EOS789, a broad-spectrum inhibitor of phosphate transport, is safe with an indication of efficacy in a phase 1b randomized crossover trial in hemodialysis patients

Gallant, Kathleen M. Hill; Stremke, Elizabeth R.; Trevino, Laurie L.; Moorthi, Ranjani N.; Doshi, Simit; Wastney, Meryl E.; Hisada, Nozomi; Sato, Jotaro; Ogita, Yoshitaka; Fujii, Naohisa; Matsuda, Yudai; Kake, Takei; Moe, Sharon M.

doi:10.1016/j.kint.2020.09.035

Cited by 31 publications

(44 citation statements)

References 34 publications

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“…NaPi-2b, PiT-1, and PiT-2, showed encouraging results in patients receiving hemodialysis. 72 Fractional phosphate absorption trended lower in patients receiving EOS789 (100 mg) in comparison to those treated with placebo, and the study drug was safe and well-tolerated. 72 EOS789 was compared to placebo as well as with/without sevelamer to study an additive benefit: EOS789 was compared to placebo as well as with/without sevelamer to study an additive benefit.…”

Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 92%

“…72 Fractional phosphate absorption trended lower in patients receiving EOS789 (100 mg) in comparison to those treated with placebo, and the study drug was safe and well-tolerated. 72 EOS789 was compared to placebo as well as with/without sevelamer to study an additive benefit: EOS789 was compared to placebo as well as with/without sevelamer to study an additive benefit. Fractional phosphate absorption was lower in patients treated with 100 mg EOS789 (0.40) than in those treated with placebo (0.53), and patients treated with 100 mg EOS789 with 1600 mg sevelamer (0.36) fared even better than EOS789 alone, indicating an additive benefit.…”

Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 92%

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Past, Present, and Future of Phosphate Management

Doshi

Wish

2022

Kidney International Reports

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Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 92%

Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 92%

Past, Present, and Future of Phosphate Management

Doshi

Wish

2022

Kidney International Reports

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“…65 A phase 1 study of EOS789 in patients receiving intermittent dialysis found no significant difference in serum phosphate between patients treated with EOS789 and patients who received a placebo. 66 To our knowledge, no phase 2 or 3 trials have been conducted for this therapy.…”

Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 99%

“… 74 A phase 1 study of EOS789 in patients receiving intermittent dialysis found no significant difference in serum phosphate concentrations between patients treated with EOS789 and patients who received a placebo. 75 To our knowledge, no phase 2 or 3 trials have been conducted for this therapy. The NaPi2b inhibitor ASP3325 reduced serum phosphate concentrations in an animal model 15 but had no effect in healthy volunteers or patients with end-stage kidney disease.…”

Section: Phosphate Absorption Pathways: a More Targeted Therapeutic Approachmentioning

confidence: 99%

Phosphate Absorption and Hyperphosphatemia Management in Kidney Disease: A Physiology-Based Review

Fishbane

Nigwekar

2021

Kidney Medicine

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“…More recently, studies in rats and humans have implicated the ubiquitously expressed, low‐affinity sodium‐dependent phosphate transporters PiT1 and possibly PiT2 in intestinal phosphate absorption. 22 , 23 …”

Section: Introductionmentioning

confidence: 99%

Effects of pharmacological inhibition of the sodium‐dependent phosphate cotransporter 2b (NPT2b) on intestinal phosphate absorption in mouse and rat models

Wang

et al. 2022

Pharmacology Res & Perspec

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An excess phosphate burden in renal disease has pathological consequences for bone, kidney, and heart. Therapies to decrease intestinal phosphate absorption have been used to address the problem, but with limited success. Here, we describe the in vivo effects of a novel potent inhibitor of the intestinal sodium‐dependent phosphate cotransporter NPT2b, LY3358966. Following treatment with LY3358966, phosphate uptake into plasma 15 min following an oral dose of radiolabeled phosphate was decreased 74% and 22% in mice and rats, respectively, indicating NPT2b plays a much more dominant role in mice than rats. Following the treatment with LY3358966 and radiolabeled phosphate, mouse feces were collected for 48 h to determine the ability of LY3358966 to inhibit phosphate absorption. Compared to vehicle‐treated animals, there was a significant increase in radiolabeled phosphate recovered in feces (8.6% of the dose, p < .0001). Similar studies performed in rats also increased phosphate recovered in feces (5.3% of the dose, p < .05). When used in combination with the phosphate binder sevelamer in rats, there was a further small, but not significant, increase in fecal phosphate. In conclusion, LY3358966 revealed a more prominent role for NPT2b on acute intestinal phosphate uptake into plasma in mice than rats. However, the modest effects on total intestinal phosphate absorption observed in mice and rats with LY3359866 when used alone or in combination with sevelamer highlights the challenge to identify new more effective therapeutic targets and/or drug combinations to treat the phosphate burden in patients with renal disease.

show abstract

EOS789, a broad-spectrum inhibitor of phosphate transport, is safe with an indication of efficacy in a phase 1b randomized crossover trial in hemodialysis patients

Cited by 31 publications

References 34 publications

Past, Present, and Future of Phosphate Management

Past, Present, and Future of Phosphate Management

Phosphate Absorption and Hyperphosphatemia Management in Kidney Disease: A Physiology-Based Review

Effects of pharmacological inhibition of the sodium‐dependent phosphate cotransporter 2b (NPT2b) on intestinal phosphate absorption in mouse and rat models

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