To the Editor:
Autosomal dominant polycystic kidney disease (ADPKD) is a progressive inherited disorder in which renal tissue is gradually replaced with fluid-filled cysts.1,2 As ADPKD advances, loss of kidney function may ultimately lead to kidney failure, at which point dialysis or kidney transplant are the only treatment options.2 Therefore, slowing the progression of ADPKD is a major goal for patients who are affected, although, until recently, existing treatments focused only on managing symptoms and complications.3
The vasopressin V2-receptor antagonist tolvaptan was the first treatment demonstrated to slow kidney function decline in adults at risk of rapidly progressing ADPKD.3 Tolvaptan was approved for this indication by the European Commission in 2015 and the US Food and Drug Administration in 2018 based on 2 randomized phase 3 trials: TEMPO 3:4 (NCT00428948) and REPRISE (NCT02160145).3, 4, 5, 6 In TEMPO 3:4, adults with early-stage ADPKD (n = 1,445) who received tolvaptan had significantly reduced kidney function decline compared with placebo by 26% over 3 years (reciprocal of the serum creatinine level, −2.61 versus −3.81 [mg per milliliter]−1 per year, respectively; P < 0.001).5 The efficacy of tolvaptan in this trial was sustained over a further 2 years in the open-label extension trial TEMPO 4:4 (NCT01214421) among the same population.6 Furthermore, in the 1-year REPRISE trial, tolvaptan reduced kidney function decline by 35% among patients with later-stage ADPKD.4
Tolvaptan has been reported to be associated with liver injury in TEMPO 3:4 and TEMPO 4:4,5,6 and the potential risk of liver injury is closely monitored under the Food and Drug Administration by the JYNARQUE Risk Evaluation and Mitigation Strategy (REMS).7 To assess the safety profile of tolvaptan, this study calculated the number needed to harm (NNH) with tolvaptan versus placebo on measures of liver function using data from TEMPO 3:4.
The safety events considered in this study were elevation in alanine aminotransferase (ALT) to >3 times (3×) and >5 times (5×) the upper limit of the normal range (ULN), and serious ALT or aspartate aminotransferase (AST) elevation. Detailed methods are described in Item S1.
This study included 961 patients from the tolvaptan arm and 483 from the placebo arm of TEMPO 3:4. The NNHs for ALT >3× ULN compared tolvaptan versus the placebo for ADPKD was 56.19 (95% confidence interval [CI], 33.60-171.33) over 12 months and 39.81 (25.59-89.57) over 24 months (Table 1). This means that for every 100 patients treated with tolvaptan instead of placebo, 1.78 and 2.51 additional patients would have ALT >3× ULN over 12 and 24 months, respectively.
Table 1.
NNH for Liver Function Abnormalities Associated With Tolvaptan Over 12 and 24 Months
| Liver Function Abnormalities | 12 M |
24 M |
||||
|---|---|---|---|---|---|---|
| % with ≥ 1 event |
NNH (95% CI) | % with ≥ 1 event |
NNH (95% CI) | |||
| Tolvaptan | Placebo | Tolvaptan | Placebo | |||
| ALT elevation | ||||||
| > 3× ULN | 2.4% | 0.6% | 56.19 (33.60-171.33) | 3.3% | 0.8% | 39.81 (25.59-89.57) |
| > 5× ULN | 0.9% | 0.2% | 136.53 (ns) | 0.9% | 0.2% | 136.53 (ns) |
| Serious ALT or AST elevationa | 0.8% | 0.2% | 159.89 (ns) | 0.9% | 0.4% | 191.41 (ns) |
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; NNH, number needed to harm; ns, not significant; ULN, upper limit of the normal range.
As defined in TEMPO 3:4.5
The proportions of patients with ALT >5× ULN and serious ALT or AST elevation were not significantly different between the 2 arms in either period, yielding NNH values above 135 (Table 1). This result means that for every 100 patients treated with tolvaptan instead of placebo, fewer than 1 additional patient would experience ALT >5× ULN or serious ALT or AST elevation over 12 or 24 months.
Tolvaptan remains the only treatment to demonstrate efficacy for slowing kidney function decline, which subsequently slows the progression to end-stage kidney failure.4, 5, 6 In the context of the efficacy benefit observed in TEMPO 3:4 (the number needed to treat to prevent one 25% decline in estimated glomerular filtration rate over 3 years was previously reported to be approximately 11),5,8 the large NNH values estimated in this study demonstrate an acceptable safety profile regarding liver abnormalities for tolvaptan among patients with ADPKD. For every 100 patients treated with tolvaptan, just 2-3 additional patients would experience ALT elevation to >3× ULN over 12 and 24 months, whereas the risks of ALT elevation to >5× ULN and serious ALT or AST elevation were not found to be statistically significantly different between tolvaptan and placebo.
The risk of liver injury among patients with ADPKD receiving tolvaptan can be mitigated through frequent monitoring, as demonstrated in the REPRISE trial.4 In the United States, tolvaptan is currently available only through the JYNARQUE REMS program, which mandates monitoring of liver function at 2 and 4 weeks after initiation, then monthly for 18 months, and every 3 months thereafter.7 In the interim analysis of 6,711 patients treated with tolvaptan through the REMS program, <1% experienced possible severe drug-induced liver injury, confirming that frequent monitoring enables timely identification of liver enzyme abnormalities and appropriate drug discontinuation.7 Thus, with sufficient monitoring, the benefits of tolvaptan outweigh the potential harm for most patients at risk of rapidly progressing ADPKD.
The results should be interpreted in light of several limitations, including those of TEMPO 3:4. In addition, these results may not be generalizable to patients with ADPKD in the real-world because the analysis were based on data from a randomized clinical trial performed in a controlled environment, which is not the situation in real-world clinical practice. Moreover, the estimates in this study may be conservative because liver enzyme testing was performed every 4 months in the TEMPO 3:4 trial, which may be less frequent than in real-world clinical practice.
Article Information
Authors’ Contributions
Study conceptualization: KAB, SN, RK, XN, and AWF; data curation and analysis: KAB and XN; data validation: KAB, SN, RK, XN, and AWF. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved.
Support
This work was supported by Otsuka Pharmaceutical Development & Commercialization, Inc. The sponsor was involved in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.
Financial Disclosure
Dr Nunna and Dr Fernandes are employees of Otsuka Pharmaceutical Development & Commercialization, Inc. and hold stock/options. Dr Kumar was an employee of Otsuka Pharmaceutical Development & Commercialization, Inc and held stock or options when the study was performed. Drs Betts and Nie are employees of Analysis Group, Inc, which has received consulting fees from Otsuka Pharmaceutical Development & Commercialization, Inc.
Acknowledgments
Medical writing assistance was provided by Shelley Batts, PhD, an employee of Analysis Group, Inc., and funded by Otsuka Pharmaceutical Development & Commercialization, Inc.
Prior Presentation
Parts of this manuscript were presented at the American Society of Nephrology Kidney Week Annual Meeting, held from November 3-6, 2022, in Orlando, FL as a poster presentation.
Data Sharing
To submit inquiries related to Otsuka clinical research, or to request access to individual participant data (IPD) associated with any Otsuka clinical trial, please visit https://clinical-trials.otsuka.com/. For all approved IPD access requests, Otsuka will share anonymized IPD on a remotely accessible data sharing platform.
Peer Review
Received July 18, 2023. Evaluated by 1 external peer reviewer, with direct editorial input from the Statistical Editor and the Editor-in-Chief. Accepted in revised form November 12, 2023.
Footnotes
Item S1: Detailed methods.
Supplementary Material
Item S1.
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Item S1.