JYNARQUE was shown to slow the rate of decline in renal function in patients at risk of rapidly progressing ADPKD in two trials; TEMPO 3:4 in patients at earlier stages of disease and REPRISE in patients at later stages. The findings from these trials, when taken together, suggest that JYNARQUE slows the loss of renal function progressively through the course of the disease.

TEMPO 3:4-NCT00428948: A Phase 3, Double-Blind, Placebo-Controlled, Randomized Trial in Early, Rapidly-Progressing ADPKD

In TEMPO 3:4, 1445 adult patients (age >18 years) with early (estimated creatinine clearance [eCrCl] ≥60 mL/min), rapidly-progressing (total kidney volume [TKV] ≥750 mL and age <51 years) ADPKD (diagnosed by modified Ravine criteria) were randomized 2:1 to treatment with tolvaptan or placebo. Patients were treated for up to 3 years; patients who discontinued medication prematurely were only required to attend clinic visits to assess renal function for up to 42 days after treatment withdrawal and to attend telephone visits at all scheduled visits for up to 36 months. Patients who completed treatment at the 3-year visit had treatment interrupted for 2 to 6 weeks to assess renal function post treatment. Patients received treatment twice a day (first dose on waking, second dose approximately 9 hours later). Patients were initiated on 45 mg/15 mg, and up-titrated weekly to 60 mg/30 mg and then to 90 mg/30 mg as tolerated. Patients were to maintain the highest tolerated dose for 3 years, but could interrupt, decrease and/or increase as clinical circumstances warranted within the range of titrated doses. All patients were encouraged to drink adequate water to avoid thirst or dehydration and before bedtime.

The primary endpoint was the intergroup difference for rate of change of TKV normalized as a percentage. 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).

At baseline, average estimated glomerular filtration rate (eGFR) was 82 mL/min/1.73 m2 (CKD-Epidemiology formula) and mean TKV was 1692 mL (height adjusted 972 mL/m). Approximately 35% had an eGFR of 90 mL/min/1.73 m2 or greater, 48% had an eGFR between 60 to 89 mL/min/1.73 m2, 14% had an eGFR of 45 to 60 mL/min/1.73 m2, and 3% had an eGFR of <45 mL/min/1.73 m2. The subjects' mean age was 39 years, 48% were female, 84% were Caucasian, 13% were Asian, and 1.7% were Black or African-American. Approximately 80% had hypertension and approximately 71% were taking an agent that acts on the renin-angiotensin system. Of the 770 subjects who submitted to genetic analysis in TEMPO 3:4's open-label extension, 749 (97%) had an identifiable mutation in the PKD1 (656 or 88%), or PKD2 (93 or 12%) gene.

The trial met its prespecified 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 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.

The third endpoint (kidney function slope) was assessed as slope of eGFR during treatment (from end of titration to last on-drug visit). The estimated difference in the annual rate of change in those who contributed to the analysis was 1.0 mL/min/1.73m2/year with a 95% confidence interval of (0.6, 1.4). 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. 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 efficacy profile was generally consistent across subgroups of interest for this indication; few Black or African-American patients were enrolled in the trial.

REPRISE-NCT02160145: A Phase 3, Double-Blind, Placebo-Controlled, Randomized Withdrawal Trial in Later-Stage ADPKD

REPRISE was a double-blind, placebo-controlled randomized withdrawal trial in adult patients (age 18 to 65 years) with chronic kidney disease (CKD) with an eGFR between 25 and 65 mL/min/1.73m2 if younger than age 56 years; or eGFR between 25 and 44 mL/min/1.73m2, plus eGFR decline >2.0 mL/min/1.73m2/year if between age 56 to 65 years. Subjects were to be treated for 12 months; after completion of treatment, patients entered a 3-week follow-up period to assess renal function. The primary endpoint was the treatment difference in the change of eGFR from pre-treatment baseline to post-treatment follow-up, annualized by dividing by each subject's treatment duration.

Prior to randomization, patients were required to complete sequential single-blind run-in periods during which they received placebo for 1 week, followed by tolvaptan titration for 2 weeks, and then treatment with tolvaptan at the highest tolerated dose achieved during titration for 3 weeks. During the titration period, tolvaptan was up-titrated every 3 to 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. Only patients who could tolerate the two highest doses of tolvaptan (60 mg/30 mg or 90 mg/30 mg) for the subsequent 3 weeks were randomized 1:1 to treatment with tolvaptan or placebo.

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. All patients were encouraged to start drinking an adequate amount of water at screening and continuing through the end of the trial to avoid thirst or dehydration.

A total of 1519 subjects were enrolled in the study. Of these, 1370 subjects successfully completed the pre-randomization period and were randomized and treated during the 12-month double-blind period. Because 57 subjects did not complete the off-treatment follow-up period, 1313 subjects were included in the primary efficacy analysis.

For subjects randomized, the baseline, average estimated glomerular filtration rate (eGFR) was 41 mL/min/1.73 m2 (CKD-Epidemiology formula) and historical TKV, available in 318 (23%) of subjects, averaged 2026 mL. Approximately 5%, 75% and 20% had an eGFR 60 mL/min/1.73 m2 or greater, between 30 to 59 mL/min/1.73 m2, and between 25 and 29 mL/min/1.73 m2, respectively. The subjects' mean age was 47 years, 50% were female, 92% were Caucasian, 4% Black or African-American and 3% were Asian, 93% had hypertension, and 87% of subjects were taking antihypertensive agents affecting the angiotensin converting enzyme or receptor. Of the 115 (8%) of subjects who had prior genetic tests, only 54 (47%) knew their results with 48 (89%) of these having PKD1 and 6 (11%) having PKD2 mutations.

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). The key secondary endpoint (eGFR slope in ml/min/1.73 m2/year assessed using a linear mixed effect model of annualized eGFR (CKD-EPI)) showed a difference between treatment groups of 1.0 ml/min/ m2/year that was also statistically significant (p <0.0001).

The efficacy profile was generally consistent across subgroups of interest for this indication; few Black or African-American patients were enrolled in the trial.