JYNARQUE® (tolvaptan) slows ADPKD progression by significantly slowing kidney function decline

REPRISE=Replicating Evidence of Preserved Renal Function: An Investigation of Tolvaptan Safety and Efficacy.

JYNARQUE significantly reduced the decline in kidney function

Change in eGFR from pretreatment baseline to posttreatment follow-up over 12 months4

Reduction in Decline of Kidney Function with JYNARQUE® (tolvaptan), Graph

REPRISE TRIAL DESIGN

REPRISE was a double-blind, placebo-controlled, randomized withdrawal trial of 1370 patients with ADPKD. The inclusion criteria were: CKD with an eGFR between 25 and 65 mL/min/1.73 m2 if younger than age 56; or eGFR between 25 and 44 mL/min/1.73 m2, plus eGFR decline >2.0 mL/min/1.73 m2/year if between ages 56-65. Subjects were to be treated for 12 months; after completion of treatment, patients entered a 3-week follow-up period to assess renal function.1,5

The primary endpoint was the treatment difference in the change of eGFR from pre-treatment baseline to post-treatment follow-up, annualized by dividing each subject’s treatment duration.4

REPRISE TRIAL DESIGN (full details) REPRISE PATIENT CHARACTERISTICS

See the full publication to learn more about the REPRISE trial.

TEMPO=Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes.

PRIMARY ENDPOINT: change in Total kidney volume

JYNARQUE slowed total kidney volume (TKV) growth

Change in TKV from baseline normalized as a percentage6

Total Kidney Volume from Baseline Normalized as a Percentage, Chart

TEMPO 3:4 Study design

TEMPO 3:4 was a double-blind, placebo-controlled, randomized trial of 1445 patients with ADPKD. The inclusion criteria were: 18 to 50 years of age; early, rapidly progressing ADPKD (diagnosed by modified Ravine criteria§); TKV ≥750 mL; creatinine clearance ≥60 mL/min. Patients were treated for up to 3 years.2

The primary endpoint was annual rate of change in the total kidney volume.2

*Percent change from baseline.

Data only included those patients who remained in the study for 3 years; effect in those who discontinued is unknown.

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.6

§Ravine criteria defined as at least 2 unilateral or bilateral kidney cysts in at-risk individuals between 15 and 30 years of age; 2 cysts in each kidney in individuals between 30 and 59 years of age; and at least 4 cysts in each kidney in individuals older than 60 years of age.7,8

TEMPO 3:4 trial design (full details) TEMPO 3:4 patient characteristics

See the full publication to learn more about the TEMPO 3:4 trial.

 

Key SECONDARY composite endpoint

JYNARQUE decreased the relative rate of ADPKD-related composite events by 13.5%II

The key secondary composite endpoint (ADPKD progression) was time to multiple clinical progression events of2:

Rate of ADPKD-Related Composite Events, TEMPO 3:4 Study
 

Secondary Endpoint: Risk of worsening kidney function

JYNARQUE significantly reduced the risk of worsening kidney function

Risk of worsening kidney function6

Reduced risk of worsening kidney function in TEMPO 3:4 Trial, Chart

JYNARQUE decreased the relative rate of ADPKD-related composite events by 13.5%

The results were driven by effects on worsening kidney function pain events.

In contrast, tolvaptan had no effect on progression of either hypertension or albuminuria.

Worsening kidney function was defined as a 25% reduction in reciprocal serum creatinine during treatment.6

See the full publication to learn more about the TEMPO 3:4 trial.

 

Secondary Endpoint: Risk of renal pain events

JYNARQUE significantly reduced the risk of renal pain events

Risk of renal pain events6

Reduced risk of renal pain events in TEMPO 3:4 Trial, Chart

JYNARQUE decreased the relative rate of ADPKD-related composite events by 13.5%

The results were driven by effects on worsening kidney function pain events.

In contrast, tolvaptan had no effect on progression of either hypertension or albuminuria.

**Requiring prescribed leave, last-resort analgesics, narcotic and antinociceptive, radiologic or surgical interventions. 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 nonnarcotic agents.6

See the full publication to learn more about the TEMPO 3:4 trial.

 

Third Endpoint: Slope of eGFR

JYNARQUE significantly reduced the rate of kidney function decline

Change in kidney function (slope of eGFR CKD-EPI)6††

Change in Kidney Function in TEMPO 3:4 Study, Graph

This endpoint was assessed as slope of eGFR during treatment (from end of titration to last on-drug visit)

  • JYNARQUE-treated patients had a 26.4% reduction in the rate of kidney function decline compared with placebo (-2.7 versus -3.7 [mL/min/1.73 m2/year], P<0.0001)2
  • Of the subjects enrolled in the trial, 5% of subjects in the tolvaptan arm and 2% in the placebo arm either had missing baseline data or discontinued from treatment prior to the end of the titration visit and hence were excluded from the analysis

††Slope of eGFR end of titration to last on-drug visit.2

See the full publication to learn more about the TEMPO 3:4 trial.

ADPKD=autosomal dominant polycystic kidney disease; CI=confidence interval; CKD=chronic kidney disease; CKD-EPI=chronic kidney disease epidemiology collaboration; eGFR=estimated glomerular filtration rate.

 

  1. Torres VE, Chapman AB, Devuyst O, et al; for the REPRISE Trial Investigators. Tolvaptan in later-stage autosomal dominant polycystic kidney disease. N Engl J Med. 2017;377(20):1930-1942.
  2. Torres VE, Chapman AB, Devuyst O, et al; for the TEMPO 3:4 Trial Investigators. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012;367(25):2407-2418.
  3. Torres VE, Meijer E, Bae KT, et al. Rationale and design of the TEMPO (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes) 3-4 study. Am J Kidney Dis. 2011;57(5):692-699.
  4. Data on file. JYN-012. Otsuka America Pharmaceutical, Inc.; Rockville, MD.
  5. Torres VE, Devuyst O, Chapman AB, et al. Rationale and design of clinical trial investigating tolvaptan safety and efficacy in autosomal dominant polycystic kidney disease. Am J Nephrol. 2017;45(3):257-266.
  6. Data on file. JYN-011 TEMPO 3:4 supplementary data points; 2018. Rockville, MD: Otsuka America Pharmaceutical, Inc.
  7. Belibi FA, Edelstein CL. Unified ultrasonographic diagnostic criteria for polycystic kidney disease. J Am Soc Nephrol. 2009;20(1):6-8.
  8. Ravine D, Gibson RN, Walker RG, Sheffield LJ, Kincaid-Smith P, Danks DM. Evaluation of ultrasonographic diagnostic criteria for autosomal dominant polycystic kidney disease 1. Lancet. 1994;343(8901):824-827.
  9. Torres VE, Chapman AB, Devuyst O, et al. Multicenter, open-label, extension trial to evaluate the long-term efficacy and safety of early versus delayed treatment with tolvaptan in autosomal dominant polycystic kidney disease: the TEMPO 4:4 Trial. Nephrol Dial Transplant. 2017;32(7):1-13.
INDICATION and IMPORTANT SAFETY INFORMATION

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

WARNING: RISK OF SERIOUS LIVER INJURY

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
  • 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.

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INDICATION and IMPORTANT SAFETY INFORMATION
INDICATION and IMPORTANT SAFETY INFORMATION

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

WARNING: RISK OF SERIOUS LIVER INJURY

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
  • 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.