Abstract: FR-PO144
EOS789, a Novel Pan-Inhibitor of NaPi-IIb/PiT-1/PiT-2, Suppressed Intestinal Phosphate Absorption in Healthy Subjects: A Phase 1 Clinical Trial
Session Information
- Bone and Mineral Metabolism: Phosphorus, FGF23, Vascular Calcification
November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Bone and Mineral Metabolism
- 402 Bone and Mineral Metabolism: Clinical
Authors
- Hisada, Nozomi, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan
- Maisawa, Shingo, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan
- Sato, Jotaro, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan
- Ikushima, Ippei, SOUSEIKAI Sumida Hospital, Tokyo, Japan
- Kake, Takei, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan
Background
Hyperphosphatemia in patients with chronic kidney disease is not well managed by existing treatments. Sodium-dependent phosphate co-transporters NaPi-IIb, PiT-1, and PiT-2 are considered to play a central role in intestinal phosphate (P) absorption, and are recognized as promising targets for a novel therapeutic strategy for hyperphosphatemia. Past clinical trials suggest blocking only NaPi-IIb is not sufficient for suppressing intestinal P absorption. We identified EOS789, a novel pan-inhibitor against NaPi-IIb, PiT-1, and PiT-2. Here we report the safety, tolerability, pharmacokinetics, and pharmacodynamic activity of the novel pan-inhibitor EOS789 in the first-in-human clinical trial in healthy subjects.
Methods
A randomized, double-blind, placebo-controlled, Phase 1 clinical trial in healthy subjects was conducted. It consisted of single (32 Japanese) and multiple (32 Japanese and 8 Caucasian) ascending dose parts. Primary endpoints were safety and tolerability of EOS789; exploratory endpoints included pharmacokinetics and pharmacodynamics, including P excretion in feces and urine.
Results
In the single ascending dose part, EOS789 was tolerated up to 600 mg and the most common adverse events were gastrointestinal (GI) disorders. In the multiple ascending dose part, EOS789 was tolerated up to 200 mg/day. Moderate GI disorders were observed in the 600 mg/day cohorts and dosing was discontinued in these cohorts. EOS789 increased fecal P and decreased urinary P excretion in a dose-dependent manner. Exposure-response analysis showed that thrice-daily dosing of EOS789 has the potential to show good efficacy at about 200 mg/day.
Conclusion
EOS789 was well tolerated up to 200 mg/day at repeated dosing for 14 days. This was the first clinical trial that showed a decrease of intestinal P absorption by inhibiting intestinal P transporters, and it suggests a new strategy for the treatment of hyperphosphatemia by pan-inhibiting NaPi-IIb, PiT-1, and PiT-2. The safety, tolerability, and efficacy of EOS789 in patients with hyperphosphatemia will be further investigated in future clinical trials.
Funding
- Commercial Support – Chugai Pharmaceutical Co., Ltd.