A RandomIzed, Double-Blind, Placebo-CoNtrolled, Two-Part Study to Evaluate the Pharmacodynamic EffIcacy and Clinical Benefit of AT 007 in Patients With SoRbitol Dehydrogenase (SORD) DEficiency

This study is designed to assess the efficacy and safety of AT-007 treatment in patients with SORD Deficiency. This randomized, double-blind study will assess the effect of AT-007 compared to Placebo in SORD Deficiency patients for 24 months.

开始日期2022-01-01

申办/合作机构

Applied Therapeutics, Inc.

NCT05418829 / Active, not recruiting临床3期

An Open-Label Study to Evaluate the Long-Term Safety and Pharmacodynamic Efficacy of AT-007 in Adult Subjects With Classic Galactosemia (CG)

This study is a 12-month open-label extension (OLE) study of AT-007 in adult subjects with CG who previously participated in Study AT-007-1001 Part D and/or Part D Extension.
The study is designed to assess the long-term safety of AT-007 in subjects with CG as well as the pharmacodynamics (PD) (inhibition of galactitol) and PK of AT-007. The effect of 12-month treatment with AT-007 on the levels of galactose and other galactose metabolites in subjects with CG will also be evaluated.

开始日期2021-10-01

申办/合作机构

Applied Therapeutics, Inc.

NCT04902781 / Active, not recruiting临床2/3期

A Sequential, Two-Part Study to Evaluate the Clinical Benefit, Safety, Pharmacokinetics, and Pharmacodynamics of AT-007 in Pediatric Patients With Classic Galactosemia (CG)

This study is designed to assess the clinical benefit as well as the safety, pharmacokinetics (PK), and pharmacodynamics (PD) (reduction of galactitol levels) of AT-007 in pediatric subjects with Classic Galactosemia (CG).

开始日期2021-03-20

申办/合作机构

Applied Therapeutics, Inc.

100 项与 Govorestat 相关的临床结果

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100 项与 Govorestat 相关的转化医学

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100 项与 Govorestat 相关的专利（医药）

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项与 Govorestat 相关的文献（医药）

2024-11-01·JOURNAL OF CLINICAL PHARMACOLOGY

Safety, Pharmacokinetics, and Pharmacodynamics of the New Aldose Reductase Inhibitor Govorestat (AT‐007) After a Single and Multiple Doses in Participants in a Phase 1/2 Study

Article

作者: Bailey, Evan ; Wang, Stella ; Mills, Richard ; Mohanlal, Ramon ; Perfetti, Riccardo ; Shendelman, Shoshana

Abstract:

In classic galactosemia (CG) patients, aldose reductase (AR) converts galactose to galactitol. In a phase 1/2, placebo‐controlled study (NCT04117711), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of govorestat were evaluated after single and multiple ascending doses (0.5‐40 mg/kg) in healthy adults (n = 81) and CG patients (n = 14). Levels of govorestat in plasma and cerebrospinal fluid (CSF) and blood levels of galactitol, galactose, and galactose‐1‐phosphate (Gal‐1p) were measured for population PK and PK/PD analyses. Govorestat was well tolerated. Adverse event frequency was comparable between placebo and govorestat. Govorestat PK displayed a 2‐compartment model with sequential zero‐ and first‐order absorption, and no effect of demographic factors. Multiple‐dose PK of govorestat was linear in the 0.5‐40 mg/kg range, and CSF levels increased dose dependently. Elimination half‐life was ∼10 h. PK/PD modeling supported once‐daily dosing. Change from baseline in galactitol was −15% ± 9% with placebo and −19% ± 10%, −46% ± 4%, and −51% ± 5% with govorestat 5, 20, and 40 mg/kg, respectively, thus was similar for 20 and 40 mg/kg. Govorestat did not affect galactose or Gal‐1p levels. In conclusion, govorestat displayed a favorable safety, PK, and PD profile in humans, and reduced galactitol levels in the same magnitude (∼50%) as in a rat model of CG that demonstrated an efficacy benefit on neurological, behavioral, and ocular outcomes.

2017-01-01·Journal of pathogens

A Laboratory Assessment of Two Local Strains of the Beauveria bassiana (Bals.) Vuill. against the Tetranychus urticae (Acari: Tetranychidae) and Their Potential as a Mycopesticide

Article

作者: Algur, Omer Faruk ; Ortucu, Serkan

This study was conducted to assess highly pathogenic Beauveria bassiana isolates to be used in biocontrol and to determine their potentials as mycopesticide. For this purpose, two B. bassiana isolates, which were locally isolated from T. urticae, were chosen. Firstly, three suspensions were investigated at the degree of humidity of 65 ± 5% and 100% RH. Secondly, these strains were selected according to their tendency to mass production, tolerance to UV radiation, and capability of producing spore at the different temperatures. Finally, identification of the selected isolate was performed by using ITS rDNA analysis. Both tested fungal isolates were pathogenic to the T. urticae. Mycelial growths of isolate AT076 at 20°C and 30°C were found to be greater than isolate AT007. It was observed that isolate AT076 had more spore production with 1.61 × 107 spore/disc at 30°C and 44.33% germination after UV radiation for 15 min. The numbers of spores per 5 mm disk area for isolates AT076 and AT007 were found to be 1.2 × 106 and 1.0 × 106. These results show that isolate AT076 was more virulent and more UV-tolerant and had higher tendency to mass production compared to isolate AT007 against T. urticae. As a result of this study, isolate AT076 can be used in the biocontrol as mycopesticide.

2016-11-01·Lung cancer (Amsterdam, Netherlands)2区 · 医学

Prostaglandin E Receptor EP4 expression, survival and pattern of recurrence in locally advanced NSCLC

2区 · 医学

Article

作者: Josephine L. Feliciano ; Amy M. Fulton ; Paul N. Staats ; Martin J. Edelman ; Neha Bhooshan

BACKGROUND:

Elevated COX-2 expression has been correlated with inferior outcome in NSCLC. COX-2 catalyzes the transformation of arachidonate to PGE₂. We and others have demonstrated that PGE₂ induces proliferation and metastatic spread and immunosuppression through the G protein-coupled EP4 receptor. We hypothesized that EP4 expression on malignant cells would correlate with outcome and patterns of relapse after treatment of LANSCLC stage IIIA (7th edition, N2+).

METHODS:

Tissue specimens from 41 pts treated for LANSC at UMGCC were obtained. A tissue microarray was prepared and examined for EP4 expression. Intensity of staining was scored semi-quantitatively as 0-4 in both the nuclear and cytoplasmic compartments by a pathologist blinded to the clinical data.

RESULTS:

EP4 nuclear staining 0-1 vs. 2+ was associated with overall survival, (OS) (44.3 vs. 18 mo; HR=0.41, p=0.024) and numerically superior progression free survival (PFS) (16.4 vs. 10.2 mo, p=0.16). EP4 cytoplasmic staining did not correlate with OS (0-1 vs. 2+, 23.8 vs. 28.8 mo; HR=1.2, p=0.81). Relapse pattern (no relapse or local vs. systemic) did not correlate with EP nuclear staining (p=1.0, X²).

CONCLUSIONS:

This is the first clinical study of EP4 expression in lung cancer. There was a significant correlation between OS and nuclear EP4 expression, indicating that this is a potential therapeutic target. Studies with AT-007, a specific inhibitor of EP4, are planned to commence this year.

项与 Govorestat 相关的新闻（医药）

2024-12-02

·MedCity News

Applied Therapeutics Drug Is Denied FDA Approval in Rare Inherited Metabolic Disease - MedCity News

An Applied Therapeutics drug widely expected to secure FDA approval has been turned down by the agency, a setback for the company’s bid to bring to market the first therapy for a rare inherited metabolic disorder that currently has no treatments. Applied offered few details about the FDA’s reasons for the complete response letter (CRL), which the company disclosed late last Wednesday ahead of the Thanksgiving holiday weekend. New York-based Applied said the agency cited non-specific “deficiencies in the clinical application” for the drug, govorestat. The Applied drug was developed as a treatment for galactosemia, a rare inherited disease that leads to severe deficiency of enzymes needed to metabolize galactose. This sugar is produced by the body but is also a metabolic byproduct of lactose in dairy products, including breast milk. The disease can become fatal in infants, which is why it’s included in newborn screening tests in the U.S. presented by Market Trends to Watch for Health Systems and Their Specialty Pharmacies The future looks bright for the integrated specialty pharmacy model – for health systems, providers, and most importantly, for patients. By Jake Gaffey, MBA, Chief Strategy Officer at Shields Health Solutions Galactosemia is managed by maintaining a dairy-free diet. But even with dietary restrictions, galactose produced by the body cannot be metabolized, resulting in complications such as cognitive dysfunction, seizures, and speech and motor pathologies. Applied estimates there are about 3,300 galactosemia patients in the U.S. and 4,400 in the European Union. Govorestat is a small molecule designed to penetrate the central nervous system to inhibit aldose reductase. This enzyme, when under oxidative stress conditions, converts glucose to sorbitol, a sugar alcohol associated with many diseases. In the Phase 2 portion of the Phase 1/2 clinical trial that was the basis for govorestat’s new drug application, the study drug did not meet the main goal of showing a statistically significant improvement according to a composite endpoint comprised of four measures of the disease. Nevertheless, the company pointed to systemic improvement on these measures over time along with reduction in blood levels of galactitol, a metabolic byproduct of galactose. The FDA initially said it would hold an advisory committee meeting to discuss the govorestat application. In September, the company issued a status update stating the agency said an advisory meeting was no longer needed and the drug was on track to receive a regulatory decision by Nov. 28. Analysts and investors viewed that development as a sign govorestat was on its way to approval. In a note sent to investors on Thanksgiving, analysts for William Blair said they expected approval “based on the totality of clinical data demonstrating efficacy in a rare disease with no approved therapies.” There were other encouraging signs. Applied’s management told William Blair that discussions about the drug’s labeling occurred before the FDA issued its letter. Such discussions are among the last steps before a drug is approved. Exclusive Heard at HLTH 2024: Insights from Innovative Healthcare Executives Executives from Imagine360, Verily, BrightInsight, Lantern, and Rhapsody shared their approaches to reducing healthcare costs and facilitating digital transformation. By MedCity News “We see the CRL as unexpected and disappointing,” the William Blair analysts said. “Given the lack of information in the CRL, it is unclear what the path forward for govorestat in galactosemia is and whether an additional clinical trial will be necessary for approval in this indication.” Applied said it will request a meeting with the FDA to discuss the deficiencies in govorestat’s application and the potential path forward in galactosemia. The company is also developing govorestat for sorbitol dehydrogenase (SORD) deficiency, a rare and progressive neuromuscular disease that has no FDA-approved treatments. The company said it expects to submit a new drug application in this indication early in the first quarter of 2025. The William Blair analysts said they do not see the galactosemia decision affecting Applied’s plans in SORD, given that the pivotal study in this indication met both of its main goals. Furthermore, the review of the drug in galactosemia raised no manufacturing or safety issues that could affect a submission in SORD. The analysts also noted govorestat’s application in SORD will be reviewed by the FDA’s neurology division, with whom Applied had already aligned on plans for an accelerated approval application. The galactosemia submission was reviewed by the FDA’s Division of Rare Diseases and Medical Genetics, which has had many leadership change in the past year.

临床2期

2024-11-30

·佰傲谷BioValley

FDA拒绝批准，股价大跌80%

近日（11月27日），Applied Therapeutics宣布FDA已就公司核心管线govorestat的新药上市申请(NDA)发出了一封完整回应函（CRL），表示因临床应用缺陷（deficiencies in the clinical application）目前无法批准govorestat上市。消息披露当天，Applied股价盘后暴跌近80%。 FDA的这一拒绝让此前因为取消召开Adcomm而充满希望的Applied白白欢喜了一场。该公司表示计划与FDA会面，探讨重新提交NDA或对该决定提出上诉的可能性，并强调了govorestat的潜在获益。空欢喜一场 govorestat是Applied开发的一种具有中枢神经系统渗透性的醛糖还原酶抑制剂（ARI），被开发用于治疗多种罕见的神经系统疾病，包括半乳糖血症、山梨醇脱氢酶缺乏症（SORD）和磷酸甘露糖变位酶2-先天性糖基化障碍（PMM2-CDG）。半乳糖血症是govorestat的首发适应症。2024年2月，govorestat治疗半乳糖血症的NDA获得了FDA受理，并获得了优先审评。 NDA申请是得到了半乳糖醇快速和持续降低的支持，包括针对2-17岁半乳糖血症儿童的Ⅲ期临床数据ACTION-Galactosemia Kid、以及针对成人半乳糖血症患者的ACTION-GalactosemiaⅠ/Ⅱ期临床数据。如果govorestat获得批准，将成为首个治疗半乳糖血症药物。不过，FDA对govorestat仍存在顾虑，因为去年4月，govorestat的Ⅲ期临床试验ACTION-Galactosemia Kid未达到主要终点，但是Applied仍选择了提交上市申请。今年3月，FDA还把上审评期延长了三个月。为此，FDA也曾计划在2024年10月召开专家咨询委员会（adcomm）来针对govorestat的上市批准进行讨论。不过在今年9月FDA又改变了主意，取消了adcomm召开，优先审查计划如期进行。这对于Applied而言是个利好信号，当时受此消息影响，Applied股价还因此上涨了近70%。召开adcomm一般会增加一款药物不被批准通过的风险，虽然FDA并不一定遵循委员会的的建议，但通常会采纳其意见。而govorestatvu不用再adcomm会议上被审判，被上市通过的可能性更大了。但事与愿违。一个篮子里 govorestat能否获得监管认可除了在商业化上的贡献之外，对于公司其他的管线的正向激励意义重大，公司剩下的另外两条管线AT-001和AT-003均为醛糖还原酶抑制剂。 AT-001已经推进到了临床Ⅲ期阶段，不过，最近报告的消息看起来也不算乐观，2024年1月，AT-001治疗糖尿病心肌病ARISE-HF的Ⅲ期临床没有达到主要终点，公司表示以外部合作的方式开发AT-001。 AT-003是一款具有眼球内的渗透性的ARI，目前还在临床前阶段，用于治疗糖尿病性视网膜病变。 govorestat是Applied最为核心的管线，如果获得批准，是Applied的首个商业化产品，公司非常需要靠着的上市来获得收入。截至2024年9月30日，现金及现金等价物、以及短期投资共计9890万美元。除了治疗半乳糖血症外，公司正在准备山梨醇脱氢酶缺乏症（SORD）的上市计划。今年2月，Govorestat治疗SORD缺乏症的Ⅲ期临床INSPIRE试验达到了主要终点和几个关键次要终点。基于迄今为止的临床数据，公司计划在2025年第一季度初提交针对该适应症的新药上市申请。参考出处： https://firstwordpharma.com/story/5917211 https://ir.appliedtherapeutics.com/news-releases/news-release-details/applied-therapeutics-receives-complete-response-letter-us-fda https://www.biospace.com/press-releases/applied-therapeutics-receives-complete-response-letter-from-u-s-fda-regarding-new-drug-application-for-govorestat-for-classic-galactosemia 本周好文推荐如需转载请联系佰傲谷并在醒目位置注明出处 · · · · · · · ·

优先审批临床3期引进/卖出申请上市抗体药物偶联物

2024-11-29

·GlobeNewswire-Health Care

Applied Therapeutics Receives Complete Response Letter from U.S. FDA Regarding New Drug Application for Govorestat for Classic Galactosemia

Nov. 27, 2024 -- Applied Therapeutics, Inc. (Nasdaq: APLT), a biopharmaceutical company dedicated to creating transformative treatments for rare disease, today announced that the U.S. Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) for the New Drug Application (NDA) for govorestat, a novel, central nervous system (CNS)-penetrant aldose reductase inhibitor (ARI), for the treatment of Classic Galactosemia. The CRL indicates that the FDA completed its review of the application and determined that it is unable to approve the NDA in its current form, citing deficiencies in the clinical application. Applied Therapeutics is reviewing the feedback from the FDA and plans to immediately request a meeting to discuss requirements for a potential resubmission of the NDA or appeal of the decision along with appropriate next steps. “We are disappointed by the FDA’s decision today. Our strong commitment to the Galactosemia community is rooted in our belief that govorestat has the potential to change the lives of patients with Galactosemia, which we believe is evidenced by the breadth of efficacy and safety data demonstrating its ability to stop the decline on progressive clinical outcomes, including cognition and behavior,” said Shoshana Shendelman, PhD, Founder and CEO of Applied Therapeutics. “Galactosemia is a progressive and debilitating disease without any existing treatment options and there remains a high unmet medical need for this community. As we move forward, we plan to work with the FDA to address the concerns in the CRL and determine an expeditious path to bring this much needed treatment to patients. We are grateful to the patients, families, and healthcare providers who participated in the govorestat clinical studies.” Govorestat has demonstrated rapid and sustained reductions in galactitol in clinical trials, which resulted in a meaningful benefit on clinical outcomes across pediatric patients, alongside a favorable safety profile. In the Phase 3 registrational ACTION-Galactosemia Kids study in children with Galactosemia aged 2-17, treatment with govorestat demonstrated clinical benefit on activities of daily living, behavioral symptoms, cognition, fine motor skills and tremor. Govorestat also significantly reduced plasma galactitol levels in both adults and children with Galactosemia. Additional supportive studies resulted in robust efficacy and safety data across 185 patients with Classic Galactosemia over 3 years. The results of the ACTION-Galactosemia Kids study and the Phase 1/2 ACTION-Galactosemia study in adult patients with Galactosemia were published in the Journal of Clinical Pharmacology. Govorestat is also being developed for the treatment of Sorbitol Dehydrogenase (SORD) Deficiency, a rare and progressive neuromuscular disease. The Company expects to submit an NDA early in the first quarter of 2025. The review and potential approval of govorestat for the treatment of SORD is independent of the ongoing review of govorestat for Classic Galactosemia. Govorestat is a central nervous system (CNS) penetrant Aldose Reductase Inhibitor (ARI) being developed for the treatment of multiple rare diseases including Classic Galactosemia, Sorbitol Dehydrogenase (SORD) Deficiency, and PMM2- congenital disorder of glycosylation (CDG). Govorestat has received Orphan Medicinal Product Designation from the European Medicines Agency (EMA) for both Galactosemia and SORD Deficiency. Govorestat has also received Orphan Drug Designation from the U.S. Food and Drug Administration (FDA) for the treatment of Galactosemia, PMM2-CDG, and SORD Deficiency; Pediatric Rare Disease designation for Galactosemia and PMM2-CDG; and Fast Track designation for Galactosemia. Galactosemia is a rare genetic metabolic disease resulting in an inability to metabolize the simple sugar galactose. Galactose is found in foods, but is also produced endogenously by the body. When not metabolized properly, galactose is converted to the toxic metabolite, galactitol, which causes neurological complications, including deficiencies in cognition, behavior, activities of daily living, adaptive skills, fine and gross motor skills and speech, as well as tremor and seizures. There are approximately 3,300 patients with Galactosemia in the U.S. and 80-100 new births per year, and approximately 4,400 patients with Galactosemia in the E.U. and approximately 120 new births per year. Newborn screening for Galactosemia is mandatory in the U.S. and most E.U. countries. Applied Therapeutics is a clinical-stage biopharmaceutical company committed to the development of novel drug candidates against validated molecular targets in rare diseases. The Company’s lead drug candidate, govorestat, is a novel central nervous system penetrant Aldose Reductase Inhibitor (ARI) for the treatment of CNS rare metabolic diseases, including Classic Galactosemia, Sorbitol Dehydrogenase (SORD) Deficiency and PMM2-congenital disorder glycosylation (CDG). The content above comes from the network. if any infringement, please contact us to modify.

申请上市孤儿药临床结果快速通道

100 项与 Govorestat 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
半乳糖血症	申请上市	欧盟	Applied Therapeutics, Inc.	2023-12-01
山梨糖醇脱氢酶缺乏症	临床3期	美国	Applied Therapeutics, Inc.	2022-01-01
山梨糖醇脱氢酶缺乏症	临床3期	捷克	Applied Therapeutics, Inc.	2022-01-01
山梨糖醇脱氢酶缺乏症	临床3期	意大利	Applied Therapeutics, Inc.	2022-01-01
山梨糖醇脱氢酶缺乏症	临床3期	英国	Applied Therapeutics, Inc.	2022-01-01
1A型先天性糖基化障碍	临床1期	-	Applied Therapeutics, Inc.	-

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临床结果

适应症

分期

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT05397665 (INSPIRE, Biospace) 人工标引	临床2/3期	山梨糖醇脱氢酶缺乏症	56	Govorestat	簾築淵糧簾鹹構遞艱鏇(膚艱廠艱繭齋齋築鑰襯) = Demonstrated statistically significant correlation between sorbitol level and the prespecified CMT-FOM composite clinical endpoint (10-meter walk-run test, 4 stair climb, sit to stand test,6-minute walk test and dorsiflexion) (p=0.05). 遞鹽繭選壓醖衊願簾範 (醖廠範繭積壓齋積繭襯 ) 达到更多	积极	2024-02-15
				Placebo
Corporate Publications 人工标引	临床3期	半乳糖血症	-	AT-007	網夢鏇窪醖築壓鹽選鹹(鏇範簾蓋製壓夢簾顧顧) = Review of the data at 12 months of treatment by the DMC indicated that while the study primary endpoint has not yet reached statistical significance, a trend exists favoring AT-007 vs. placebo. 齋選獵齋齋簾膚製鹽鑰 (夢鹽醖壓壓網夢積蓋艱 )	积极	2022-10-06
				Placebo