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 Pharmacodynamic of AT-007 in Pediatric Subjects 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）

2023-05-22·JCI insight

Sorbitol reduction via govorestat ameliorates synaptic dysfunction and neurodegeneration in sorbitol dehydrogenase deficiency.

Article

作者: Shy, Michael ; Perfetti, Riccardo ; Saporta, Mario ; Canic, Tijana ; Rebelo, Adriana P ; Shendelman, Shoshana ; Tao, Xianzun ; Zhu, Yi ; Lobato, Amanda G ; Züchner, Stephan ; Zhai, R Grace ; Ortiz-Vega, Natalie ; Yanick, Christopher ; Syed, Sheyum

Sorbitol dehydrogenase (SORD) deficiency has been identified as the most frequent autosomal recessive form of hereditary neuropathy. Loss of SORD causes high sorbitol levels in tissues due to the inability to convert sorbitol to fructose in the 2-step polyol pathway, leading to degenerative neuropathy. The underlying mechanisms of sorbitol-induced degeneration have not been fully elucidated, and no current FDA-approved therapeutic options are available to reduce sorbitol levels in the nervous system. Here, in a Drosophila model of SORD deficiency, we showed synaptic degeneration in the brain, neurotransmission defect, locomotor impairment, and structural abnormalities in the neuromuscular junctions. In addition, we found reduced ATP production in the brain and ROS accumulation in the CNS and muscle, indicating mitochondrial dysfunction. Applied Therapeutics has developed a CNS-penetrant next-generation aldose reductase inhibitor (ARI), AT-007 (govorestat), which inhibits the conversion of glucose to sorbitol. AT-007 significantly reduced sorbitol levels in patient-derived fibroblasts, induced pluripotent stem cell-derived (iPSC-derived) motor neurons, and Drosophila brains. AT-007 feeding in Sord-deficient Drosophila mitigated synaptic degeneration and significantly improved synaptic transduction, locomotor activity, and mitochondrial function. Moreover, AT-007 treatment significantly reduced ROS accumulation in Drosophila CNS, muscle, and patient-derived fibroblasts. These findings uncover the molecular and cellular pathophysiology of SORD neuropathy and provide a potential treatment strategy for patients with SORD deficiency.

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）

2024-04-04

·GlobeNewswire-Health Care

Applied Therapeutics to Present Results from Phase 3 ARISE-HF Study in Diabetic Cardiomyopathy at ACC 2024

NEW YORK, April 04, 2024 (GLOBE NEWSWIRE) -- Applied Therapeutics, Inc. (Nasdaq: APLT), a clinical-stage biopharmaceutical company developing a pipeline of novel drug candidates against validated molecular targets in indications of high unmet medical need, today announced that it will present full results from the Phase 3 ARISE-HF study evaluating AT-001 (caficrestat) in Diabetic Cardiomyopathy (DbCM) in an oral presentation at the 2024 American College of Cardiology (ACC) Annual Scientific Session to take place April 6-8, 2024 in Atlanta, Georgia. The Company announced topline results from ARISE-HF in January 2024, demonstrating a strong trend in stabilizing cardiac functional capacity with AT-001 treatment, and a statistically significant difference in cardiac functional capacity in a prespecified subgroup of patients not receiving concomitant treatment with an SGLT2 or GLP-1 while preventing clinically significant worsening. The presentation at ACC will also include important data on progression to overt heart failure and other secondary outcome measures. AT-001 treatment prevented progression to overt heart failure in patients with DbCM as compared to placebo (p=0.0285). Detailed safety data will also be presented, demonstrating that AT-001 was safe and well tolerated in a large cohort of patients, providing proof of concept that the technology has overcome the selectivity and safety issues of “old” aldose reductase inhibitors. The oral presentation at ACC will be followed by simultaneous publication of the study results in the Journal of the American College of Cardiology Journal (JACC). ACC Presentation: A Selective Aldose Reductase Inhibitor (AT-001) For the Treatment of Diabetic Cardiomyopathy: Primary Results of the Phase 3 Randomized Controlled ARISE-HF Study James L. Januzzi Jr, Javed Butler, Stefano Del Prato, Justin A. Ezekowitz, Nasrien E. Ibrahim, Carolyn S.P. Lam, Gregory D. Lewis, Thomas H. Marwick, Riccardo Perfetti, Julio Rosenstock, Scott D. Solomon, W.H. Wilson Tang, Faiez Zannad on behalf of the ARISE-HF Investigators Monday, April 8, 2024, 8:30 – 9:45 am ET, Main Tent (Hall B1) JACC Publication: Randomized Trial of a Selective Aldose Reductase Inhibitor in Patients with Diabetic Cardiomyopathy James L. Januzzi Jr, Javed Butler, Stefano Del Prato, Justin A. Ezekowitz, Nasrien E. Ibrahim, Carolyn S.P. Lam, Gregory D. Lewis, Thomas H. Marwick, Riccardo Perfetti, Julio Rosenstock, Scott D. Solomon, W.H. Wilson Tang, Faiez Zannad on behalf of the ARISE-HF Investigators Journal of the American College of Cardiology Published online April 8, 2024 About AT-001 (Caficrestat) AT-001 (caficrestat) is an investigational oral, novel, potent Aldose Reductase inhibitor in Phase 3 clinical development for the treatment of Diabetic Cardiomyopathy. The global ARISE-HF Phase 3 study evaluated the ability of AT-001 to improve or prevent worsening of disease, as measured by changes in cardiac functional capacity, in 675 patients with DbCM at high risk of progression to overt heart failure. The study demonstrated a positive impact of AT-001 treatment, which was statistically significant in a prespecified subgroup of patients not on concomitant treatment with an SGLT2 or GLP-1 inhibitor. AT-001 has been previously studied in a Phase 1/2 study in approximately 120 patients with type 2 diabetes, a subset of which had DbCM. About Applied Therapeutics Applied Therapeutics is a clinical-stage biopharmaceutical company developing a pipeline of novel drug candidates against validated molecular targets in indications of high unmet medical need. 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 Galactosemia, SORD Deficiency, and PMM2-CDG. The Company is also developing AT-001, a novel potent ARI, for the treatment of Diabetic Cardiomyopathy, or DbCM, a fatal fibrosis of the heart. The preclinical pipeline also includes AT-003, an ARI designed to cross through the back of the eye when dosed orally, for the treatment of Diabetic retinopathy. To learn more, please visit www.appliedtherapeutics.com and follow the company on Twitter @Applied_Tx. Forward-Looking Statements This press release contains “forward-looking statements” that involve substantial risks and uncertainties for purposes of the safe harbor provided by the Private Securities Litigation Reform Act of 1995. Any statements, other than statements of historical fact, included in this press release regarding the strategy, future operations, prospects, plans and objectives of management, including words such as “may,” “will,” “expect,” “anticipate,” “plan,” “intend,” “predicts” and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) are forward-looking statements. Forward-looking statements in this release involve substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by the forward-looking statements, and we, therefore cannot assure you that our plans, intentions, expectations or strategies will be attained or achieved. Such risks and uncertainties include, without limitation, (i) our plans to develop, market and commercialize our product candidates, (ii) the initiation, timing, progress and results of our current and future preclinical studies and clinical trials and our research and development programs, (iii) our ability to take advantage of expedited regulatory pathways for any of our product candidates, (iv) our estimates regarding expenses, future revenue, capital requirements and needs for additional financing, (v) our ability to successfully acquire or license additional product candidates on reasonable terms and advance product candidates into, and successfully complete, clinical studies, (vi) our ability to maintain and establish collaborations or obtain additional funding, (vii) our ability to obtain and timing of regulatory approval of our current and future product candidates, (viii) the anticipated indications for our product candidates, if approved, (ix) our expectations regarding the potential market size and the rate and degree of market acceptance of such product candidates, (x) our ability to fund our working capital requirements and expectations regarding the sufficiency of our capital resources, (xi) the implementation of our business model and strategic plans for our business and product candidates, (xii) our intellectual property position and the duration of our patent rights, (xiii) developments or disputes concerning our intellectual property or other proprietary rights, (xiv) our expectations regarding government and third-party payor coverage and reimbursement, (xv) our ability to compete in the markets we serve, (xvi) the impact of government laws and regulations and liabilities thereunder, (xvii) developments relating to our competitors and our industry, (xviii) our ability to achieve the anticipated benefits from the agreements entered into in connection with our partnership with Advanz Pharma and (xix) other factors that may impact our financial results. In light of the significant uncertainties in these forward-looking statements, you should not rely upon forward-looking statements as predictions of future events. Although we believe that we have a reasonable basis for each forward-looking statement contained in this press release, we cannot guarantee that the future results, levels of activity, performance or events and circumstances reflected in the forward-looking statements will be achieved or occur at all. Factors that may cause actual results to differ from those expressed or implied in the forward-looking statements in this press release are discussed in our filings with the U.S. Securities and Exchange Commission, including the “Risk Factors” contained therein. Except as otherwise required by law, we disclaim any intention or obligation to update or revise any forward-looking statements, which speak only as of the date they were made, whether as a result of new information, future events or circumstances or otherwise. Contacts Investors:Maeve Conneighton (212) 600-1902 orappliedtherapeutics@argotpartners.com Media:media@appliedtherapeutics.com

临床3期临床结果

2024-04-02

·Pharmaceutical Technology

Alexion’s Voydeya gains FDA approval for extravascular haemolysis

Alexion is exploring the potential of Voydeya as a monotherapy. Credit: Sai Thaw Kyar/Shutterstock.com. Alexion, AstraZeneca Rare Disease has received approval from the US Food and Drug Administration (FDA) for Voydeya (danicopan) as an add-on therapy to treat extravascular haemolysis (EVH) in adults with paroxysmal nocturnal haemoglobinuria (PNH). A first-in-class, oral Factor D inhibitor, Voydeya has been developed for patients who continue to suffer from EVH despite treatment with C5 inhibitors such as Ultomiris (ravulizumab) or Soliris (eculizumab). The FDA’s decision is grounded in the positive outcomes of the ALPHA Phase III trial, which demonstrated that Voydeya met its primary endpoint of haemoglobin change from baseline to week 12, alongside all key secondary endpoints. The drug was generally well-tolerated with no new safety concerns. As part of the ALPHA double-blind, placebo-controlled, multiple-dose trial, patients were enrolled and randomised to receive Voydeya or placebo apart from their ongoing Soliris or Ultomiris therapy over 12 weeks. See Also: US FDA grants fast track status to LISCure’s LB-P8 drug for PSC FDA extends review period for Applied Therapeutics’ govorestat NDA It aimed to assess the superiority of Voydeya as an adjunct to C5 inhibitor therapy. The trial included a prespecified interim analysis and an option for a two-year extension period for those completing the initial 24 weeks. Japan already approved Voydeya and the European Union is poised to follow suit. The drug has also achieved breakthrough therapy designation in the US and PRIority MEdicines (PRIME) status in the EU. Alexion CEO Marc Dunoyer stated: “The approval of first-in-class, Factor D inhibitor Voydeya marks an important advancement in the treatment of PNH and builds on our leadership and commitment to bring forward innovation in complement science. “As the ALPHA trial suggests, dual complement pathway inhibition at Factor D and C5 may be an optimal treatment approach for this subset of patients with EVH, enabling them to continue with proven standard-of-care therapy.” Alexion is also exploring Voydeya’s potential as a monotherapy for geographic atrophy in a Phase II clinical trial. The FDA recently approved Alexion’s Ultomiris to treat adults with anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder.

临床3期快速通道临床结果临床2期上市批准

2024-03-29

·FierceBiotech

FDA decision delay for Applied Tx rare disease drug sends biotech's stock tumbling after hours

Applied Therapeutics shared news of the FDA delay after market close on Thursday, sending the company’s stock down 14% after hours. Even after a failed phase 3 pediatric clinical trial, Applied Therapeutics forged ahead with an FDA filing for potential market approval. Now the regulatory agency has extended the review period for the rare disease prospect, pushing back a possible decision date into November and sending the biotech’s stock tumbling. The drug at question is govorestat, an aldose reductase inhibitor designed to treat classic galactosemia, an inherited metabolic disorder. In February, the FDA accepted the investigational drug for review, granting priority review, with a decision slated for Aug. 28. Now, the agency has moved that date back three months to Nov. 28, according to a March 28 release. The FDA told Applied that more time was needed to examine supplemental analyses of already submitted data and determined that the additional info constitutes a major amendment to the new drug application, according to the release. Applied shared news of the delay after market close on Thursday, sending the company’s stock down 14% after hours, dropping from $6.80 per share at close to $5.80 as of 7:57 p.m. ET, March 28. “While the PDUFA action date extension represents a delay, we remain confident in the potential for govorestat approval for galactosemia and we will continue to work closely with the FDA throughout the review process,” Applied founder and CEO Shoshana Shendelman, Ph.D., said in the release. “During this time, we are committed to maintaining the expanded access program for govorestat to ensure patients with galactosemia have the opportunity to receive this important treatment.” Last April, the biotech shared phase 3 results assessing the asset, which is the company’s lead pipeline program. The study found that govorestat was no better than placebo at improving a composite of four measures—including language skills, self-care capabilities and more—among children with galactosemia. Despite the failure, the New York-based biotech argued that the data show “consistent and sustained clinical benefit on activities of daily living, behavioral symptoms, cognition, adaptive behavior and tremor,” and filed a new drug application with the FDA. Initially, Applied had planned to ask for U.S. approval on the strength of biomarker data, only for the FDA to say it would likely need evidence the drug candidate improves clinical outcomes to receive a positive decision. The phase 3 trial gave Applied evidence of the effect of govorestat, also known as AT-007, on clinical outcomes. This isn’t the first of the company’s troubles with the drug. Back in August 2020, the FDA placed a partial clinical hold on the late-stage govorestat program, requesting more technical information to ensure patients had "access to the prospect of direct benefit of the drug." If approved, govorestat would become the first medication for treating galactosemia. The candidate has snagged orphan drug designation, fast track status and pediatric rare disease designation from the FDA in the indication. Applied is also assessing govorestat as a potential treatment for two other rare neurological diseases: SORD Deficiency and PMM2-CDG.

临床3期优先审批快速通道孤儿药临床结果

100 项与 Govorestat 相关的药物交易

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研发状态

适应症	最高研发状态	国家/地区	公司
半乳糖血症	申请上市	欧盟更多	Applied Therapeutics, Inc. 更多
1A型先天性糖基化障碍	临床1期	-	Applied Therapeutics, Inc. 更多
腓骨肌萎缩症	临床阶段不明	欧盟更多	Advanz Pharma Corp. Ltd. 更多
山梨糖醇脱氢酶缺乏症	无进展	美国更多	Applied Therapeutics, Inc. 更多

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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	顧積齋簾築繭糧製餘願(餘艱積齋網遞餘窪積製) = 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). 範簾網鹹蓋繭鬱範遞醖 (遞壓糧餘窪鏇獵夢餘簾 ) 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	淵蓋膚窪淵鑰範繭淵窪(簾淵選蓋範簾製餘鑰淵) = 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. 夢夢繭鹹簾鬱簾襯衊簾 (願積鑰鏇鑰艱築窪餘繭 )	积极	2022-10-06
				Placebo