The FDA has approved tolvaptan (Jynarque, Otsuka Pharmaceutical Co., Ltd.) as the first drug treatment to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD).
ADPKD is a genetic disease with consequences that can lead to dialysis or kidney transplantation. It is a progressively debilitating and often painful disorder in which fluid-filled cysts develop in the kidneys over time. These cysts enlarge the kidneys and impair their ability to function normally, leading to kidney failure in most patients. ADPKD is diagnosed in approximately 140,000 people in the U.S., and impacts families across multiple generations because a parent with ADPKD has a 50% chance of passing the disease on to each of their children.
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 estimated glomerular filtration rate (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 per year with tolvaptan compared with −3.6 mL/min/1.73 m2 per year with placebo, corresponding to a treatment effect of 1.3 mL/min/1.73 m2 per year (P < 0.0001).
In the three-year TEMPO 3:4 study, tolvaptan reduced the rate of decline in eGFR by 1.0 mL/min/1.73m2 per year (95% confidence interval, 0.6–1.4) compared with 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 two years of tolvaptan 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 prespecified primary endpoint of three-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 2 and 3. In years 4 and 5 during the TEMPO 3:4 extension trial, both groups received tolvaptan, 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 (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, radiological or surgical interventions); 3) worsening hypertension (defined as a persistent increase in blood pressure category or an increased antihypertensive prescription); 4) worsening albuminuria (defined as a persistent increase in albumin/creatinine ratio category). The relative rate of ADPKD-related events was decreased by 13.5% in tolvaptan-treated patients, (44 versus 50 events per 100 person-years; hazard ratio, 0.87; 95% CI, 0.78–0.97; P = 0.0095). 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 radiological or surgical intervention for kidney pain. Most kidney pain events reflected use of a medication to treat pain, such as paracetamol, tricyclic antidepressants, narcotics, and other non-narcotic agents.
Tolvaptan will be sold in a 28-day treatment pack at a wholesale acquisition cost of $13,041.10, according to Otsuka.
Source: Otsuka Pharmaceutical Co., Ltd.; April 24, 2018.