Randomized, Double Blind, Placebo Controlled, Multicenter, 12 Weeks Phase 2 Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Oral AZ-3102 in Patients With GM2 Gangliosidosis or Niemann-Pick Type C Disease

This phase 2 is a randomized, double-blind, placebo controlled, 12 weeks study with daily oral administration of AZ-3102 aiming to evaluate the safety and pharmacokinetic (PK) profile in GM2 Gangliosidosis and Niemann-Pick type C disease (NP-C) patients. If approved by the country health authorities, a double-blind extension period will be proposed to the patients who complete the 12-week study.

开始日期2023-04-24

申办/合作机构

Azafaros BV初创企业

ACTRN12621000576820 / Completed临床1期

A First-in-Human, Randomized, Double-Blind, Placebo-Controlled, Sequential-Panel, Ascending Single- and Multiple-Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AZ-3102 in Healthy Volunteers

开始日期2021-03-23

申办/合作机构

Azafaros BV初创企业

100 项与 Nizubaglustat 相关的临床结果

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100 项与 Nizubaglustat 相关的转化医学

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100 项与 Nizubaglustat 相关的专利（医药）

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项与 Nizubaglustat 相关的文献（医药）

2022-06-01·Planta2区 · 生物学

Screening, cloning and functional characterization of key methyltransferase genes involved in the methylation step of 1-deoxynojirimycin alkaloids biosynthesis in mulberry leaves

2区 · 生物学

Article

作者: Du, Wenmin ; Wan, Jingqiong ; Liao, Yangzhen ; Wei, Yuan ; Ouyang, Zhen ; Liu, Jia ; Liu, Chang

MAIN CONCLUSIONThe novel C-methyltransferase, MaMT1, could catalyze the conversion of piperidine to 2-methylpiperidine, which may be involved in the methylation step of DNJ biosynthesis in mulberry leaves. Mulberry (Morus alba L.) is a worldwide crop with medicinal, feeding and nutritional value, and 1-deoxynojirimycin ((2R, 3R, 4R, 5S)-2-hydroxymethyl-3, 4, 5-trihydroxypiperidine, DNJ) alkaloid, a potent α-glucosidase inhibitor, is its main active ingredient. Our previous researches clarified the biosynthetic pathway of DNJ from lysine to Δ¹-piperideine, but its downstream pathway is unclear. Herein, eight differential methyltransferases (MTs) genes were screened from transcriptome profiles of mulberry leaves with significant differences in DNJ content (P < 0.01). Subsequently, MaMT1 (OM140666) and MaMT2 (OM140667) were hypothesized as candidate genes related to DNJ biosynthesis by correlation analysis of genes expression levels and DNJ content of mulberry leaves at different dates. Functional characterization of MaMT1 and MaMT2 were performed by cloning, prokaryotic expression and enzymatic reaction in vitro, and it showed that MaMT1 protein could catalyze the conversion of piperidine to 2-methylpiperidine. Moreover, molecular docking confirmed the interaction of MaMT1 protein with piperidine and S-adenosyl-L-methionine (SAM), indicating that MaMT1 had C-methyltransferase activity, while MaMT2 did not. The above results suggested that MaMT1 may be involved in the methylation step of DNJ alkaloid biosynthesis in mulberry leaves, which is a breakthrough in the analysis of DNJ alkaloid biosynthetic pathway. It is worth mentioning that the novel MaMT1, annotated as serine hydroxymethyltransferase, could rely on SAM to perform C-methyltransferase function. Therefore, our findings contribute new insights into the research of DNJ alkaloid biosynthesis and C-methyltransferase family.

2006-07-01·Journal of Medicinal Chemistry1区 · 医学

Further Structural Exploration of Trisubstituted Asymmetric Pyran Derivatives (2S,4R,5R)-2-Benzhydryl-5-benzylamino-tetrahydropyran-4-ol and Their Corresponding Disubstituted (3S,6S) Pyran Derivatives: A Proposed Pharmacophore Model for High-Affinity Interaction with the Dopamine, Serotonin, and Norepinephrine Transporters

1区 · 医学

Article

作者: Fernandez, Fernando ; Reith, Maarten E. A. ; Zhen, Juan ; Zhang, Shijun ; Deschamps, Jeffrey ; Hazeldine, Stuart ; Dutta, Aloke K.

In our previous report, we described a novel series of asymmetric pyran derivatives (2S,4R,5R)-2-benzhydryl-5-benzylamino-tetrahydropyran-4-ol and their enantiomers as blockers of monoamine transporters in the brain. In this report, we describe the further exploration of this series of molecules by incorporating functional groups in the molecular template, which should promote the formation of H bonds with the transporters. In addition, a new synthetic scheme for the asymmetric synthesis of disubstituted cis-(6-benzhydryl-tetrahydro-pyran-3-yl)-benzylamine analogues and their biological characterization is reported. All synthesized derivatives were tested for their affinities for the dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET) in the brain by measuring their potency in inhibiting the uptake of [(3)H]DA, [(3)H]5-HT, and [(3)H]NE, respectively. The compounds were also tested for their binding potency at the DAT by their ability to inhibit binding of [(3)H]WIN 35, 428. The results indicated that the presence of functional groups, such as -OH, -NH(2), and the bioisosteric 5-substituted indole moiety in both di and trisubstituted compounds, significantly increased their potencies for the SERT and NET, especially for the NET. Among the trisubstituted compounds, (-)-4b exhibited the highest potency for the NET and the SERT (K(i) of 2.13 and 15.3 nM, respectively) and was a serotonin norepinephrine reuptake inhibitor (SNRI). Compound (-)-4a exhibited the highest selectivity for the NET. Among the disubstituted compounds, a number of compounds, such as (-)-9a, (+)-9b, (-)-9b, and (+)-9d, exhibited significant low-nanomolar potencies for the SERT and the NET. Interestingly, compound (-)-9d exhibited appreciable potencies at all three transporters. On the basis of our present and past findings, we propose a qualitative model for the interaction of these compounds with monoamine transporters, which will be refined further in the future.

2005-01-01·Chemical Communications2区 · 化学

Stereoselective synthesis of (2S,3S,4R,5S)-5-methylpyrrolidine-3,4-diol derivatives that are highly selective α-l-fucosidase inhibitors

2区 · 化学

Article

作者: Ana T. Carmona ; Inmaculada Robina ; Antonio J. Moreno-Vargas ; Pierre Vogel ; Federico Mora

N-Phenylaminomethyl benzimidazolyl moieties attached at C-2 of (2S,3S,4R,5S)-5-methylpyrrolidine-3,4-diol increase the potency and selectivity of the inhibitory activity of these systems towards alpha-L-fucosidases.

项与 Nizubaglustat 相关的新闻（医药）

2024-09-24

·Outsourcing Pharma

FDA greenlights first treatment for Niemann-Pick disease type C

NPC is a progressive disease where the patient has a mutation in NPC1 or NPC2 – genes that are involved in the processing of cholesterol and other lipids inside cells. Cells with this mutation have a faulty management of lipids, leading to organ damage and neurological symptoms including difficulty with speech and cognition. Delivered as an oral treatment three times per day, Miplyffa boosts the activity of two proteins in the cell called transcription factors EB (TFEB) and E3 (TFE3). These proteins upregulate genes encoding proteins that help lipids within cells to return to healthy levels. Miplyffa is specifically approved for use in combination with miglustat, a drug that is used off-label to treat NPC in around 80% of patients in the U.S. Miplyffa was approved based on results from a phase 2 trial where the drug slowed the progression of NPC compared to patients given a placebo. The company plans to launch the drug within 12 weeks of its approval and expects to set an average price of $85,000 per month for each patient, said president and CEO of Zevra Therapeutics Neil McFarlane in a public conference call . At the same time, Zevra launched a patient support program called AmplifyAssist to help patients and carers with personalized insurance coverage education and assistance with finding funding for their needs. “The FDA approval of Miplyffa marks a significant moment for those living with NPC and the global NPC community,” stated Elizabeth Berry-Kravis, professor at Rush University Medical Center, who worked with Zevra to research Miplyffa use in a real-world setting. She added that effective NPC treatment “requires multiple treatment options due to the complexity of the disease” and that “patients will now have more access to treatments to tackle this devastating disease.” googletag.cmd.push(function () { googletag.display('text-ad1'); }); Arimoclomol was previously developed by the Danish company Orphazyme, which rose to fame in 2021 as a so-called ‘meme’ stock whose price was influenced by social media. In the same year, Orphazyme was slapped with a rejection of arimoclomol from the U.S. FDA in 2021, with the regulator requesting more data. Grappling with bankruptcy, Orphazyme sold its assets to Zevra (then known as KemPharm) in 2022 for $12.8 million. Another candidate in development is IntraBio’s small molecule therapy which is being reviewed by the U.S. FDA with a decision expected in the coming days. And the Dutch company Azafaros is taking its candidate nizubaglustat into phase 3 testing in patients with a genetic diagnosis of either GM2 gangliosidosis or NPC next year .

临床2期上市批准临床3期并购临床结果

2024-09-10

·Business Wire

Positive Niemann-Pick disease type C (NPC) and GM2 gangliosidosis data from nizubaglustat Phase 2 RAINBOW study conducted by Azafaros presented at major metabolic disease conference

LEIDEN, Netherlands--( BUSINESS WIRE )--Azafaros has announced that data from the ongoing double-blind, placebo-controlled Phase 2 RAINBOW study investigating its lead asset, nizubaglustat in patients with Niemann-Pick disease type C (NPC) or GM2 gangliosidosis, were presented at the Society for the Study of Inborn Errors of Metabolism (SSIEM) annual symposium in Porto, Portugal. The results of part one of the study, designed to determine the safety, pharmacodynamics, and pharmacokinetics of the Company’s lead asset nizubaglustat, demonstrated the compound had a positive safety profile and was well-tolerated in the 13 participants in the study. All patients are now enrolled in the extension phase of the trial, where initial unblinded data on 10 patients showed 8 had improved or stabilized SARA (Scale for the Assessment and Rating of Ataxia) scores. Additionally, a reduction in seizure frequency was observed for the participants who had experienced daily seizures before recruitment into the study. Data from the RAINBOW study will be used to inform the target dose for Azafaros’ planned Phase 3 pivotal studies, due to be initiated 2025. At the conference, Azafaros also presented 12-month follow-up data from the company’s PRONTO trial, a natural history study of late-infantile/juvenile GM1 and GM2 gangliosidoses. PRONTO is the largest prospective natural history study of these two rare diseases, providing valuable insights for the further development of nizubaglustat in GM1 and GM2 and for the gangliosidoses research community in general. Stefano Portolano , MD, CEO of Azafaros, said: “ The RAINBOW trial results support the positive safety profile of nizubaglustat and provide us with encouraging early efficacy trends for the compound. We greatly appreciate the opportunity to discuss these data with the scientific community at the SSIEM annual symposium, and believe our compound offers a potential new solution to patients with rare lysosomal storage disorders with neurological involvement where there is a strong unmet medical need. We look forward to using the insights provided by results from both RAINBOW and PRONTO to keep the strong momentum of our clinical program and move the compound into pivotal trials next year .” Azafaros is thankful to the patients and their families for their participation in the RAINBOW study. Ends About the RAINBOW study The RAINBOW trial is a Phase 2 clinical study designed to evaluate safety, tolerability, pharmacokinetics and pharmacodynamics of AZ-3102 (nizubaglustat) in patients with GM2 and Niemann-Pick type C (NPC) diseases. The study was conducted across three sites in Brazil, involving 13 patients older than 12 years of age. In the first part of the study patients were randomized to receive either a high dose or low dose of nizubaglustat or placebo. All patients continued into the second part of the study where they are randomized to receive either high or low dose nizubaglustat for 52 weeks. About the PRONTO study The PRONTO study is a prospective natural history study designed to assess the progression of neurological disease in late-infantile and juvenile GM1 and GM2 gangliosidoses. The study includes participants with a late-infantile/juvenile form, genetic diagnosis, and who are between 2 and 20 years old and the main objective was to provide insight and understanding of disease progression using clinical scales, caregiver questionnaires, and actigraphy. A total of 30 participants were recruited from 6 countries with at least 12-month follow-up data on 21 participants. About nizubaglustat Nizubaglustat is a small molecule, orally available and brain penetrant azasugar with a unique dual mode of action, developed as a potential treatment for rare lysosomal storage disorders with neurological involvement, including GM1 and GM2 gangliosidoses and Niemann-Pick disease type C (NPC). Nizubaglustat has received the following designations and support: United States Food and Drug Administration (FDA) Rare Pediatric Disease Designations (RPDD) for the treatment of GM1 and GM2 gangliosidoses and NPC. Orphan Drug Designations (ODD) for GM2 gangliosidosis (Sandhoff and Tay-Sachs Diseases) and NPC. IND Clearance and Fast Track Designation for GM1/GM2 gangliosidoses and NPC European Medicines Agency (EMA) Orphan Medicinal Product Designation (OMPD) for the treatment of GM2 gangliosidosis. UK Medicines and Healthcare Products Regulatory Agency (MHRA) Innovation Passport for the treatment of GM1 and GM2 gangliosidoses. About GM1 and GM2 Gangliosidoses GM1 gangliosidosis and GM2 gangliosidosis (Tay-Sachs and Sandhoff diseases) are lysosomal storage disorders caused by the accumulation of GM1 or GM2 gangliosides respectively, in the central nervous system (CNS), resulting in progressive and severe neurological impairment and early death. These diseases mostly affect infants and children, and no disease-modifying treatments are currently available. About Niemann-Pick Disease Type C (NPC) Niemann-Pick disease type C (NPC) is a progressive, life-limiting neurological lysosomal storage disorder caused by mutations in the NPC1 or NPC2 gene and aberrant endosomal-lysosomal trafficking, leading to the accumulation of various lipids, including gangliosides in the CNS. The onset of disease can happen throughout the lifespan of an affected individual, from prenatal life through adulthood. About Azafaros Azafaros is a clinical-stage company founded in 2018 by scientists with a deep understanding of rare genetic disease mechanisms, using discoveries made by scientists at Leiden University and Amsterdam UMC. Azafaros is led by a team of highly experienced industry experts and aims to build a pipeline of disease-modifying therapeutics to offer new treatment options to patients and their families. The Azafaros team is dedicated to rapidly bring new drugs to the rare disease patients who need them. The company is supported by a syndicate of leading investors including Forbion, BioGeneration Ventures (BGV), BioMedPartners, Asahi Kasei Pharma Ventures, and Schroders Capital.

临床2期孤儿药快速通道临床结果

2024-03-12

·BioSpace

Azafaros announces completion of 12-week Phase 2 RAINBOW study evaluating lead asset nizubaglustat in rare disease patients

Azafaros announces completion of 12-week Phase 2 RAINBOW study evaluating lead asset nizubaglustat in rare disease patients Major milestone reached in bringing new treatment options to patients and their families. Leiden, The Netherlands, March 12, 2024 – Azafaros B.V. today announced the completion of its 12-week Phase 2 clinical study, RAINBOW (Phase 2 RAINBOW studyNCT05758922). The randomized, double-blind, placebo-controlled study, conducted in Brazil, involved 13 patients from the age of 12 years who are affected by GM2 gangliosidosis or Niemann-Pick disease type C (NPC). The aim of the RAINBOW study is to determine the safety, pharmacodynamics, and pharmacokinetics of two different doses of nizubaglustat in patients, in order to identify the target dosage for Azafaros’ planned Phase 3 pivotal studies. The main part of the study is now complete, and patients are entering the extension phase, in which all of them will be given the study drug. Top line results of the RAINBOW study are expected to be announced in Q2 2024 and presented to the scientific community later this year. Prof. Dr. Roberto Giugliani, Chief of the Medical Genetics Clinical Research Group at the Hospital de Clinicas de Porto Alegre and Lead Principal Investigator for the study, said: “This is an important milestone because nizubaglustat has a dual mode of action that represents a leap forward from other agents. This dual activity targets some of the fundamental biology of the diseases with high potency and it might offer promise in pivotal studies.” Chris Freitag, Chief Medical Officer at Azafaros, said: “This is a major milestone on our journey to provide patients and their families with a potentially transformative treatment. With the RAINBOW data, we will be able to identify the optimal dose for a pediatric population in our Phase 3 efficacy study, which we plan to initiate as soon as the dose is determined, and the required approvals are in place. We are looking forward to presenting the data from RAINBOW to the scientific community. Azafaros is grateful to the patients and their families who made the decision to participate in this study.” About nizubaglustat Nizubaglustat is a small molecule, orally available and brain penetrant azasugar with a unique dual mode of action, developed as a potential treatment for rare lysosomal storage disorders with neurological involvement, including GM1 and GM2 gangliosidoses and Niemann-Pick disease type C (NPC). Nizubaglustat has received the following designations and support: United States Food and Drug Administration (FDA) Rare Pediatric Disease Designations (RPDD) for the treatment of GM1 and GM2 gangliosidoses and NPC. Orphan Drug Designations (ODD) for GM2 gangliosidosis (Sandhoff and Tay-Sachs Diseases) and NPC. Fast Track Designation and IND clearance for GM1 and GM2 gangliosidoses. European Medicines Agency (EMA) Orphan Medicinal Product Designation (OMPD) for the treatment of GM2 gangliosidosis. UK Medicines and Healthcare Products Regulatory Agency (MHRA) Innovation Passport for the treatment of GM1 and GM2 gangliosidoses. About GM1 and GM2 Gangliosidoses GM1 gangliosidosis and GM2 gangliosidosis (Tay-Sachs and Sandhoff diseases) are lysosomal storage disorders caused by the accumulation of GM1 or GM2 gangliosides respectively, in the central nervous system (CNS), resulting in progressive and severe neurological impairment and early death. These diseases mostly affect infants and children, and no disease-modifying treatments are currently available. About Niemann-Pick Disease Type C (NPC) Niemann-Pick disease type C (NPC) is a progressive, life-limiting neurological lysosomal storage disorder caused by mutations in the NPC1 or NPC2 gene and aberrant endosomal-lysosomal trafficking, leading to the accumulation of various lipids, including gangliosides in the CNS. The onset of disease can happen throughout the lifespan of an affected individual, from prenatal life through adulthood. About Azafaros Azafaros is a clinical-stage company founded in 2018 with a deep understanding of rare genetic disease mechanisms, a compound library from Leiden University, and led by a team of highly experienced industry experts. Azafaros aims to build a pipeline of disease-modifying therapeutics to offer new treatment options to patients and their families. By applying its knowledge, network and courage, the Azafaros team challenges traditional development pathways to rapidly bring new drugs to the rare disease patients who need them. Azafaros is supported by a syndicate of leading Dutch and Swiss investors including Forbion, BioGeneration Ventures, BioMedPartners, Asahi Kasei Pharma Ventures, and Schroders Capital. Media ICR Consilium Amber Fennell, Ashley Tapp +44 (0)20 3709 5700 Azafaros@consilium-comms.com

孤儿药临床2期快速通道

100 项与 Nizubaglustat 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
GM2神经节苷脂贮积症	临床2期	巴西	Azafaros BV初创企业	2023-04-24
C型尼曼匹克病	临床2期	巴西	Azafaros BV初创企业	2023-04-24
溶酶体贮积病	临床前	澳大利亚	Azafaros BV初创企业	2021-03-27

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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


NCT05758922 (RAINBOW, BusinessWire) 人工标引	临床2期	C型尼曼匹克病 \| GM2神经节苷脂贮积症	13	Nizubaglustat	(衊繭壓遞築鏇廠齋範齋) = had a positive safety profile and was well-tolerated in the 13 participants in the study. 範鹽窪遞鏇築廠鹽齋製 (鑰簾艱網憲淵顧餘獵網 ) 更多	积极	2024-09-10
				Placebo