A Phase 2/3, Randomised, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Davunetide for the Treatment of Progressive Supranuclear Palsy.

开始日期2010-11-08

申办/合作机构

Allon Therapeutics, Inc.

NCT01110720 / Completed临床2/3期

A Phase 2/3, Randomized, Double-Blind, Placebo-Controlled, Study to Evaluate the Safety and Efficacy of Davunetide for the Treatment of Progressive Supranuclear Palsy

The purpose of the study is to evaluate the safety and efficacy of davunetide for the treatment of Progressive Supranuclear Palsy.

开始日期2010-10-01

申办/合作机构

Allon Therapeutics, Inc.

NCT00505765 / Completed临床2期IIT

A Multicenter Ascending Dose, Double Blind, Placebo-controlled Study of NAP (AL-108) in Chronic Schizophrenia

The TURNS is a NIMH-funded contract for the evaluation of new compounds for the treatment of cognitive impairments in schizophrenia (HHSN 27820044 1003C; P.I.: Steve Marder, M.D.). Despite advances in the safety, tolerability, and effectiveness of antipsychotic medications for the treatment of schizophrenia, many patients continue to be plagued by impairments in social and work functioning. Persons with schizophrenia commonly show deficits in a number of areas of cognition that include impairments in attention, memory, and executive functioning (the ability and organize one's behavior). Importantly, a large body of literature now shows a link between cognition and community functioning in schizophrenia. It is believed that treatments that improve cognitive deficits may lead to improvements in work and social functioning.
One approach to improve the community functioning of patients with schizophrenia is to develop new agents that treat the cognitive deficits of the illness. A promising agent is called AL-108. This drug is administered as a nasal spray. Studies in animals suggest that this drug may protect neurons and may improve cognition in schizophrenia. The current study is a twelve-week multicenter, double-blind, randomized clinical trial of two doses of AL-108 (5 and 30 mg/day intranasally) versus placebo in the treatment of persistent cognitive dysfunction in schizophrenia. The study medication will be added to patients' current atypical antipsychotic medication or to their current injectable first-generation antipsychotic medication. The primary outcome measure will consist of the composite score of the MATRICS neuropsychological battery. Secondary outcome measures will include scores on symptoms, functional outcome, and safety measures. Sixty clinically stable patients with schizophrenia, drawn from eight sites, will participate in the study. Twenty-five patients will be enrolled at UCLA.

开始日期2007-07-01

申办/合作机构

University of California, Los Angeles

[+7]

100 项与 Davunetide 相关的临床结果

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100 项与 Davunetide 相关的转化医学

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100 项与 Davunetide 相关的专利（医药）

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项与 Davunetide 相关的文献（医药）

2024-01-01·Cytoskeleton (Hoboken, N.J.)

Tau, ADNP, and sex

Article

作者: Gozes, Illana

Abstract:

With 50 years to the original discovery of Tau, I gave here my perspective, looking through the prism of activity‐dependent neuroprotective protein (ADNP), and the influence of sex. My starting point was vasoactive intestinal peptide (VIP), a regulator of ADNP. I then moved to the original discovery of ADNP and its active neuroprotective site, NAP, drug candidate, davunetide. Tau–ADNP–NAP interactions were then explained with emphasis on sex and future translational medicine.

2024-01-01·ZOOLOGICAL RESEARCH

Integrated ribosome and proteome analyses reveal insights into sevoflurane-induced long-term social behavior and cognitive dysfunctions through ADNP inhibition in neonatal mice

Article

作者: Zhai, Mei-Ting ; Zeng, Tian ; Zhang, Yao ; Shi, Xiao-Tong ; Zhang, Hui ; Cao, Shu-Hui ; Zhao, You-Yi ; Fan, Ze ; Ma, San-Xin ; Liang, Li-Rong ; He, Dan-Yi ; Liu, Bing

A growing number of studies have demonstrated that repeated exposure to sevoflurane during development results in persistent social abnormalities and cognitive impairment. Davunetide, an active fragment of the activity-dependent neuroprotective protein (ADNP), has been implicated in social and cognitive protection. However, the potential of davunetide to attenuate social deficits following sevoflurane exposure and the underlying developmental mechanisms remain poorly understood. In this study, ribosome and proteome profiles were analyzed to investigate the molecular basis of sevoflurane-induced social deficits in neonatal mice. The neuropathological basis was also explored using Golgi staining, morphological analysis, western blotting, electrophysiological analysis, and behavioral analysis. Results indicated that ADNP was significantly down-regulated following developmental exposure to sevoflurane. In adulthood, anterior cingulate cortex (ACC) neurons exposed to sevoflurane exhibited a decrease in dendrite number, total dendrite length, and spine density. Furthermore, the expression levels of Homer, PSD95, synaptophysin, and vglut2 were significantly reduced in the sevoflurane group. Patch-clamp recordings indicated reductions in both the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs). Notably, davunetide significantly ameliorated the synaptic defects, social behavior deficits, and cognitive impairments induced by sevoflurane. Mechanistic analysis revealed that loss of ADNP led to dysregulation of Ca ²⁺ activity via the Wnt/β-catenin signaling, resulting in decreased expression of synaptic proteins. Suppression of Wnt signaling was restored in the davunetide-treated group. Thus, ADNP was identified as a promising therapeutic target for the prevention and treatment of neurodevelopmental toxicity caused by general anesthetics. This study provides important insights into the mechanisms underlying social and cognitive disturbances caused by sevoflurane exposure in neonatal mice and elucidates the regulatory pathways involved.

2023-09-11·Cells

NAP (Davunetide): The Neuroprotective ADNP Drug Candidate Penetrates Cell Nuclei Explaining Pleiotropic Mechanisms.

Article

作者: Ivashko-Pachima, Yanina ; Karmon, Gidon ; Ganaiem, Maram ; Gozes, Illana ; Shazman, Shula ; Gildor, Nina D

(1) Background: Recently, we showed aberrant nuclear/cytoplasmic boundaries/activity-dependent neuroprotective protein (ADNP) distribution in ADNP-mutated cells. This malformation was corrected upon neuronal differentiation by the ADNP-derived fragment drug candidate NAP (davunetide). Here, we investigated the mechanism of NAP nuclear protection. (2) Methods: CRISPR/Cas9 DNA-editing established N1E-115 neuroblastoma cell lines that express two different green fluorescent proteins (GFPs)-labeled mutated ADNP variants (p.Tyr718* and p.Ser403*). Cells were exposed to NAP conjugated to Cy5, followed by live imaging. Cells were further characterized using quantitative morphology/immunocytochemistry/RNA and protein quantifications. (3) Results: NAP rapidly distributed in the cytoplasm and was also seen in the nucleus. Furthermore, reduced microtubule content was observed in the ADNP-mutated cell lines. In parallel, disrupting microtubules by zinc or nocodazole intoxication mimicked ADNP mutation phenotypes and resulted in aberrant nuclear-cytoplasmic boundaries, which were rapidly corrected by NAP treatment. No NAP effects were noted on ADNP levels. Ketamine, used as a control, was ineffective, but both NAP and ketamine exhibited direct interactions with ADNP, as observed via in silico docking. (4) Conclusions: Through a microtubule-linked mechanism, NAP rapidly localized to the cytoplasmic and nuclear compartments, ameliorating mutated ADNP-related deficiencies. These novel findings explain previously published gene expression results and broaden NAP (davunetide) utilization in research and clinical development.

项与 Davunetide 相关的新闻（医药）

2022-05-26

·BioSpace

Research Roundup: New Insight into Gene Mutations Associated with Autism, Schizophrenia

Researchers have associated gene mutations with certain neurological disorders, such as autism and schizophrenia. However, it wasn’t entirely clear how these mutations resulted in the disorders they were associated with. Now, new research has tied some of the mechanisms together. For that and more research news, continue reading. Mutational Mechanism in Different Genes Linked to Autism, Schizophrenia and More Researchers at Tel Aviv University have worked out a mechanism shared by mutations in the ADNP and SHANK3 genes, which cause autism, schizophrenia and other conditions. They also conducted assays using an experimental drug developed in Prof. Illana Gozes’ laboratory that is effective in laboratory models for the mutations. They believe it provides encouraging results for possible treatments for a range of diseases that impair brain functions and cause autism, schizophrenia, and neurodegenerative diseases such as Alzheimer’s. The research was published in Molecular Psychiatry. “Some cases of autism are caused by mutations in various genes,” said Gozes, who led the research. “Today we know of more than 100 genetic syndromes associated with autism, 10 of which are considered relatively common (though still extremely rare). In our lab we focus mainly on one of these, the ADNP syndrome, caused by mutations in the ADNP gene, which disrupt the function of the ADNP protein, leading to structural defects in the skeleton of neurons in the brain. In the current study, we identified a specific mechanism that causes this damage in mutations in two different genes: ADNP and SHANK3 — a gene associated with autism and schizophrenia. According to estimates, these two mutations are responsible for thousands of cases of autism around the world.” They found that when the ADNP protein is defective, it forms neurons with faulty microtubules, which impairs brain functions. Also, ADNP mutations take different forms, which can result in varying levels of damage. In some cases, a mutation added to the protein protects it and reduces the damage. That same control site is found on SHANK3. They also found that more sites on the ADNP protein can bond with SHANK3 and similar proteins. One of the sites is located on NAP, a section of ADNP that was developed into their experimental drug, davunetide. Gozes said, “We concluded that the ability to bond with SHANK3 and other similar proteins provides some protection against the mutation’s damaging effects.” Single Nucleotide Mutation Provides Insight into Epilepsy Researchers at Linkoping University found a previously unidentified mutation in a child with epilepsy. It involved a single nucleotide in the KCNA2 gene, which produces an ion channel protein. These proteins form pores in the cell surface membrane. In epilepsy, the balance in the brain between signals that increase cell activity and signals that suppress it is disturbed, and the nerve cells send signals in an uncontrolled fashion. In the patient, the mutated ion channel would typically have a calming effect on nerve signaling. The researchers noted that mutations in ion channels that increase function and others that decrease function have been linked to epilepsy. It appears that there needs to be just the right amount of activity. In the case of this patient, because he had one mutated copy and one normal, they would have expected 50% functional ion channels. But they found the channel activity in the laboratory was as low as 20% compared to normal. The mutation seemed to decrease the function of the normal proteins. Possible New Marker for Breast Cancer Patients Investigators from the University of Southampton identified “crown-like structures” surrounding breast tumors in overweight and obese patients that may inhibit their response to therapy. They believe this may eventually be used to enhance personalized treatments for patients with HER2-positive overexpressed breast cancer. The crown-like structures are formed from inflammatory immune cells called macrophages. This appears to cause an inflammatory environment in the breast, leading to the initiation and growth of new tumors. In the study, patients who were overweight or obese had significantly more of these structures in their fat tissue surrounding the tumor, which was associated with a faster shift to metastatic disease. They then identified a potential molecular biomarker, CD32B, on the surface of the macrophages in these structures. When CD32B was present in these patients, their response to trastuzumab therapy was worse. Preventing or Delaying Type 2 Diabetes The 21-year follow-up from the Diabetes Prevention Program Outcomes Study (DPPOS) was published in Circulation. The new findings describe the 21-year follow-up of more than 3,200 adults with prediabetes who participated in the original Diabetes Prevention Program trial. The study found that lifestyle changes or the use of metformin were effective long-term in preventing or delaying Type 2 diabetes in adults with prediabetes, but these changes didn’t appear to decrease the risk of heart attack, stroke or dying from cardiovascular disease compared to the standard care group. Almost 11% of the U.S. population has been diagnosed with Type 2 diabetes or more than 34 million people. It is caused by the body’s inability to efficiently utilize insulin manufactured in the pancreas. Adults with type 2 diabetes are twice as likely to die from cardiovascular disease than adults without T2D. People with T2D often have other risk factors, including overweight or obesity, high blood pressure or high cholesterol. “The fact that neither a lifestyle intervention program nor metformin led to a decrease in cardiovascular disease among people with prediabetes may mean that these interventions have limited or no effectiveness in preventing cardiovascular disease, even though they are highly effective in preventing or delaying the development of Type 2 diabetes,” Dr. Ronald B. Goldberg, M.D. said, chair of the writing group for the DPPOS and a professor of medicine, biochemistry and molecular biology in the division of diabetes, endocrinology and metabolism, and senior faculty member and co-director of the Diabetes Research Institute Clinical Laboratory at the University of Miami’s Miller School of Medicine in Miami, Florida. “It’s important to note that most study participants also received treatment with cholesterol and blood pressure medications, which are known to reduce CVD risk. Therefore, the low rate of development of cardiovascular disease found overall may have been due to these medications, which would make it difficult to identify a beneficial effect of lifestyle or metformin intervention. Future research to identify higher risk subgroups is needed to develop a more targeted approach to cardiovascular disease prevention in people with prediabetes and Type 2 diabetes.”

2010-11-10

·BioSpace

Allon Therapeutics, Inc.'s Founding Scientist Illana Gozes Awarded Olson Prize From Peptides Journal

VANCOUVER, BRITISH COLUMBIA--(Marketwire - November 10, 2010) - Allon Therapeutics Inc. (TSX: NPC) announced today that Professor Illana Gozes, Allon's founding scientist and the discoverer of Allon's clinical-stage neuroprotective drug candidate davunetide, has been awarded the Olson Prize for her research insights into the behavioral effects of peptides by the journal PEPTIDES. Awarded annually for the most meritorious original research article on the behavioral effects of peptides published during the previous year, the Olson Prize honors the outstanding contributions of Drs. Gayle A. and Richard D. Olson to the field of peptide research. Prof. Gozes' article, entitled "NAP (davunetide) enhances cognitive behavior in the STOP heterozygous mouse-A microtubule-deficient model of schizophrenia", was published in PEPTIDES in April 2010, and involved studies in mice that are bred to be deficient in a protein called stable tubule-only polypeptide (STOP) protein. Associated with proper function of microtubular network, the STOP protein is important for the survival of the nerve cell. The deficient mice are a reliable model for schizophrenia and, in Prof. Gozes' study, the mice showed schizophrenia-like symptoms (hyperactivity) that were ameliorated by chronic treatment with the antipsychotic drug, clozapine. Prof. Gozes' study showed that daily intranasal treatment with NAP (davunetide) significantly decreased hyperactivity and also protected the visual memory of the STOP-deficient mice. This result is consistent with previous research by Prof. Gozes in mouse models where brain pathology is characterized by the hyperphosphorylation of the microtubule-associated protein tau, often referred to as tauopathies. Prof. Gozes' research has shown that davunetide increases the ratio of non-phosphorylated tau to phosphorylated tau, resulting in the maintenance of the essential microtubular network. These results, and Allon's clinical development program, suggest that davunetide is the most advanced tau-targeting drug candidate in clinical development. Allon expects to have started the progressive supranuclear palsy (PSP) study before the end of this quarter. PSP is a type of frontotemporal dementia (FTD) where there are extensive tauopathies. FTD is a group of rapidly progressive and fatal degenerative brain diseases, often misdiagnosed as Parkinson's or Alzheimer's disease. The Company has previously demonstrated human efficacy in amnestic mild cognitive impairment, a precursor to Alzheimer's disease, and cognitive impairment associated with schizophrenia. Prof. Gozes, Ph.D, is a Professor of Clinical Biochemistry at the Sackler Faculty of Medicine of Tel Aviv University. She is the Lily and Avraham Gildor Chair for the Investigation of Growth Factors and the Director of the Adams Super Center for Brain Studies and the Edersheim Levie-Gitter Institute for Functional Brain Imaging. Prof Gozes is also Head of the Dr. Diana and Zelman Elton (Elbaum) Laboratory for Molecular Neuroendocrinology. Prof. Gozes serves or has served as a member (or chair) of several faculty/university/national and international committees and is currently the Editor-in Chief of the Journal of Molecular Neuroscience and the President of the Israel Society for Neuroscience. Collaborative research led by Prof. Gozes has been supported by Allon, Tel Aviv University, the U.S. National Institutes of Health and the Canadian Friends of Tel Aviv University. Co-authors of the award-winning article are students Avia Merenlender-Wagner, Regina Pikman, and research staff Dr. Eliezer Giladi, at Prof. Gozes laboratory at Tel Aviv University, and Dr. Annie Andrieux, of the Institut des Neurosciences de Grenoble, Universite Joseph Fourier and Institut de Recherches en Technologies et Sciences pour le Vivant Direction des Sciences du Vivant, Grenoble, France. About Allon's neuroprotective platforms Allon's two neuroprotective technology platforms are based on two naturally occurring proteins produced by the brain in response to a range of insults. The platforms are activity-dependent neuroprotective protein (ADNP) and activity-dependent neurotrophic factor (ADNF). Because the two platforms are based on different proteins, the drugs from each are different molecules with different therapeutic mechanisms and distinct commercial opportunities. Clinical-stage drugs based on davunetide are derived from ADNP, while preclinical stage drug AL-309 is derived from ADNF. Davunetide is focused on Alzheimer's disease, cognitive impairment associated with schizophrenia, and progressive supranuclear palsy (PSP). AL-309 is being developed for the treatment of peripheral neuropathies and is administered orally or subcutaneously. About Allon Allon Therapeutics Inc. is a clinical-stage biotechnology company developing treatments for major neurodegenerative conditions. Allon's drug davunetide has demonstrated human efficacy in amnestic mild cognitive impairment, a precursor to Alzheimer's disease, and cognitive impairment associated with schizophrenia. Allon has Phase 2 human efficacy programs pursuing large underserved markets, such as Alzheimer's disease and cognitive impairment associated with schizophrenia, and in orphan markets, such as frontotemporal dementias. The Company is listed on the Toronto Stock Exchange under the trading symbol "NPC" (Neuro Protection Company™) and based in Vancouver. For additional information please visit the Company's website: . Forward Looking Statements Statements contained herein, other than those which are strictly statements of historical fact may include forward-looking information. Such statements will typically contain words such as "believes", "may", "plans", "will", "estimate", "continue", "anticipates", "intends", "expects", and similar expressions. While forward-looking statements represent management's outlook based on assumptions that management believes are reasonable, forward-looking statements by their nature are subject to known and unknown risks, uncertainties and other factors that may cause the actual results, events or developments to be materially different from any future results, events or developments expressed or implied by them. Such factors include, among others, the inherent uncertainty involved in scientific research and drug development, Allon's early stage of development, lack of product revenues, its additional capital requirements, the risks associated with successful completion of clinical trials and the long lead-times and high costs associated with obtaining regulatory approval to market any product which Allon may eventually develop. Other risk factors include the limited protections afforded by intellectual property rights, rapid technology and product obsolescence in a highly competitive environment and Allon's dependence on collaborative partners and contract research organizations. These factors can be reviewed in Allon's public filings at and should be considered carefully. Readers are cautioned not to place undue reliance on such forward-looking statements. Contacts: Allon Therapeutics Inc. - Investor Contact Aaron Keay Director, Investor Relations (604) 742-2540 or Cell: (604) 323-6911 akeay@allontherapeutics.com GCI Health - Media Contact Edie DeVine (415) 365-8543 edie.devine@gcihealth.com

100 项与 Davunetide 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D09401	-	-	DB12613

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
进行性核上性麻痹	临床3期	美国	Allon Therapeutics, Inc.	2010-10-01
进行性核上性麻痹	临床3期	澳大利亚	Allon Therapeutics, Inc.	2010-10-01
进行性核上性麻痹	临床3期	加拿大	Allon Therapeutics, Inc.	2010-10-01
进行性核上性麻痹	临床3期	法国	Allon Therapeutics, Inc.	2010-10-01
进行性核上性麻痹	临床3期	德国	Allon Therapeutics, Inc.	2010-10-01
进行性核上性麻痹	临床3期	英国	Allon Therapeutics, Inc.	2010-10-01
轻度认知障碍	临床2期	美国	Allon Therapeutics, Inc.	2006-08-01
轻度认知障碍	临床2期	加拿大	Allon Therapeutics, Inc.	2006-08-01
认知功能障碍	临床2期	-	Paladin Pharma SpA	-
痴呆	临床2期	-	Paladin Pharma SpA	-

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临床结果

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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


NCT00505765 (AL-108, CTgov)	临床2期	慢性精神分裂症	63	AL-108 (AL-108, 30 mg/Day)	築繭餘鬱遞窪選憲積夢(壓壓遞鏇構餘獵壓簾窪) = 網獵蓋衊窪顧憲醖廠壓艱築網鹹繭齋遞觸糧簾 (醖觸鏇鏇鬱繭淵構願餘, 積積夢餘衊網衊築願襯 ~ 蓋積糧積鹽鏇繭築廠簾) 更多	-	2017-01-27
				AL-108 (AL-108, 5 mg/Day)	築繭餘鬱遞窪選憲積夢(壓壓遞鏇構餘獵壓簾窪) = 醖膚簾製鑰鏇窪繭構襯艱築網鹹繭齋遞觸糧簾 (醖觸鏇鏇鬱繭淵構願餘, 鬱鹽衊網鏇窪構窪蓋鹽 ~ 獵窪鑰醖襯蓋鹽壓鬱餘) 更多