ISIS-388626(ISIS-388626) - 药物靶点：SGLT2_在研适应症：2型糖尿病_专利_临床

概要

基本信息

药物类型

ASO

别名

ISIS-SGLT2RX

靶点

SGLT2

作用机制

SGLT2抑制剂(钠-葡萄糖协同转运蛋白-2抑制剂)

治疗领域

内分泌与代谢疾病

在研适应症

2型糖尿病

非在研适应症-

原研机构

Ionis

在研机构

Ionis

非在研机构

Ionis Pharmaceuticals, Inc.

最高研发阶段临床1期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构

使用我们的RNA技术数据为新药研发加速。

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序列信息

Sequence Code 227509928

关联

2

项与 ISIS-388626 相关的临床试验

NL-OMON35464 / CompletedN/A

A Phase 1, Double Blind, Placebo-Controlled, Dose-Escalation Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Doses of ISIS 388626 Administered to Healthy Volunteers - Phase 1 Study with Single and Multiple Doses of ISIS 388626

开始日期2009-01-26

申办/合作机构-

NCT00836225 / Completed临床1期

A Phase I , Double-Blind, Placebo-Controlled, Dose-Escalation Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Doses of ISIS 388626 Administered to Healthy Volunteers

The primary purpose of this trial is to assess the safety and tolerability of ISIS-SGLT2Rx when given at increasing single doses and to assess the safety and tolerability of the same doses when given multiple times.

开始日期2009-01-01

申办/合作机构

Ionis Pharmaceuticals, Inc.

100 项与 ISIS-388626 相关的临床结果

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100 项与 ISIS-388626 相关的转化医学

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100 项与 ISIS-388626 相关的专利（医药）

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3

项与 ISIS-388626 相关的文献（医药）

2017-02-01·Pharmacology Research & Perspectives4区 · 医学

Novel SGLT2 inhibitor: first-in-man studies of antisense compound is associated with unexpected renal effects

4区 · 医学

ArticleOA

作者: van Meer, Leonie ; Moerland, Matthijs ; Burggraaf, Jacobus ; de Kam, Marieke ; van Dongen, Marloes ; Cohen, Adam

The antisense compound ISIS 388626 selectively inhibits renal glucose reabsorption by inhibiting the sodium-glucose cotransporter-2 (SGLT2) mRNA expression. It is developed as an insulin-independent treatment approach for type 2 diabetes mellitus (T2DM). The safety, tolerability, pharmacokinetics, and pharmacodynamics after subcutaneous administration of the drug were planned to be evaluated in healthy volunteers in a single-ascending-dose study (50-400 mg) and a multiple-ascending-dose study (6 weeks; weekly doses of 50-400 mg with loading dose regimen of three doses during the first week). The study was halted early because increases in serum creatinine occurred in the subjects participating in the 100 mg multiple-dose cohort. The pronounced changes in serum creatinine were accompanied by increased urinary excretion of beta-2-microglobulin and KIM1. The possible mechanisms for these findings remain elusive and are in contrast to preclinical findings as comparable treatment with ISIS 388626 of animals did not reveal similar changes. Although exposure was limited, there was an indication that glucosuria increased upon active treatment. Before the concept of antisense-mediated blocking of SGLT2 with ISIS 388626 can be explored further, more preclinical data are needed to justify further investigations.

2016-11-01·Journal of Pharmacology and Experimental Therapeutics3区 · 医学

Renal Effects of Antisense-Mediated Inhibition of SGLT2

3区 · 医学

Article

作者: van Meer, Leonie ; van Dongen, Marloes ; Goulouze, Bas ; Cohen, Adam ; Moerland, Matthijs ; de Kam, Marieke ; Burggraaf, Jacobus ; Klaassen, Erica

ISIS 388626 is an antisense sodium-glucose cotransporter 2 (SGLT2) inhibitor designed to treat type 2 diabetes mellitus by induction of glucosuria. ISIS 388626 was demonstrated to be safe and effective in preclinical trails in several species. We undertook the present study to evaluate the safety and efficacy of 13 weekly doses of 50, 100, and 200 mg of ISIS 388626 in humans. ISIS 388626 increased 24-hour urinary glucose excretion dose dependently with 508.9 ± 781.45 mg/day in the 100-mg and 1299.8 ± 1833.4 mg/day in the 200-mg cohort, versus 88.7 ± 259.29 mg/day in the placebo group. ISIS 388626 induced a reversible increase in serum creatinine, with the largest effect after eight doses of ISIS 388626 (200 mg; 0.38 ± 0.089 mg/dl; 44% increase over baseline). Three subjects were discontinued as a result of creatinine increases. The renal clearance test revealed no indications for impairment of glomerular filtration or renal perfusion. The creatinine increases were accompanied by a rise in the levels of urinary renal damage markers [β-2-microglobulin (B2M), total protein, kidney injury molecule (KIM1), α-glutathione S-transferase (aGST), N-acetyl-β-(d)-glucosaminidase (NAG)]. Other treatment-related adverse events included mild injection site reactions occurring in 8-19% of the subjects. In conclusion, ISIS 388626 treatment induced glucosuria at a dose level of 200 mg/week. This intended pharmacological effect was small, amounting to approximately 1% of the total amount of filtered glucose. Changes in serum and urinary markers were indicative of transient renal dysfunction, most probably of tubular origin. Whether the glucosuria is caused by specific SGLT2 inhibition or general tubular dysfunction or a combination remains uncertain.

2012-11-01·Journal of Pharmacology and Experimental Therapeutics3区 · 医学

Pharmacodynamics and Subchronic Toxicity in Mice and Monkeys of ISIS 388626, a Second-Generation Antisense Oligonucleotide That Targets Human Sodium Glucose Cotransporter 2

3区 · 医学

Article

作者: Thomas A. Zanardi ; Su-Cheol Han ; Rosie Z. Yu ; Scott P. Henry ; Soyub Rime ; Eun Ju Jeong ; Kaushik Chakravarty

ISIS 388626, a 2'-methoxyethyl (MOE)-modified antisense oligonucleotide (ASO) that targets human sodium glucose cotransporter 2 (SGLT2) mRNA, is in clinical trials for the management of diabetes. SGLT2 plays a pivotal role in renal glucose reabsorption, and inhibition of SGLT2 is anticipated to reduce hyperglycemia in diabetic subjects by increasing urinary glucose elimination. To selectively inhibit SGLT2 in the kidney, ISIS 388626 was designed as a "shortmer" ASO, consisting of only 12 nucleotides with two 2'-MOE-modified nucleotides at the termini. Mice and monkeys received up to 30 mg/kg/week ISIS 388626 via subcutaneous injection for 6 or 13 weeks. Dose-dependent decreases in renal SGLT2 mRNA expression were observed, which correlated with dose-related increases in glucosuria without concomitant hypoglycemia. There were no histologic changes in the kidney attributed to SGLT2 inhibition after 6 or 13 weeks of treatment. The remaining changes observed in these studies were typical of those produced in these species by the administration of oligonucleotides, correlated with high doses of ISIS 388626, and were unrelated to the inhibition of SGLT2 expression. The kidney contained the highest concentration of ISIS 388626, and dose-dependent basophilic granule accumulation in tubular epithelial cells of the kidney, which is evidence of oligonucleotide accumulation in these cells, was the only histologic change identified. No changes in kidney function were observed. These results revealed only readily reversible changes after the administration of ISIS 388626 and support the continued investigation of the safety and efficacy of ISIS 388626 in human trials.

100 项与 ISIS-388626 相关的药物交易

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