FDA Approves ADPKD Treatment: JYNARQUE™ (tolvaptan), Avella Pharmacy Selected to Distribute JYNARQUE™

PKD Treatment

From PKD Foundation

BREAKING NEWS: FDA Approves First Treatment for ADPKD

Today is a historic day in providing hope to patients with polycystic kidney disease! We are excited to announce that the U.S. Food and Drug Administration (FDA) granted approval of JYNARQUE™ (tolvaptan) to be the first treatment in the United States for adult patients with autosomal dominant polycystic kidney disease (ADPKD).

For the past 35 years, the PKD Foundation’s goal has been to support PKD patients and families from care to cure. We are proud to not only have supported early studies that led to the development of JYNARQUE™ as a treatment, but also helped guide PKD patients to the JYNARQUE™ clinical trials. It is gratifying to play a part in the discovery of this treatment and to see it come to fruition.

Many thanks to the patients who graciously took the time and resources to participate in the clinical trials to bring JYNARQUE™ to the PKD community.This treatment would not exist without these patients.

To read our full press release and sign up for JYNARQUE™ updates, please visit pkdcure.org/jynarque. We are also hosting a special webinar about the new treatment with Ron Perrone, M.D., next Monday, April 30. To register, please click here.

We hope that this is just the beginning of new treatments on the horizon. Our work to provide access to future studies and to new treatments is more energized than ever.

And, as always, we will continue to stand right beside you, until there is a cure.

Sincerely,



Andy Betts
CEO




From Business Wire

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)

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) 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).

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.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 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.12Visit 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

From PR NewsWire

Avella Selected by Otsuka to distribute JYNARQUE


Avella announced that it has been selected by Otsuka America Pharmaceutical, Inc. (Otsuka) to distribute JYNARQUE™ (tolvaptan), the very first FDA-approved therapy for patients diagnosed with autosomal dominant polycystic kidney disease (ADPKD). Avella is one of just three pharmacies providing access to the medication.

ADPKD is one of the most common, life-threatening genetic diseases, diagnosed in 140,000 Americans. In patients with this condition, fluid-filled cysts develop and enlarge in both kidneys and eventually leading to kidney failure. ADPKD is the fourth leading cause of kidney failure and more than 50 percent of people with this condition will develop kidney failure by age 57.

JYNARQUE is a selective vasopressin V2-receptor antagonist. This means it blocks vasopressin, an anti-diuretic hormone secreted by the pituitary gland, which plays a key role in the fluid balance of the kidneys. By blocking this hormone, the drug can decrease cyst-cell proliferation and fluid secretion, which ultimately can reduce cyst growth. JYNARQUE was shown to reduce the rate of kidney function decline by 35 percent over a 12-month period when compared to a placebo, in patients with ADPKD.

"Avella is proud to be among a very select group of pharmacies extending access to this important therapy, the first of its kind available to treat this condition," said Leslie Yendro, Director of Business Development for Avella. "Since ADPKD can be a painful and debilitating disease for patients, it is exciting to see a new medication is finally available to help support these individuals."