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Abstract: TH-PO411

Number Needed to Harm (NNH) Analysis of Tolvaptan in Patients With Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Session Information

Category: Genetic Diseases of the Kidneys

  • 1101 Genetic Diseases of the Kidneys: Cystic

Authors

  • Nunna, Sasikiran, Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, New Jersey, United States
  • Betts, Keith A., Analysis Group Inc, Los Angeles, California, United States
  • Kumar, Retesh Kumar, Otsuka Pharmaceutical Europe Ltd, Wexham, Buckinghamshire, United Kingdom
  • Nie, Xiaoyu, Analysis Group Inc, Los Angeles, California, United States
  • Fernandes, Ancilla, Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, New Jersey, United States
Background

ADPKD is the most prevalent monogenic kidney disease and can lead to progressive loss of kidney function and ultimately, kidney failure. Tolvaptan is the first approved treatment to slow kidney function decline in adults at risk of rapidly progressing ADPKD. The potential risk of liver injury associated with tolvaptan is closely monitored in the United States Food and Drug Administration Risk Evaluation and Mitigation Strategy (JYNARQUE REMS) program. The objective of this study is to assess the safety profile of tolvaptan related to liver function using the NNH approach.

Methods

Individual patient-level data from the TEMPO 3:4 trial (NCT00428948) was used to evaluate liver function abnormalities, serious alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevation adverse events (AEs) over 12 months and 24 months of treatment. Liver function abnormalities were defined as ALT>3 times (3x) and >5 times (5x) the upper limit of the normal range (ULN). NNH was calculated as the reciprocal of the difference in the proportion of patients experiencing a given outcome between tolvaptan and placebo.

Results

This study included 961 patients in the tolvaptan arm and 483 in the placebo arm. The NNHs for ALT>3xULN were 56.19 (95% confidence interval [CI]: 33.60, 171.33) over 12 months and 39.81 (25.59, 89.57) over 24 months, which suggests that for every 100 patients treated with tolvaptan instead of placebo, only 1.78 and 2.51 additional patients would have ALT>3xULN over 12 and 24 months, respectively. The proportions of patients with ALT>5xULN and serious ALT or AST elevation were not statistically different between the two arms in either period, yielding NNH values above 135, which suggests that for every 100 patients treated with tolvaptan instead of placebo, fewer than one additional patient would experience ALT>5xULN or serious ALT or AST elevation over 12 or 24 months.

Conclusion

The large NNH values help further characterize the safety profile of tolvaptan by demonstrating an acceptable benefit-risk profile.

Funding

  • Commercial Support