Abstract: FR-PO312

Reversibility of Serum Creatinine Elevation Observed in ADPKD Subjects Receiving the Tyrosine Kinase Inhibitor Tesevatinib

Session Information

Category: Genetic Diseases of the Kidney

  • 801 Cystic Kidney Diseases

Authors

  • Eiznhamer, David A., Kadmon Corporation, LLC, Cambridge, Massachusetts, United States
  • Rastogi, Anjay, UCLA Medical Center, Los Angeles, California, United States
  • Chonchol, Michel, University of Colorado, Aurora, Colorado, United States
  • El-Meanawy, Ashraf, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  • Steinman, Theodore I., Beth Israel Deaconess Medical Center , Boston, Massachusetts, United States
  • Herrera, Karin, Kadmon Corporation, LLC, Cambridge, Massachusetts, United States
  • Schueller, Olivier, Kadmon Corporation, LLC, Cambridge, Massachusetts, United States
  • Ryan, John L., Kadmon Corporation, LLC, Cambridge, Massachusetts, United States
  • Pergola, Pablo E., Renal Associates PA, San Antonio, Texas, United States
Background

The KD019-101 trial has evaluated the safety and preliminary efficacy of tesevatinib in patients with ADPKD. Preliminary data suggested that subjects with ADPKD receiving tesevatinib experienced elevations of serum creatinine without concomitant elevations of cystatin C. Pre-clinical laboratory investigations determined that tesevatinib inhibited the human multidrug and toxin extrusion transporters MATE1 and MATE2-K (IC50 = 80nM and 68nM, respectively). This inhibition could result in increased serum creatinine in the absence of decrease in kidney function, due to the reduced tubular secretion of creatinine.

Methods

An additional cohort in Study KD019-101 enrolled subjects with eGFR ≥ 35 but ≤ 80 mL/min/1.73m2 and htTKV ≥ 1000mL. These subjects had a mandatory 4-week drug holiday after the first 4 weeks of 50 mg QD tesevatinib treatment. During, and for 4 weeks after the drug holiday, subjects returned to the clinic weekly for serum creatinine and cystatin C measurement.

Results

13 patients (6 males/7 females) were enrolled. Consistent with previous data, after an initial increase, serum creatinine stabilized. Creatinine levels begin to decrease after 14 days of drug holiday and continued to decrease to baseline levels after 4 weeks of drug holiday. Resumption of drug resulted in similar increases as seen initially. Serum cystatin C levels were variable and did not show a pattern of increase before, during, or after the drug holiday period.

Conclusion

Serum creatinine elevations following tesevatinib dosing in patients with ADPKD are reversible upon cessation of dosing, and do not appear to result in a meaningful alteration in kidney function. This provides support for the hypothesis that serum creatinine elevation is a consequence of drug transporter inhibition resulting in the reduced tubular secretion of creatinine.

Funding

  • Commercial Support