SP331TP0463518, A NOVEL ORAL INHIBITOR OF HYPOXIA INDUCIBLE FACTOR PROLYL HYDROXYLASE (HIF-PH) INDUCES ERYTHROPOIETIN SECRETION DOMINANTLY DERIVED FROM LIVER IN NON-DIALYSIS AND HEMODIALYSIS PATIENTS WITH CHRONIC KIDNEY DISEASE

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INTRODUCTION AND AIMS: TP0463518, a novel potent HIF-PH inhibitor being developed for anemia in chronic kidney disease (CKD) has a unique feature to induce liver-specific erythropoietin (EPO) secretion in bilaterally nephrectomized rats. In the previous study of Japanese healthy male subjects, TP0463518 induced EPO secretion mainly derived from liver. Thus, this First-in-Patient, clinical pharmacology study was conducted to confirm whether TP0463518 could induce liver-derived EPO (L-EPO) in non-dialysis (ND) and hemodialysis (HD) patients with CKD. METHODS: In this open-label, single dose-escalation study, 29 patients were orally administered TP0463518 (ND: 1, 6 and 11 mg, HD: 1 and 11 mg). In order to elucidate whether kidney-derived EPO (K-EPO) or L-EPO induced by TP0463518 administration, glycosylation patterns of EPO were determined as percentage of migrated isoform (PMI) values by using a commercial test kit (MAIIA AB, Sweden). These PMI values were compared with peripheral blood of adult healthy volunteers, mainly containing K-EPO and umbilical cord blood, mainly containing L-EPO. RESULTS: The plasma TP0463518 exposures dose-dependently increased in each group. In 11 mg administration, the AUC0-24h in the ND and HD patients were 4920 ± 1140 (N=10) and 7040 ± 3810 h*ng/mL (N=5). Baseline EPO levels in serum in the ND and HD patients were 10.4 ± 4.6 and 6.6 ± 2.2 mIU/mL. The EPO levels in serum after TP0463518 administration increased dose-dependently, and those at 11 mg were 212.0 ± 129.1 and 1331.4 ± 1190.7 mIU/mL in the ND and HD patients, respectively. Mean PMI values of EPO in peripheral and umbilical cord blood were 25.8 ± 2.5% and 57.2 ± 5.5% (N=3, respectively). In the ND patients, mean PMI values of EPO before and after 11 mg TP0463518 administration were 32.0 ± 5.1% (pattern of K-EPO) and 66.6 ± 12.0% (pattern of L-EPO), respectively. Point estimate with 95% confidence interval for change in the PMI values was 34.6% (27.0-42.1). While in the HD patients, mean PMI values of EPO before and after TP0463518 11 mg administration were 57.9 ± 17.3% (pattern of L-EPO) and 84.4 ± 3.5% (pattern of L-EPO). Point estimate with 95% confidence interval for change in the PMI values was 26.5% (6.5-46.6). The correlations coefficients between the pharmacokinetic parameters (Cmax and AUCs) and the pharmacodynamic parameters (ΔCmax and AUCs of EPO) were calculated from 0.81 to 0.94. No adverse events were observed in all patients studied. CONCLUSIONS: These results indicate that TP0463518 has the potential to sustainably improve anemia regardless the renal function in end stage renal disease. In ND and HD patients with CKD, TP0463518 induced EPO secretion dominantly derived from liver without safety concerns.

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