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

REPRISE

REPRISE—A 12-month study of patients with CKD late stage 2 to early stage 4

Primary end point: eGFR change

PRIMARY END POINT: THE TREATMENT DIFFERENCE IN THE CHANGE OF eGFR FROM PRETREATMENT BASELINE TO POSTTREATMENT FOLLOW-UP, ANNUALIZED BY DIVIDING BY EACH SUBJECT'S TREATMENT DURATION

JYNARQUE significantly reduced the decline in kidney function2

REPRISE—A 12-month study of patients with CKD late stage 2 to early stage 4

Study design

STUDY DESIGN

  • Phase 3, double-blind, placebo-controlled withdrawal trial
  • 1370 patients randomized 1:1 to treatment with JYNARQUE or placebo
    • 18 to 55 years of age: eGFR between 25 and 65 mL/min/1.73 m2
    • 56 to 65 years of age: eGFR between 25 and 44 mL/min/1.73 m2 plus eGFR decline >2.0 mL/min/1.73 m2/year
  • Patients were up-titrated every 3 to 4 days with JYNARQUE or placebo doses studied:
    • 45 mg AM + 15 mg PM/day
    • 60 mg AM + 30 mg PM/day
    • 90 mg AM + 30 mg PM/day
  • Only patients who could tolerate the 2 highest doses of tolvaptan (60 mg/30 mg or 90 mg/30 mg) were randomized 1:1 to treatment with tolvaptan or placebo, but could interrupt, decrease and/or increase as clinical circumstances warranted
  • Primary end point: the treatment difference in the change of eGFR from pretreatment baseline to posttreatment follow-up, annualized by dividing by each subject's treatment duration

Trial phases3,4

Reprise Study, Trial Phases
Reprise Study, Trial Phases

 

 

TEMPO 3:4

TEMPO 3:4—A 3-year study of patients with CKD stages 1, 2, and 3

Primary end point: change in kidney volume

PRIMARY END POINT: DIFFERENCE IN RATE OF CHANGE IN TOTAL KIDNEY VOLUME NORMALIZED AS A PERCENTAGE

JYNARQUE slowed total kidney volume (TKV) growth

DIFFERENCE IN RATE OF CHANGE IN TOTAL KIDNEY VOLUME NORMALIZED AS A PERCENTAGE
DIFFERENCE IN RATE OF CHANGE IN TOTAL KIDNEY VOLUME NORMALIZED AS A PERCENTAGE

TEMPO 3:4—A 3-year study of patients with CKD stages 1, 2, and 3

Key secondary composite end point

KEY SECONDARY COMPOSITE END POINT

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

The key secondary composite end point (ADPKD progression) was time to multiple clinical progression events of:

 

 

 

Composite events
Composite events

The effect on the composite end point was driven by:

  • 61.4% reduction in the risk of an event of worsening kidney function (2 events per 100 person-years of follow-up in the tolvaptan group versus 5 in the placebo group; HR, 0.39; 95% CI, 0.26 to 0.57; P<0.001)6
  • 35.8% reduction in the risk of an event of worsening pain (5 events per 100 person-years of follow-up in the tolvaptan group versus 7 in the placebo group; HR, 0.64; 95% CI, 0.47 to 0.89; P=0.007)6

In contrast, there was no effect of JYNARQUE on either progression of hypertension or albuminuria.

 

 

§

44 versus 50 events per 100 person-years of follow-up. HR, 0.87; 95% CI, 0.78 to 0.97; P=0.0095.

TEMPO 3:4—A 3-year study of patients with CKD stages 1, 2, and 3

Risk of worsening kidney function

SECONDARY COMPOSITE END POINT COMPONENT: WORSENING KIDNEY FUNCTION

JYNARQUE significantly reduced the risk of worsening kidney function6||

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

The results were 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.

TEMPO 3:4—A 3-year study of patients with CKD stages 1, 2, and 3

Risk of renal pain events

SECONDARY COMPOSITE END POINT COMPONENT: RENAL PAIN EVENTS

JYNARQUE significantly reduced the risk of renal pain events6

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

The results were 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.

TEMPO 3:4—A 3-year study of patients with CKD stages 1, 2, and 3

Slope of eGFR

THIRD END POINT: SLOPE OF eGFR

JYNARQUE significantly reduced the rate of kidney function decline6

This end point 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)6
  • 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.

TEMPO 3:4—A 3-year study of patients with CKD stages 1, 2, and 3

Study design

STUDY DESIGN

  • Phase 3, double-blind, placebo-controlled trial
  • 1445 patients randomized 2:1 to treatment with JYNARQUE or placebo
    • 18 to 50 years of age
    • Early, rapidly progressing ADPKD (meeting modified Ravine criteria**)
    • TKV 750 mL
    • Creatinine clearance 60 mL/min
  • Patients were up-titrated weekly with JYNARQUE or placebo doses studied:
    • 45 mg AM + 15 mg PM/day
    • 60 mg AM + 30 mg PM/day
    • 90 mg AM + 30 mg PM/day
  • Patients were to maintain the highest tolerated dose for 3 years
  • Primary end point: difference for rate of change of TKV normalized as a percentage
  • An extension trial, TEMPO 4:4, was designed to provide an additional 2 years of data on the long-term safety and efficacy of tolvaptan in subjects completing TEMPO 3:4.7

 

 

Trial phases5,8

Tempo Study, Trial Phases
Tempo Study, Trial Phases

 

**

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.9,10

 

ADPKD
=autosomal dominant polycystic kidney disease.
CKD
=chronic kidney disease.
CKD-EPI
=Chronic Kidney Disease Epidemiology Collaboration.
eGFR
=estimated glomerular filtration rate.
IMPORTANT SAFETY INFORMATION and INDICATION for JYNARQUE (tolvaptan)

IMPORTANT SAFETY INFORMATION:

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
  • OATP1B1/3 and OAT3 Transporter Substrates: Patients who take JYNARQUE should avoid concomitant use with 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).

INDICATION:

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

Please see FULL PRESCRIBING INFORMATION, including BOXED WARNING.

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IMPORTANT SAFETY INFORMATION and INDICATION for JYNARQUE (tolvaptan)
IMPORTANT SAFETY INFORMATION and INDICATION for JYNARQUE (tolvaptan)

IMPORTANT SAFETY INFORMATION:

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
  • OATP1B1/3 and OAT3 Transporter Substrates: Patients who take JYNARQUE should avoid concomitant use with 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).

INDICATION:

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

Please see FULL PRESCRIBING INFORMATION, including BOXED WARNING.