Comparative Bioavailability Studies

Double-blind, balanced, randomized, single-dose, two-treatment, two-sequence, two-period crossover oral bioequivalence study compared LUPIN-TOLVAPTAN tablets 90 mg with PrJINARC® (Tolvaptan) tablets 90 mg in healthy, adult, human male subjects.1

Summary of Comparative Bioavailability Data – Fasted study1

Comparative bioavailability data from 36 subjects that were included in the statistical analysis are presented in the following table.

† LUPIN-TOLVAPTAN tablets 90 mg per tablet.

‡ PrJinarc® 90 mg tablets, distributed by Otsuka Canada Pharmaceutical, Canada.

§ Expressed as the arithmetic mean (CV%) only.

Summary of Comparative Bioavailability Data – Fed study1

Comparative bioavailability data from 38 subjects that were included in the statistical analysis are presented in the following table.

† LUPIN-TOLVAPTAN tablets 90 mg per tablet.

‡ PrJinarc® 90 mg tablets, distributed by Otsuka Canada Pharmaceutical, Canada.

§ Expressed as the arithmetic mean (CV%) only.

Efficacy Data for Tolvaptan

The efficacy of Tolvaptan in slowing the progression of kidney enlargement (reflecting cyst growth) and kidney function decline was based on randomized, double-blind, placebo-controlled trials in early to late stage of ADPKD.1

Study Design Overview

TEMPO 3:4: a double-blind, 36-month, placebo-controlled, multi-center trial1

† Randomization was stratified based on several predictors of more rapid progression, namely baseline hypertension status, kidney volume and renal function.1

Adapted from LUPIN-TOLVAPTAN Product Monograph1

A total of 1,444 patients were treated for up to 3 years, then followed for 14-42 days after treatment withdrawal. All patients remained on concomitant medications. Patients were evaluated at screening, baseline, during weekly titration steps and at intervals of at least 4 months for outcome, laboratory and safety assessments.1

TEMPO 4:4 was an open-label extension study of TEMPO 3:4:1

  • Following completion of TEMPO 3:4, and after a washout period, most placebo-treated and Tolvaptan-treated patients were offered ongoing Tolvaptan treatment.
  • This trial evaluated the effects of Tolvaptan on safety, TKV and eGFR in subjects receiving active treatment for 5 years (early-treated), compared with subjects treated with placebo for 3 years, then switched to active treatment for 2 years (delayed-treated).

REPRISE: a double-blind, placebo-controlled, multi-center trial1

† 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 age 56-65.1

‡ Tolvaptan was initiated during the single-blind pre-randomization phase and up-titrated every 3-4 days from a daily oral dose of 30 mg/15 mg to 45 mg/15 mg, 60 mg/30 mg and up to a maximum dose of 90 mg/30 mg.1

§ A total of 1,370 patients were randomized and treated during the 12-month double-blind period. Randomization was stratified by patients’ baseline characteristics of eGFR, age, and TKV (if available).1

Patients were maintained on their highest tolerated dose for a period of 12 months but could interrupt, decrease and/or increase as clinical circumstances warranted within the range of titrated doses.1

Adapted from LUPIN-TOLVAPTAN Product Monograph1

All patients remained on concomitant medications. Patients were evaluated weekly during the pre-randomization phases and monthly during randomized treatment for efficacy and safety assessments. After completion of treatment the patients entered a 3-week follow-up period.1

Efficacy Results

TEMPO 3:4

49% reduction in TKV growth rate vs. placebo over 3 years (primary endpoint, p<0.0001)1

TKV increased in the Tolvaptan group at a rate of 2.8% per year (95% CI: 2.5-3.1%) vs. 5.5% per year (95% CI: 5.1-6.0%) for placebo.

The effect of treatment on TKV growth was greatest in the first year and included negative cyst growth for the Tolvaptan group (−1.7%), compared with positive cyst growth in the placebo group (4.6%), for a treatment effect of −6.3%, a statistically significant difference between groups (p<0.0001).1

Tolvaptan has a short-term, so-called “secretory” effect on TKV, presumably due to its aquaretic effect, leading to a diminution of renal cyst fluid, which appears largely reversible upon discontinuation of Tolvaptan.1

  • This phenomenon will thus apparently overstate the effect of Tolvaptan on renal cyst proliferation in the first year when measured by TKV.

During the second and third years, kidney enlargement progressed in both groups.1

  • Further absolute reductions in TKV growth (relative to placebo) of 1.92% per year (95% CI 2.81 to 1.03%) and 1.78% per year (95% CI 2.77 to 0.78%) were observed at Year 2 and Year 3 of therapy, respectively.

TEMPO 4:4

No difference in change (-1.7%) over 5-year treatment between early- and delayed-treated subjects at the pre-specified threshold of statistical significance (primary endpoint, p=0.3580)1

Both groups’ TKV growth trajectory was slowed, relative to placebo in the first 3 years, suggesting both early- and delayed-Tolvaptan treated subjects benefited to a similar degree.1

Early-treated subjects experienced a greater overall benefit in renal function than the delayed-treated subjects based on eGFR change over the 5-year treatment period (p=0.0003).1

REPRISE

35% slower decline in renal function with Tolvaptan compared to placebo over 12 months (primary endpoint, p<0.0001)1

Change of eGFR from pre-treatment baseline to post-treatment follow-up was -2.34 mL/min/1.73 m2/year with Tolvaptan vs. -3.61 mL/min/1.73 m2/year with placebo, with a treatment effect of 1.271 mL/min/1.73 m2/year.

ADPKD=autosomal dominant polycystic kidney disease; AUC=area under curve; CKD=chronic kidney disease; CV=coefficient of variation; eGFR=estimated glomerular filtration rate; TKV=total kidney volume.

PrJINARC® is a registered trademark of Otsuka Canada Pharmaceutical Inc.

Reference: 1. LUPIN-TOLVAPTAN DRAFT Product Monograph. Lupin Pharma Canada Ltd. January 28, 2025.