A study of the safety, tolerability and pharmacokinetics of NNZ-2591 and measures of efficacy in children and adolescents with Phelan-McDermid Syndrome.

开始日期2022-08-08

申办/合作机构

Neuren Pharmaceuticals Ltd.

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项与 NNZ-2591 相关的文献（医药）

2013-06-01·Recent patents on CNS drug discovery

Insulin-Like Growth Factor-1 and its Derivatives: Potential Pharmaceutical Application for Treating Neurological Conditions

Review

作者: Liang, Hua-ping ; Gunn, Alistair J. ; Guan, Jian ; Mathai, Sam

Ischemic brain damage remains a major cause of disability at all ages. This review examines the efficacy, mode of action and mechanisms of insulin-like growth factor (IGF)-1 and its derivatives in animal models of acute brain injury and neurodegenerative conditions, their potential in pharmaceutical developments. IGF-1 reduces cell loss and improves long-term neurological function in animal models. IGF-1 needs to be given within a few hours of the insult. However, the therapeutic window can be extended by mild hypothermia, likely by delaying apoptosis. Nevertheless, the poor central uptake of IGF-1 and its mitogenic potential limit clinical translation. Thus, recent studies have examined related compounds. For example, intravenous infusion of the N-terminal tripeptide of IGF-1 (glycine- proline-glutamate, GPE) can alleviate brain injury and improve long-term function in rats, with a broad effective dose range and a 3-7 hour therapeutic window, but has a short half-life. G-2meth-PE(G-2mPE), a GPE analogue with a longer half-life, is also neuroprotective. GPE/G-2mPE do not interact with IGF receptors and may act by modulating postinjury inflammation, astrogliosis and vascular remodeling. Cyclo-glycyl-proline (cGP), an endogenous diketopiperazine possibly derived from GPE is also neuroprotective. An analogue, cyclo-L-glycyl-L-2-allylproline (NNZ-2591) improves long-term somatosensory-motor function and histology after ischemic injury. Treatment with NNZ-2591 after 6-hypdroxydopamine injection in adult rats improves neurogenesis and long-term motor function. Further, oral administration of NNZ-2591 also prevents scopolamine-induced acute memory impairment. These beneficial effects may mediated by improved neuroplasticity. This review is an updated version of a previous publication in Recent Pat CNS Drug Discov.

2010-08-18·Frontiers in CNS Drug Discovery

Insulin-Like Growth Factor-1 and its Derivatives: Potential Pharmaceutical Application for Ischemic Brain Injury

作者: Guan, Jian

A review.Brain ischemia induces the IGF-1 system in damaged regions, and exogenous administration of IGF-1 after injury is neuroprotective and improves long-term neurol. function.The short treatment window can be extended by mild hypothermia, probably due to delayed apoptosis.Nevertheless, the poor central uptake of IGF-1 and its mitogenic potential preclude clin. application.The N-terminal tripeptide of IGF-1 (glycine-proline-glutamate, GPE) is neuroprotective after central administration.Central uptake of GPE is injury dependent, and it is rapidly degraded in the plasma.I.v. infusion of GPE prevents brain injury and improves long-term functional recovery, with a broad ED range and a 3-7 h therapeutic window.Its neuroprotective effects are also independent of cerebral reperfusion and not age selective.GPE does not interact with IGF receptors.G-2meth-PE, a GPE analog with improved stability, has a prolonged plasma half life and is neuroprotective after ischemic injury.Neuroprotection by GPE and its analog may involve modulating inflammation, promoting astrocytosis and inhibiting apoptosis and vascular remodeling Cyclo-glycyl-proline (cGP) is an endogenous diketopiperazine possibly derived from GPE.Cyclic GP and its analog cyclo-L-glycyl-L-2-allylproline (NNZ 2591) are neuroprotective after ischemic injury.NNZ 2591 crosses the BBB independent of injury and remains detectable several hours after a single administration.Repeated peripheral administration of NNZ 2591 improves somatosensory-motor function and long-term histol. outcome.

2010-07-01·Behavioural brain research3区 · 心理学

NNZ-2591, a novel diketopiperazine, prevented scopolamine-induced acute memory impairment in the adult rat

3区 · 心理学

Article

作者: Vickers, Mark H. ; Hodgkinson, Steve ; Dale-Gandar, Linden ; Guan, Jian ; Zhang, Rong

In rats, cyclo-L-glycyl-L-2-allylproline (NNZ-2591), a diketopiperazine, is neuroprotective after ischemic brain injury and also improves motor function in a rat model of Parkinson's disease. Given nootropic actions of diketopiperazines, we investigated the effects of and potential role for acetylcholine neurotransmission in NNZ-2591 on spatial memory after scopolamine-induced amnesia in rats. Adult male Wistar rats were assigned to four groups: saline/water; saline/NNZ-2591; scopolamine/water and scopolamine/NNZ-2591. Morris Water Maze (MWM) tasks were used to determine spatial learning and memory. Thirty minutes prior to each of four daily acquisition trials, rats were intraperitoneally injected with either scopolamine (0.5 mg/kg) or saline. Either NNZ-2591 (30 mg/kg) or water was administered orally (gavages) 10 min after the injection. Immediately after completion of the day 4 acquisition trial a spatial probe trial was performed. The brains were then collected for immunohistochemical analysis. Scopolamine impaired spatial learning and memory compared to saline treated group, particularly in the day 1 acquisition trial. NNZ-2591 did not reverse this deficit, however it significantly improved memory retention by showing more time spent in the correct quadrant. NNZ-2591 also counteracted the scopolamine-induced up-regulation of choline-acetyltransferase positive neurons in the striatum and similarly counteracted the increased synaptophysin density in the hippocampus. Furthermore, a scopolamine-independent antagonistic effect on muscarinic M2 acetylcholine receptors was found after NNZ-2591 treatment, supporting its modulation of acetylcholine neurotransmission. The data suggest that NNZ-2591 prevents scopolamine-induced acute impairment in memory and modulation of acetylcholine neurotransmission may be the mode of action underlying the memory improvement.

项与 NNZ-2591 相关的新闻（医药）

2025-06-26

·BioPharmaDive

Acadia’s ‘very bullish’ sales forecast restores some confidence on Wall Street

Acadia Pharmaceuticals has proposed that its pipeline of experimental medicines could, if eventually brought to market, peak at $12 billion in annual sales.The brain drug developer disclosed this estimate Thursday, during its first major research and development event. The company expects eight programs to be in human testing this year, and to have data from five mid- to late-stage trials between now and the end of 2027. Five of those programs could potentially reach blockbuster status, or $1 billion or more in yearly sales, according to analysts at the investment firm Mizuho Securities.In a note to clients, Mizuho analyst Uy Ear wrote that among those programs, the majority of value comes from a drug code-named ACP-204. Researchers are currently conducting a couple mid-stage clinical trials to evaluate this drug as a possible treatment for the psychosis tied to Alzheimers disease and a related condition known as Lewy body dementia. Data from the Alzheimers study are slated to come next year.Acadia said ACP-204 is designed to build upon one of the companys two marketed products, Nuplazid, which has a similar chemical structure and was first approved in the U.S. a decade ago to treat Parkinsons disease psychosis. Nuplazid accounted for nearly two-thirds of the $958 million in revenue Acadia recorded last year. But a key patent protecting the drug from generic competition is set to expire in 2030.On Wednesday, Acadia also predicted the combined peak sales of Nuplazid and its other commercial medication, Daybue, will fall in the range of $1.5 billion to $2 billion. Approved in 2023, Daybue is used for patients with Rett syndrome, a rare, genetic disorder that impairs brain function and development.Marc Goodman, an analyst at Leerink Partners, described that forecast as very bullish. Consensus on Wall Street, according to Ear, is that sales for the two products will crest around $1.3 billion.Ear added that the wide range offered by Acadia is likely due to the recent uncertainty surrounding how many patients will stop taking Daybue because of its side effects. The drugs label includes warnings for diarrhea and weight loss.Along with ACP-204, Acadias pipeline includes ACP-101, a drug for another rare, genetic, neurological disease called Prader-Willi Syndrome. High-level results from a Phase 3 experiment should arrive sometime between October and December. Theres also ACP-211, for major depression; ACP-711, for essential tremor; and ACP-2591, a next-generation approach to addressing Rett syndrome. Each of those three programs are in early-stage testing.Forecasting Acadia's pipeline potentialDrugStageIndicationPeak sales potentialACP-101Ph. 3Prader-Willi Syndrome~$1-2BACP-204Ph. 2Alzheimers psychosis, Lewy body dementia psychosis>$2BACP-211Ph. 2Major depressive disorder>$2BACP-271Ph. 1-readyHuntingtons disease, tardive dyskinesia~$1-2BACP-711Ph. 2Essential tremor>$2BSOURCE: Table and estimates from research by Mizuho Securities analyst Uy Ear.Additionally, Acadia has a preclinical therapy, ACP-271, that it plans to test in patients with Huntingtons disease or tardive dyskinesia, a condition hallmarked by uncontrolled movements and a side effect that can arise from the long-term use of some brain-stabilizing medications like antipsychotics.Analysts reacted well to Acadias updates. Ear left the R&D presentation encouraged, while Goodman wrote how his team is now incrementally more positive on the company. Acadias stock price has been weighed down over much of the last five years, as the company hit setbacks trying to expand the use of Nuplazid into more lucrative markets.In his note, Goodman acknowledged that investors will probably have a show me the data attitude regarding these new assets as well as a healthy skepticism around the potential of both ACP-204 and ACP-101. So it may take some time for pipeline value to creep into the companys valuation.Should Nuplazid and Daybue ultimately achieve Acadias new forecast, that would make the companys stock attractive even if the experimental programs dont pan out, Goodman wrote.However, the real upside is that Acadia hits on an asset or two to make the name a sustainable growth story, he added. We are certainly willing to be patient to see this story play out.Acadia shares traded around $22.60 apiece late Thursday morning, essentially flat from the prior days close. '

上市批准临床3期

2025-03-17

·BioSpace

Opinion: Angelman Syndrome Race Heats Up Among Ionis, Ultragenyx and Neuren

iStock, z_wei Ionis and Ultragenyx are competing to develop oligonucleotide treatments for Angelman syndrome, but will Neuren’s peptide catch up? Several companies are working on new investigational treatments for Angelman syndrome , a rare genetic disorder that affects the nervous system and causes developmental delays, intellectual disability, seizures and speech impairment. Ionis and Ultragenyx are competing to bring investigational antisense oligonucleotide treatments to the market, while Neuren is betting on a synthetic peptide that can be delivered orally. It’s a tight race in a disease space with a high unmet need. Affecting 500,000 to 1 million patients worldwide, Angelman syndrome has no approved disease-modifying treatments. Although antiseizure medication is available, these drugs do not address the root cause, a genetic mutation in the UBE3A gene on chromosome 15. In Angelman syndrome, only the copy of the UBE3A gene inherited from the mother is functional, while the father’s allele is mutated. Both Ionis and Ultragenyx are currently in Phase III trials with their oligonucleotides, called ION582 and GTX-102, respectively. Meanwhile, Neuren is conducting a mid-stage trial on NNZ-2591 , a twice-daily oral solution consisting of a synthetic peptide that modulates acetylcholine neurotransmission. Ionis’ ION582 is an investigational intrathecal injection that targets a long noncoding RNA to increase expression of the UBE3A protein in neurons. In November 2024, Ionis announced positive Phase II results from its Phase I/IIa HALOS trial. According to Ionis , 97% of participants given the medium or high dose saw an improvement on the Angelman Syndrome Clinical Global Improvement Change (SAS-CGI-C) scale. The HALOS trial had three parts. The first consisted of five multiple ascending dose cohorts, while the second and third part each used two groups to assess the long-term effects of ION582. Ionis has said it plans to start Phase III trials for ION582 in the first half of 2025. Ultragenyx’s GTX-102 is an intrathecally administered antisense oligonucleotide that inhibits expression of UBE3A by using a human-mouse hybrid protein to reactivate expression of the deficient protein. In November 2024, Ultragenyx announced positive data from its Phase I/II trial of the investigational drug. According to Ultragenyx , 22 of 28 patients achieved clinically meaningful improvement in at least one domain within the Multi-domain Responder Index, a tool for assessing clinical benefit in rare diseases such as Angelman. As of December 2024, Ultragenyx had dosed the first patient in its Phase III ASPIRE trial for Angelman syndrome. For its part, Neuren is focusing on a different mechanism. Excessive acetylcholine has been found to lead to neural hyperexcitability and seizures in Angelman syndrome patients. In August 2024, the company released positive Phase II results from an open-label trial of NNZ-2591. According to Neuren , participants showed statistically significant and clinically meaningful improvement from baseline. (In addition to Angelman syndrome, NNZ-2591 is undergoing clinical trials for other diseases , including Phelan-McDermid Syndrome, Pitt Hopkins Syndrome and Prader-Willi Syndrome.) Overall, while Ionis and Ultragenyx are currently ahead in the Angelman syndrome race for approval, Neuren’s NNZ-2591 has potential in multiple indications that could allow for flexibility in the market. All three investigational products so far appear to be safe and efficacious, and the ultimate deciding factor in their success may boil down to whichever reaches the market first. But there are other factors to consider. Ionis and Ultragenyx are still determining optimal dosing strategies, testing injection frequencies ranging from approximately once per month to once every three months, while Neuren’s oral administration route is the least invasive of the three products. The race may seem to be too close to call, but given that both Ionis and Ultragenyx are relying on improvement in the Bayley Scales for Infant and Toddler Development-4 as a primary endpoint for their Phase III trials, relatively direct comparisons can be made between the two intrathecal products when the final clinical trial results are released. Keep an eye on the Angelman syndrome race as more data come out in the next 2–3 years.

临床结果临床3期临床2期寡核苷酸

2024-11-06

·Firstwordpharma

Acadia pockets $100M from paediatric voucher sale

After scoring the first FDA approval for a Rett syndrome treatment last year, Acadia Pharmaceuticals has now sold the rare paediatric disease priority review voucher it gained along with the greenlight. Daybue (trofinetide), an analogue of the neuropeptide IGF-1, was cleared to treat adult and paediatric patients two years and older with the rare genetic disorder.Acadia said the voucher sold for $150 million, but did not disclose the buyer. The drug developer will only profit $100 million off the sale, however, as Neuren Pharmaceuticals — from whom Acadia gained North American rights for Daybue — is entitled to one-third, or $50 million, of the proceeds. The funds will be invested into Acadia's commercial efforts, as well as its R&D work in central nervous system disorders and rare diseases.In addition to Daybue, the firm markets one other drug — Nuplazid (pimavanserin) for Parkinson’s disease psychosis.The company's pipeline features three clinical assets, and several undisclosed programmes in preclinical development. The most advanced, ACP-101, is in Phase III testing for hyperphagia in Prader-Willi syndrome. The next, ACP-204, is in Phase II testing for Alzheimer's disease psychosis, and Acadia has exclusive, worldwide rights to Phase I-stage candidate ACP-2591 for Rett and fragile X syndromes from Neuren. In March, Acadia's attempt to expand Nuplazid's label beyond psychosis and into schizophrenia crumbled after the inverse serotonin 5-HT2A receptor agonist failed a Phase III study.

临床3期临床2期优先审批上市批准

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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
普拉德-威利综合症	临床2期	美国	Neuren Pharmaceuticals Ltd.	2023-09-01
Pitt-Hopkins综合征	临床2期	美国	Neuren Pharmaceuticals Ltd.	2022-10-14
Phelan-McDermid 综合征	临床2期	美国	Neuren Pharmaceuticals Ltd.	2022-08-08
经前综合征	临床2期	美国	Neuren Pharmaceuticals Ltd.	2022-08-08
天使综合征	临床2期	澳大利亚	Neuren Pharmaceuticals Ltd.	2022-07-12
脆性X综合征	临床1期	-	ACADIA Pharmaceuticals, Inc.	-
Rett综合征	临床1期	-	ACADIA Pharmaceuticals, Inc.	-
Rett综合征	临床1期	-	Neuren Pharmaceuticals Ltd.	-
缺氧缺血性脑病	临床前	澳大利亚	Neuren Pharmaceuticals Ltd.	2025-05-01

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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


PRNewswire 人工标引	临床2期	Pitt-Hopkins综合征	16	NNZ-2591	獵鑰醖蓋憲觸蓋構壓繭(鏇廠襯壓鑰範鑰衊壓鏇) = None 鑰獵鬱選醖鬱獵鏇遞鏇 (鹹獵範鬱網襯艱顧衊夢 ) 更多	积极	2024-05-27
PRNewswire 人工标引	临床2期	Phelan-McDermid 综合征	18	NNZ2591	淵衊夢築遞選顧窪鬱觸(膚鑰廠窪襯廠積醖壓顧) = 觸壓膚選窪鬱遞顧顧繭糧鏇壓膚網積鏇襯糧淵 (獵鹽繭鹹餘範遞夢衊蓋 ) 更多	积极	2023-12-18