作者: Stark, Jeffrey G. ; Zahir, Hamim ; Limsakun, Tharin ; Ford, Daniel ; Tao, Ben ; Maruyama, Sonomi ; Visser, Hester ; Chou, Hubert S. ; Zamora, Cynthia A. ; Ito, Takashi

AbstractTissue‐nonspecific alkaline phosphatase (TNAP) hydrolyzes and inactivates inorganic pyrophosphate (PPi), a potent inhibitor of calcification; therefore, TNAP inhibition is a potential target to treat ectopic calcification. These two first‐in‐human studies evaluated safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of single (SAD) and multiple‐ascending doses (MAD) of DS‐1211, a TNAP inhibitor. Healthy adults were randomized 6:2 to DS‐1211 or placebo, eight subjects per dose cohort. SAD study subjects received one dose of DS‐1211 (range, 3–3000 mg) or placebo, whereas MAD study subjects received DS‐1211 (range, 10–300 mg) once daily, 150 mg twice daily (b.i.d.), or placebo for 10 days. Primary end points were safety and tolerability. PK and PD assessments included plasma concentrations of DS‐1211, alkaline phosphatase (ALP) activity, and TNAP substrates (PPi, pyridoxal 5′‐phosphate [PLP], and phosphoethanolamine [PEA]). A total of 56 (DS‐1211: n = 42; placebo: n = 14) and 40 (DS‐1211: n = 30; placebo: n = 10) subjects enrolled in the SAD and MAD studies, respectively. In both studies, adverse events were mild or moderate and did not increase with dose. PKs of DS‐1211 were linear up to 100 mg administered as a single dose and 150 mg b.i.d. administered as a multiple‐dose regimen. In multiple dosing, there was minimal accumulation of DS‐1211. Increased DS‐1211 exposure correlated with dose‐dependent ALP inhibition and concomitant increases in PPi, PLP, and PEA. In two phase I studies, DS‐1211 appeared safe and well‐tolerated. Post‐treatment PD assessments were consistent with exposure‐dependent TNAP inhibition. These data support further evaluation of DS‐1211 for ectopic calcification diseases.

2020-12-01·Journal of Bone and Mineral Research

In Vitro and In Vivo Pharmacological Profiles of DS-1211, a Novel Potent, Selective, and Orally Bioavailable Tissue-Nonspecific Alkaline Phosphatase Inhibitor

Article

作者: Yamamoto, Yuko ; Miyazaki, Shojiro ; Watanabe, Kengo ; Soma, Kaori ; Izumi, Masanori

ABSTRACTInhibition of tissue-nonspecific alkaline phosphatase (TNAP) may prevent ectopic soft tissue calcification by increasing endogenous pyrophosphate (PPi). DS-1211 is a potent and selective novel small molecule TNAP inhibitor with well-characterized pharmacokinetics (PKs) in rodent and monkey. Herein, we report a comprehensive summary of studies establishing the pharmaceutical profile of DS-1211. In vitro studies characterized the mode of inhibition and inhibitory effects of DS-1211 on three human alkaline phosphatase (ALP) isozymes—TNAP, human intestinal ALP, human placental ALP—and on ALP activity across species in mouse, monkey, and human plasma. In vivo PK and pharmacodynamic (PD) effects of a single oral dose of DS-1211 in mice and monkeys were evaluated, including biomarker changes in PPi and pyridoxal 5′-phosphate (PLP). Oral bioavailability (BA) was determined through administration of DS-1211 at a 0.3-mg/kg dose in monkeys. In vitro experiments demonstrated DS-1211 inhibited ALP activity through an uncompetitive mode of action. DS-1211 exhibited TNAP selectivity and potent inhibition of TNAP across species. In vivo studies in mice and monkeys after single oral administration of DS-1211 showed linear PKs, with dose-dependent inhibition of ALP activity and increases in plasma PPi and PLP. Inhibitory effects of DS-1211 were consistent in both mouse and monkey. Mean absolute oral BA was 73.9%. Overall, in vitro and in vivo studies showed DS-1211 is a potent and selective TNAP inhibitor across species. Further in vivo pharmacology studies in ectopic calcification animal models and clinical investigations of DS-1211 in patient populations are warranted. © 2022 Daiichi Sankyo, Inc. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Scientific Reports

Anticalcification effects of DS-1211 in pseudoxanthoma elasticum mouse models and the role of tissue-nonspecific alkaline phosphatase in ABCC6-deficient ectopic calcification

Article

作者: Watanabe, Kengo ; Izumi, Masanori ; Soma, Kaori

AbstractPseudoxanthoma elasticum (PXE) is a multisystem, genetic, ectopic mineralization disorder with no effective treatment. Inhibition of tissue-nonspecific alkaline phosphatase (TNAP) may prevent ectopic soft tissue calcification by increasing endogenous pyrophosphate (PPi). This study evaluated the anticalcification effects of DS-1211, an orally administered, potent, and highly selective small molecule TNAP inhibitor, in mouse models of PXE. Calcium content in vibrissae was measured in KK/HlJ and ABCC6-/- mice after DS-1211 administration for 13–14 weeks. Pharmacokinetic and pharmacodynamic effects of DS-1211 were evaluated, including plasma alkaline phosphatase (ALP) activity and biomarker changes in PPi and pyridoxal-phosphate (PLP). Anticalcification effects of DS-1211 through TNAP inhibition were further evaluated in ABCC6-/- mice with genetically reduced TNAP activity, ABCC6-/-/TNAP+/+ and ABCC6-/-/TNAP+/-. In KK/HlJ and ABCC6-/- mouse models, DS-1211 inhibited plasma ALP activity in a dose-dependent manner and prevented progression of ectopic calcification compared with vehicle-treated mice. Plasma PPi and PLP increased dose-dependently with DS-1211 in ABCC6-/- mice. Mice with ABCC6-/-/TNAP+/- phenotype had significantly less calcification and higher plasma PPi and PLP than ABCC6-/-/TNAP+/+ mice. TNAP plays an active role in pathomechanistic pathways of dysregulated calcification, demonstrated by reduced ectopic calcification in mice with lower TNAP activity. DS-1211 may be a potential therapeutic drug for PXE.

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适应症	最高研发状态	国家/地区	公司	日期
弹性假黄瘤	临床2期	欧盟	Daiichi Sankyo Co., Ltd.	2022-01-30
弹性假黄瘤	临床2期	美国	Daiichi Sankyo Co., Ltd.	2022-01-30
异位骨化	临床1期	-	Daiichi Sankyo Co., Ltd.	-
异位骨化	临床1期	-	Sanford Burnham Prebys Medical Discovery Institute	-