Chertow GM, Mardsen PA, Skorecki K, Yu ASL, Brenner BM, eds. Brenner
& Rector's The Kidney.
Philadelphia, PA: Elsevier Saunders;
2012:1626-1667

8 Irazabal MV. Imaging Classification of autosomal dominant
polycystic kidney disease: a simple model for selecting patients for
clinical trials. J Am Soc Neph. 2015 vol. 26 no. 1 160-172.

9 Chapman A. et al. Kidney Volume and Functional Outcomes in
Autosomal Dominant Polycystic Kidney Disease. Clin J Am Soc Nephrol
2012; 7; 479-486.

10 Gansevoort RT. Recommendations for the use of tolvaptan in
autosomal dominant polycystic kidney disease: a position statement on
behalf of the ERA-EDTA Working Groups on Inherited Kidney Disorders and
European Renal Best Practice. Nephrology Dialysis Transplantation 2016,
Vol. 31, 337–3489

11 Schrier JASN 2010/p891/col1/1/ln1-3]

12 Cornec Le Gall E. The PROPKD score: a new algorithm to
predict renal survival in autosomal dominant polycystic kidney disease.
J Am Soc Nephrol. 2016 Mar;27(3):942-51

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