TOKYO--(BUSINESS WIRE)--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).

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 V 2 -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

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.

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)

Tolvaptan is an inhibitor of BCRP. Patients who take JYNARQUE, should avoid concomitant use with BCRP substrates (e.g., rosuvastatin) V 2 -Receptor Agonist: Tolvaptan interferes with the V 2 -agonist activity of desmopressin (dDAVP). Avoid concomitant use of JYNARQUE with a V 2 -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