Long-Term Safety of Tolvaptan in ADPKD

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inheritable kidney disorder, with a prevalence of one in 1000 individuals (1). Approximately 50% of patients with ADPKD progress to ESKD by the age of 60. Prior to the approval of tolvaptan, management of ADPKD was limited to BP control, treatment of cyst complications (infection, hemorrhage, and rupture), pain control, and lifestyle modifications such as salt restriction and high fluid intake.

In 2009, the vasopressin V2-receptor antagonist tolvaptan (marketed as Samsca for this indication) was approved by the US Food and Drug Administration (FDA) for use in patients with euvolemic or hypervolemic hyponatremia. No severe liver toxicity was reported in this non-ADPKD population, despite no limitation on the initial duration of drug dosing (2).

With evidence that vasopressin antagonism could inhibit cystogenesis and kidney growth in animal models of ADPKD (1), tolvaptan soon moved into clinical trials in ADPKD. In the landmark Tolvaptan Efficacy and Safety in Management of ADPKD and Its Outcomes (TEMPO) 3:4 trial (3), tolvaptan treatment decreased kidney growth by about 50% (primarily in the first year of treatment) and slowed the rate of decline in kidney function by about 1 ml/min per year. Treated patients had fewer pain events but more treatment-related, aquaretic adverse events, commonly thirst and polyuria.

In addition, about 5% of patients treated with tolvaptan developed liver function test (LFT) abnormalities, and two patients met Hy's law criteria. Hy's law assesses risk of severe drug-induced liver injury, identifying patients who demonstrate hepatocellular injury in the absence of an obstructive component (alanine aminotransferase [ALT] or aspartate aminotransferase [AST] more than three times normal, total bilirubin more than two times normal, and normal alkaline phosphatase). Crossing the Hy's law threshold is associated with >10% risk of death or need for liver transplantation. One additional patient from the placebo arm of Tempo 3:4 met Hy’s law criteria 3 months after initiation of tolvaptan in the Tempo 4:4 (4) trial. In response, the Independent Data Monitoring Committee for TEMPO 4:4 recommended increasing LFT surveillance to every 3 months and then monthly in patients with <18 months of tolvaptan treatment and every 3 months thereafter.

Partly because of these concerns, the FDA did not approve tolvaptan for use in ADPKD on the basis of TEMPO 3:4, despite its approval in other countries, including those of the European Union, Japan, and Canada. The FDA also added an additional warning limiting use of Samsca to ≤30 days and prohibiting its use in patients with cirrhosis.

The Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD (REPRISE) study (5) was designed to further address concerns regarding tolvaptan safety, tolerability, and efficacy in patients with later-stage ADPKD. All patients were given tolvaptan during the single-blind tolvaptan titration period (2 weeks). Subjects who were able to tolerate the 60/30 mg dosing were moved to the tolvaptan run-in period (3 weeks). Patients were then randomized to tolvaptan or placebo for an additional year. LFT monitoring was done monthly. In REPRISE, 5.6% of subjects developed LFT abnormalities, although none met Hy's law criteria. REPRISE also provided data supporting use of tolvaptan in patients up to age 55 and with an eGFR as low as 25 ml/min per 1.73 m².

The FDA approved tolvaptan for use in patients with ADPKD at risk of rapid disease progression in 2018. For this indication, tolvaptan was marketed as Jynarque, with a product label that mandated use of a Risk Evaluation and Mitigation Strategy (REMS) to monitor transaminases and bilirubin at 2 and 4 weeks after initiation, monthly for 18 months, and then every 3 months thereafter (6).

In this issue of CJASN, Torres et al. (7) provide clinical trial evidence that the REMS protocol captures early signs of liver damage and helps avoid liver toxicity in patients with ADPKD taking tolvaptan. Most patients (all but nine) in this trial had successfully completed REPRISE or TEMPO 3:4 and 4:4. Patients who completed TEMPO 4:4 had the longest prior tolvaptan exposure, with the majority having >24 months of exposure, whereas patients from the REPRISE tolvaptan arm had >13 months of exposure and those in the REPRISE placebo arm had 5 weeks of exposure. The trial captured safety data over a median tolvaptan exposure of 651 days, including data on patients who had been on tolvaptan for up to 11 years. LFTs were checked monthly for all subjects for the first 18 months of tolvaptan exposure, followed by liver function testing every 3 months thereafter.

Hepatic enzyme elevations were noted as follows: 51 patients (2.8%) had ALT abnormalities, ten patients (0.6%) had AST abnormalities, and 19 patients (1.1%) had gamma-glutamyl transferase abnormalities. Of these patients, eight patients with ALT abnormalities and two patients with AST abnormalities permanently discontinued tolvaptan therapy.

Thirty percent of participants were on statins throughout the study period, with no increase in liver toxicity, replicating findings from a post hoc analysis of TEMPO 3:4 and REPRISE (8). There were no Hy's law cases.

A strength of this study was the use of a blinded, independent Hepatic Adjudication Committee (HAC) to review liver function abnormalities and determine probable cause. The HAC adjudicated 53 cases of liver enzyme elevations and classified two as having “probable” association with tolvaptan, 24 as having “possible” association, 23 cases as being “unlikely” associated, and four events as having “insufficient data.” No events were classified as having “definite” or “highly likely” association with tolvaptan, although multiple patients had improvement in LFTs with cessation of the drug. In one case, a patient with LFT abnormalities restarted tolvaptan at a lower dose after blood work had normalized, but again experienced LFT abnormalities and then permanently discontinued tolvaptan.

Patients in the REPRISE placebo arm had the least amount of prior tolvaptan exposure, and they experienced more aquaretic side effects and LFT abnormalities compared with patients from the tolvaptan arm of REPRISE or from TEMPO 4:4. Liver injury triggering HAC adjudication occurred at a mean of 316 days, and patients from the REPRISE placebo arm accounted for all patients who had ALT or AST elevations ≥10 times or ≥20 times the upper limit of normal. This study supports prior evidence that patients are at highest risk of liver toxicity during the first 18 months of tolvaptan exposure (2).

Unexpected signals for skin malignancy and glaucoma emerged in TEMPO 3:4 but were less common in this long-term follow-up study (7). Additional adverse effects were pharyngitis in 287 patients (15.9%), upper respiratory tract infections in 198 patients (11%), urinary tract infections in 180 patients (10%), and fatigue in 156 patients (8.7%), which have been previously reported (3,5).

The study by Torres et al. (7) is impressive in its inclusion of 1800 patients with ADPKD, but because these are the same patients who volunteered for the prior randomized controlled trials and then the open label study, the risk of liver adverse events may be underestimated and the efficacy of the serial LFT monitoring may be overestimated compared with patients in a general clinical practice. However, this structure did support evidence that patients who had already tolerated tolvaptan for >18 months were less likely to have further adverse events.

Although the intention was to have each participant complete at least 18 months of tolvaptan therapy, 489 (27%) of the 1800 patients analyzed for safety signals completed treatment for <18 months in the extension. Additional limitations of the study include exclusion of patients with prior episodes of liver enzyme abnormalities, perhaps skewing outcomes by eliminating a subset of patients more susceptible to liver injury. We also note that 94% of patients were White, raising concern that safety signals have not been sufficiently analyzed in non-White populations.

Regardless, the study by Torres et al. (7) provides valuable safety data from a large cohort of patients with ADPKD treated with tolvaptan and provides evidence that the REMS adopted in the United States limits patient risk for severe drug-induced liver injury. About 5000 patients have entered the REMS for Jynarque in the United States, with no reports of severe liver injury to date.

One patient with ADPKD treated with tolvaptan in Japan was reported to have severe liver injury resulting in liver failure and need for liver transplant (9), emphasizing the need for vigilance for both the prescriber and the patient. A protocol provides guidance when LFT abnormalities develop (6), which may take up to 4 months after drug discontinuation to resolve (2). Additional postmarketing data will come from ongoing registries, such as Canadian Medical Assessment of Jinarc Outcomes Registry (C-MAJOR) in Canada.

The liver toxicity seen with tolvaptan may be specific to this drug rather than all V2 receptor antagonists. Lixivaptan, another oral V2 receptor antagonist, is currently in a clinical trial (NCT04152837) for patients with ADPKD who have experienced LFT abnormalities with tolvaptan.

Moving forward, several questions regarding the optimal treatment strategies for patients with ADPKD remain. Additional long-term data on the efficacy of tolvaptan in reducing total kidney volume or symptoms such as pain, and in slowing progression to ESKD, would be invaluable. This is especially important considering the extended inclusion criteria in Torres et al. (7), which included patients with an eGFR of ≥20 ml/min per 1.73 m², although patients with an eGFR<20 ml/min per 1.73 m² could also be included if approved by a sponsor. We also await data on the ability of tolvaptan to affect patient satisfaction and/or quality of life (10).

At this time, tolvaptan continues to be the only disease-modifying agent approved for clinical use in ADPKD. The study by Torres et al. (7) provides evidence that with close monitoring of LFTs throughout the course of tolvaptan therapy, signs of liver toxicity can be caught early, resulting in drug dose adjustment or discontinuation and, ultimately, preventing any severe drug-induced liver injury.

Disclosures

N.K. Dahl was a principal investigator for this study at Yale. N.K. Dahl also reports consultancy agreements with Otsuka Pharmaceuticals; serving as a PI for clinical trials sponsored by Allena, Kadmon, Reata, Regulus, and Sanofi; receiving honoraria from the National Kidney Foundation and Otsuka Pharmaceuticals; serving as a scientific advisor or member of Natera and the PKD Foundation; and having other interests/relationships with New England Chapter of the National Kidney Foundation Medical Advisory Board and ESRD Network, Region 1 of Medical Advisory Board. The remaining author has nothing to disclose.

Funding

None.