Overview
Name: NIC5-15
Synonyms: Pinitol, D-Pinitol
Chemical Name: 3-O-Methyl-D-chiro-inositol
Therapy Type: Small Molecule (timeline), Supplement, Dietary (timeline)
Target Type: Amyloid-Related (timeline), Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Humanetics Pharmaceuticals Corporation
Background
NIC5-15 is pinitol, a naturally occurring cyclic sugar alcohol. It is found in soy and several other plants and fruits. Pinitol is known to act as an insulin sensitizer. According to company press releases, the compound also modulates γ-secretase to reduce Aβ production while sparing cleavage of the γ-secretase substrate Notch. Company press releases say the compound improves cognitive function and memory deficits in preclinical models of AD neuropathology (see company website). No peer-reviewed papers on NIC5-15/pinitol have been published in the scientific literature. Pinitol is commercially available as a food supplement.
Findings
A Phase 2a trial at the VA Medical Center, Bronx, New York, and Icahn School of Medicine at Mt. Sinai, New York, assessed 1,500, 3,000, and 5,000 mg doses of NIC5-15 in 15 people with mild to moderate Alzheimer's disease over seven weeks for safety and efficacy (see MSSM website). This trial ended in 2008. At the 2009 ICAD conference in Vienna, preliminary results were reported to indicate good tolerability, as well as stabilization of cognition as measured by the ADAS-Cog. This trial was sponsored by the Department of Veterans Affairs, the National Center for Complementary and Alternative Medicine, and Humanetics Corporation.
In June 2012, the U.S. Patent and Trademark Office issued a patent for the use of D-pinitol in the treatment of Alzheimer's disease, and a second single-site Phase 2b study was begun. This trial is enrolling an estimated 40 patients with mild to moderate AD and assesses cognition, measured by ADAS-Cog as primary outcome. For all clinical trials of this compound, see clinicaltrials.gov.
Clinical Trial Timeline
- Phase 2
- Study completed / Planned end date
- Planned end date unavailable
- Study aborted
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Last Updated: 20 Oct 2023
Further Reading
No Available Further Reading
Species: Mouse
Genes: APP
Modification: APP: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: B6;SJL-Tg(APPSWE)2576Kha
Summary
The Tg2576 model is one of the most well characterized, and widely used, mouse models of AD. It overexpresses a mutant form of APP (isoform 695) with the Swedish mutation (KM670/671NL), resulting in elevated levels of Aβ and ultimately amyloid plaques. The Tg2576 model was developed by Karen Hsiao Ashe and is now distributed through Taconic and Charles River. Hemizygous mice develop extensive amyloid pathology and cognitive deficits (Hsiao et al., 1996).
Phenotype Characterization
When visualized, these models will distributed over a 18 month
timeline
demarcated at the following intervals: 1mo, 3mo, 6mo,
9mo, 12mo, 15mo, 18mo+.
Plaques
Numerous parenchymal Aβ plaques by 11-13 months.
Synaptic Loss
Dendritic spine loss by 4.5 months In the CA1 region of the hippocampus (Lanz et al., 2003).
Gliosis
Increase in microglial density and size in plaque-forming areas of the brain including the hippocampus, frontal cortex, entorhinal cortex, and occipital cortex in 10-16 month old hemizygotes (Frautschy et al., 1998).
Changes in LTP/LTD
By 5 months, there was a decline in LTP in the dentate gyrus after perforant path stimulation compared to wild-type; impairment was not observed at 2 months (Jacobsen et al., 2006). Both the CA1 and dentate gyrus of aged mice (>15 months) are impaired (Chapman et al., 1999). Differences have been observed between the Schaffer collateral and mossy fiber pathways (Jung et al., 2011).
Cognitive Impairment
Impaired spatial learning, working memory, and contextual fear conditioning at <6 months although other studies have reported normal cognition at this age with progressive impairment by >12 months.
Last Updated: 29 Jan 2025
Further Reading
No Available Further Reading
Overview
Name: NSC001
Synonyms: AF267B , NGX267, NI004
Chemical Name: (2S)-2-ethyl-8-methyl-1-thia-4,8-diazaspiro[4.5]decan-3-one
Therapy Type: Small Molecule (timeline)
Target Type: Cholinergic System (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1/2)
Company: Neurimmune, TorreyPines Therapeutics, Inc.
Approved for: None
Background
Insufficient activity of the cholinergic system is associated with AD and cognitive decline. Two different strategies have been used to increase cholinergic activity in the AD brain: 1) acetylcholinesterase inhibitors and 2) direct stimulation of cholinergic receptors. NGX267 is a selective agonist at the M1 muscarinic acetylcholine receptor (Fisher et al., 2002). Like other M1 agonists such as AF102B (cevimeline), AF267B has been shown to increase αAPPs, decrease Aβ levels and tau hyperphosphorylation, and block Aβ-induced neurotoxicity in vitro via M1 receptor-mediated modulation of kinases (e.g. PKC, MAPK and GSK3β; reviewed in Fisher, 2007; Fisher, 2008; Fisher, 2011). AF267B was reported to improve spatial memory in 3xTg-AD mice and was associated with reduced Aβ and tau pathology in the hippocampus and cortex (Caccamo et al., 2006).
NSC001 is a rigid analog of acetylcholine, which is is claimed to have high brain penetration and a better safety margin than other M1 agonists. NSC001 is taken by mouth.
Findings
A first-in-human dose-escalation study, sponsored by TorreyPines, treated 34 healthy men with doses from 1 to 45 mg NGX267, or placebo. The study determined a maximum tolerated dose of 35 mg in this population. Unspecified moderate or severe adverse events occurred after the 35 and 45 mg doses (Ivanova and Murphy 2009).
TorreyPines ran a second Phase 1, enrolling 26 healthy men and women between the ages of 65 and 80. According to a July 2006 press release, the drug was well-tolerated at single doses up to 15 mg, and showed evidence of cholinergic activation. In September 2007, the company announced results of a third Phase 1 study geared toward a schizophrenia indication, where doses up to 30 mg were shown to be safe and well-tolerated in healthy men 55 and younger (press release).
In September 2008, the company stopped development of NGX267 (press release).
In December 2008, TorreyPines reported positive Phase 2 data on NGX267 to ease dry mouth in 26 people with Sjogren's syndrome. Treatment with 10, 15, or 20 mg increased salivation, with no safety concerns. Gastrointestinal discomfort was seen (press release).
In 2018, Neurimmune and NeuroScios co-founded NSC Therapeutics to develop NGX267 for the treatment of neurodegenerative diseases with cholinergic deficits, such as Alzheimer's and dementia with Lewy bodies. The drug was renamed NSC001/NI004.
In 2019-2020, a Phase 1b trial evaluated the safety of NSC001 in 65 healthy elderly volunteers. Participants took 2.5, 5, 10, or 15 mg, or placebo, daily for four weeks. Exploratory endpoints included CSF and plasma biomarkers, cognition, depression, salivation, and quantitative EEG, among others. According to results presented at the March 2024 AD/PD conference, 62 participants completed the study. Adverse events were mostly mild or moderate. Severe adverse events occurred; they were mainly attributed to lumbar puncture and 24-hour CSF collection on day 1. No typical cholinergic side effects were noted, nor effects on cognition or psychiatric symptoms. The most common adverse event was headache, which was seen equally in the treatment and placebo groups. Brain uptake of the drug was high, with CSF concentrations reaching half that in plasma. NSC001 caused no change in CSF Aβ40 or Aβ42 or NfL, and only a slight reduction in total tau. A significant reduction in pTau181 was attributed to GSK3β inhibition. Four weeks of treatment altered circadian rhythms and normalized alpha waves on EEG; this was interpreted as an indication of target engagement. This study took place in Sweden and Spain, and does not appear in registries.
Last Updated: 10 May 2024
Further Reading
No Available Further Reading
Overview
Name: Neramexane
Synonyms: MRZ 2/579
Chemical Name: 1,3,3,5,5-pentamethylcyclohexanamine
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: Forest Laboratories, Inc., Merck
Approved for: None
Background
Similar to memantine, neramexane is an NMDA receptor channel blocker with moderate affinity. It displays voltage dependency, and rapid unblocking kinetics (Gilling et al., 2007). Neramexane also has been shown to block acetylcholine-evoked responses by antagonizing the alpha-9 alpha-10 nicotinic acetylcholine receptor (Plazas et al., 2007).
Last Updated: 12 Dec 2013
Further Reading
No Available Further Reading
Overview
Name: NeoTrofin
Synonyms: AIT-082, leteprinim
Chemical Name: 4-{[3-(6-oxo-3,6-dihydro-9H-purin-9-yl)propanoyl]amino}benzoic acid
Therapy Type: Small Molecule (timeline)
Target Type: Unknown
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: NeoTherapeutics, Inc.
Approved for: None
Background
NeoTrofin is a derivative of the purine hypoxanthin. It was found to stimulate the production mRNA for NGF, neurotrophin-3, and bFGF in cultured mouse astrocytes (Glasky et al., 1995).
Last Updated: 09 Jan 2014
Further Reading
No Available Further Reading
Overview
Name: Nefiracetam
Chemical Name: N-(2,6-dimethylphenyl)-2-(2-oxopyrrolidin-1-yl)acetamide
Therapy Type: Small Molecule (timeline)
Target Type: Cholinergic System (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: Daiichi Sankyo Pharmaceuticals
Approved for: None
Background
Nefiracetam is a pyrrolidone-type agent that affects multiple neurotransmitter systems including: aminergic, glutaminergic, and cholinergic. It has been shown to stimulate α4β2-type neuronal nicotinic acetylcholine receptors, activating protein kinase C, and reducing magnesium block of the NMDA receptor 13—19. In addition, nefiracetam increased brain-derived neurotrophic factor (BDNF) expression (Ando et al., 2005) as well as regional blood flow and glucose utilization after cerebral ischemia in rats (Jin et al., 2002).
Last Updated: 12 Dec 2013
Further Reading
No Available Further Reading
Overview
Name: Naproxen
Synonyms: Aleve™, Anaprox™, Naprosyn™
Therapy Type: Small Molecule (timeline)
Target Type: Inflammation (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: Procter & Gamble
Approved for: Over-the-counter drug for reduction of pain, fever, inflammation, and stiffness.
Background
Naproxen is an over-the-counter nonsteroidal anti-inflammatory drug (NSAID). It inhibits COX-1 and COX-2, both isoforms of the cyclooxygenase enzyme, and reduces inflammation through reduced prostaglandin synthesis.
In the Alzheimer's field, interest in NSAIDs arose when epidemiological studies started reporting lower rates of Alzheimer's or cognitive decline among people who had been taking these drugs for chronic treatment of inflammatory conditions (e.g., Mar 1997 news; in't Veld et al., 1998; Nov 2001 news; Vlad et al., 2008; Obermann et al., 2013). Experimental studies supported the argument that inflammation plays a role in Alzheimer's disease, prompting a wave of clinical trials of various NSAIDs, e.g., ibuprofen, rofecoxib, celecoxib, and R-flurbiprofen.
Findings
Three clinical trials of naproxen in Alzheimer's disease have been conducted.
In 2000 and 2001, the Alzheimer's Disease Study Group conducted a 40-center trial that compared one year of treatment with 220 mg twice daily of naproxen or 25 mg once daily of rofecoxib to placebo in 351 people with mild to moderate Alzheimer's disease. The trial assessed whether these drugs would slow cognitive decline, but found that neither showed any consistent benefit over placebo (Jul 2002 conference news; Aisen et al., 2003).
The second trial was the Alzheimer's Disease Anti-Inflammatory Prevention Trial, aka ADAPT. Funded by the NIA, this primary prevention study started in 2001 to enroll 2,625 people 70 or older who had a parent or sibling with Alzheimer's or another dementing illness of aging. Conducted at six U.S. sites, this study aimed to determine whether naproxen or celecoxib can delay the onset of AD or age-related cognitive decline. ADAPT was to conduct annual cognitive assessments for five to seven years; however, the trial soon became embroiled in a public controversy (see Sep 2002 news). In September 2004, Merck withdrew the related NSAID celebrex. In December 2004, the NIA halted dosing in ADAPT, citing an increase in cardiovascular side effects in its naproxen arm (Sep 2004 news; Dec 2004 news). A separate report raising concerns about a slightly elevated risk of heart attack with long-term naproxen and other NSAID treatment soon followed (Graham et al., 2005). ADAPT safety data were subsequently published but failed to end ongoing controversy over the decision to halt the trial (Nov 2006 news).
Efficacy data from ADAPT showed that neither naproxen nor celecoxib delayed incident dementia or cognitive decline; naproxen was reported to have hastened cognitive decline slightly (ADAPT Research Group 2007; ADAPT Research Group 2008). ADAPT came to exemplify conflicting findings between observational epidemiology, which continued to report protective effects of NSAIDs on cognition, and RTCs, which were negative (May 2008 news story).
Analysis of ADAPT data continued for some years. Results from a further two years of follow-up until 2007 indicated a dichotomy whereby people who were symptomatic at baseline worsened on naproxen compared to placebo, but people who were cognitively normal at baseline were less likely to decline and had a healthier CSF biomarker signature at that point (Jul 2009 conference news; Breitner et al., 2011). A subsequent follow-up evaluation of some 1,500 participants in 2010 and 2011 reported that one to three years of preventive treatment with naproxen in people with a family history of AD conferred no protection against cognitive decline (Alzheimer's Disease Anti-inflammatory Prevention Trial Research Group 2013; ADAPT-FS Research Group 2014 ).
Additional analyses attempted to distinguish between slow and fast decliners and to identify a time window during the prodromal phase of AD in which naproxen might be beneficial. A possible benefit of naproxen only during the presymptomatic phase was seen as being consistent with both ADAPT and epidemiological data (e.g., Leoutsakos et al., 2011).
A third trial, started in 2012 in Montreal, enrolled 195 cognitively normal people 55 and older who have a parent or multiple siblings with AD; biomarker evidence of preclinical AD was not required for inclusion. Participants were randomized to 220 mg twice daily of naproxen or placebo for two years. Primary outcomes were the global score on the Repeatable Battery for Assessment of Neuropsychological Status, as well as a composite Alzheimer progression score (APS) derived from multiple cognitive and biomarker measures of preclinical Alzheimer's disease. Safety parameters, naproxen kinetics, CSF biomarkers of AD pathology, and plasma/CSF markers of inflammation were secondary outcome measures. Efficacy data indicated no benefit of naproxen over placebo on the trajectory of the APS, or on any of the underlying measures. The naproxen group had more adverse events, including hypertension, gastrointestinal, and vascular or cardiac problems. While the trial was underpowered to have detected a potential small naproxen effect, the authors conclude such an effect would be difficult to demonstrate in a randomized prevention trial, and that the drug’s proven adverse effects would raise ethical concerns (see Meyer et al., 2019, Apr 2019 news).
Last Updated: 12 Apr 2019
Further Reading
No Available Further Reading
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