FDA approves Jynarque for autosomal dominant polycystic kidney disease.-Otsuka.

Otsuka has announced that the 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. In the three-year TEMPO 3:4 study, tolvaptan reduced the rate of decline in eGFR by 1.0 mL /min /1.73m2 /year 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.

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. 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; 2) medically significant kidney pain; 3) worsening hypertension; 4) worsening albuminuria. The relative rate of ADPKD-related events was decreased by 13.5% in tolvaptan-treated patients, (44 vs. 50 events per 100 person-years). 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.

Comment: In November 2017, the FDA accepted Otsuka�s resubmission to support a regulatory review of Otsuka�s New Drug Application for tolvaptan in the treatment of adults with Autosomal Dominant Polycystic Kidney Disease.