Overview
Name: PXT864
Synonyms: PXT00864
Therapy Type: Combination, Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: Pharnext
Background
PXT864 is an example of a repurposed drug combination. It uses baclofen and acamprosate, taken twice a day. Baclophen is a derivative of y-aminobutyric acid, aka GABA, and acts as a GABA-B receptor agonist. It is used as a muscle relaxant to treat spasticity, for example in cerebral palsy and multiple sclerosis. Acamprosate is a drug of unclear mechanism of action, which is used to treat alcohol dependence. Pharnext claims that the low-dose combination of these two compounds, PXT864, is neuroprotective by way of restoring the brain’s balance between excitatory glutamatergic and inhibitory glycine and GABA activity, which in Alzheimer’s disease is disrupted by Aβ oligomers (Chumakov et al., 2015). The company also published positive preclinical data in Parkinson’s disease animal models (Hajj et al., 2015), and cell models of amyotrophic lateral sclerosis due to SOD1 mutations (Boussicault et al., 2020).
Findings
From February 2013 to June 2015, Pharnext ran PLEODIAL I, a Phase 2 study in Bordeaux and several other sites in France. It compared an eight-week course (four weeks treatment, four weeks washout, four more weeks of treatment) of PXT864 to placebo in 47 participants with mild Alzheimer's disease. The trial used three doses—0.4 mg acamprosate and 6 mg baclofen, 1 mg acamprosate and 15 mg baclofen, 20 mg acamprosate and 12 mg baclofen—with acamprosate and baclofen being taken as separate capsules twice daily. Primary endpoints included change from baseline in the ADAS-cog11 and adverse events; secondary outcomes included several cognitive, clinical, and global measures.
In addition, the trial used EEG measures of cognitive event-related potential (ERPs) as an ancillary outcome measure. At the 2016 AAIC conference in Toronto, Pharnext collaborators reported that the cognitive ERP results indicated neurophysiological activity of PXT864 in three patients (see abstract).
From June 2013 to December 2015, Pharnext ran a six-month open-label extension trial of PXT864 for 45 people who had completed the PLEODIAL 1 trial. Here, too, ADAS-cog 11 and safety were the main outcomes. According to data presented at meetings, there was no significant change from baseline in ADAS-Cog after 36 weeks in any group. People in each dose group declined more slowly on the ADAS-Cog over the entire 36-week trial than expected based on historical controls. However, the results may have been affected by some participants taking donepezil during the last 12 weeks of the trial (Dec 2016 conference news; Touchon et al., 2017).
According to Pharnext's website, PXT864 is in Phase 1 for amyotrophic lateral sclerosis as well, but no trial has been registered.
On Feb 14, 2023, the company announced it would stop PTX864 development for Alzheimer’s disease, citing financial reasons (press release).
For all trials of PXT864, see clinicaltrials.gov.
Last Updated: 15 Feb 2023
Further Reading
No Available Further Reading
Overview
Name: Piromelatine
Synonyms: Neu-P11
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline), Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Neurim Pharmaceuticals Ltd.
Background
Piromelatine is a multimodal sleep drug. It acts primarily as an agonist of MT1/MT2/MT3 melatonin receptors and serotonin 5-HT1A and 5-HT1D receptors, but reportedly also is a low-affinity antagonist of 5-HT2B, P2X3, and TRPV1 receptors.
Neurim Pharmaceuticals claims that this compound may benefit control of circadian rhythm, metabolism, cognition, and mood. Preclinical studies have reported cognitive improvement in rats that had received hippocampal Aβ42 injections to simulate Alzheimer’s disease (He et al., 2013). There are also reports on analgesic and hypnotic effects in a mouse model of neuropathic pain (Liu et al., 2014), as well as blood pressure lowering and metabolic benefits in rats (Huang et al., 2013; Zhou et al., 2017).
Disrupted sleep is common in Alzheimer's disease. A prior clinical trial of melatonin itself was negative (Dec 2003 news), but since then, numerous human and animal studies have implicated poor sleep quality in Alzheimer's pathogenesis. Proposed mechanisms relate to theta-wave memory consolidation, protein translation, as well as nocturnal clearance of Aβ and other waste proteins (e.g., Sep 2009 news; Aug 2012 news; Aug 2012 conference news; Jun 2014 news; May 2016 conference news; Varga et al., 2016).
Findings
Between 2010 and 2013, Neurim Pharmaceuticals ran Phase 1 and 2 trials of piromelatine in primary insomnia. Results are not reported in the peer-reviewed literature, but the company announced at the time that various sleep parameters improved in a Phase 2 trial in 120 participants who took a four-week course of piromelatine.
In September 2016, the company started enrolling for ReCOGNITION, a Phase 2 study of piromelatine in Alzheimer's disease. This study compared a six-month course of 5, 20, or 50 mg once daily to placebo in 371 people with a clinical diagnosis of mild Alzheimer's disease as per NIA-AA criteria. The primary outcome was a computerized version of the neuropsychological test battery (cNTB); secondary outcomes included functional, clinical, global, and neuropsychiatric AD scales, as well as safety and a sleep-quality index. In other words, this trial evaluated piromelatine on its ability to affect AD itself, not merely sleep in AD patients. The trial was conducted at 56 centers across the United States, and finished in November 2019. According to results presented at the 2021 CTAD conference, piromelatine did not significantly change the cNTB, or secondary outcomes of the ADAS-Cog14, and Pittsburg Sleep Quality Index (PSQI). The drug was safe. A subsequent GWAS for drug responsiveness in 107 participants identified a cluster of six polymorphisms in chromosome 2q12, present in one-quarter of participants, that was associated with improvement on the cNTB, but significant deterioration on the ADAS-Cog14 and PSQI. Participants without the polymorphisms significantly improved on the ADAS-Cog14 and PSQI with piromelatine. The work was published after peer review (Schneider et al., 2022).
In March 2022, the company registered a new prospective trial in AD that will exclude carriers of this polymorphism. The study will enroll 225 participants for six months of 20 mg piromelatine daily, or placebo, followed by a one-year, open-label extension. The primary outcome is ADAS-Cog14, with secondaries of ADCS-Instrumental Activities of Daily Living, ADCS-Clinical Global Impression of Change, MMSE, and safety. The study is planned to run from May 2022 to June 2025.
In addition, piromelatine has been evaluated in Spain for insomnia, irritable bowel syndrome, and glaucoma.
For all trials of piromelatine, see clinicaltrials.gov and WHO ICTRP registries.
Clinical Trial Timeline
- Phase 2
- Study completed / Planned end date
- Planned end date unavailable
- Study aborted
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Last Updated: 07 Jun 2022
Further Reading
No Available Further Reading
Overview
Name: Gemfibrozil
Synonyms: Lopid, Jezil, Gen-Fibro
Therapy Type: Small Molecule (timeline)
Target Type: Cholesterol
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Approved for: Hyperlipidemia
Background
Gemfibrozil is an old member of the fibrate class of drugs. These drugs activate peroxisome proliferator-activated receptor-α (PPARα), nuclear receptors involved in lipid metabolism. Fibrates reduce triglyceride levels. They are widely prescribed to control cholesterol and for related indications. Gemfibrozil came into use in the 1980s and is available as a generic.
Some studies have linked the use of fibrates to reduced AD risk (Defouil et al., 2005). More recently, gemfibrozil in particular has been considered to increase expression of microRNA 107 (NIH GrantOme). Expression of miR107 has been reported to be reduced in Alzheimer's, which may contribute to the upregulation of BACE levels in this disease (Feb 2008 news; Nelson and Wang, 2010; Hebert et al., 2013). MiR107 has also been reported to be expressed in cerebrovascular endothelial cells, and proposed as a biomarker for mild cognitive impairment or Alzheimer's disease (Wang et al., 2016; Wang et al., 2015; Liu et al., 2016; Wang et al., 2016). Panels for measuring CSF microRNA in neurodegeneration research are being developed (Wang et al., 2016).
Gemfibrozil-mediated activation of PPARα has also been reported to stimulate non-amyloidogenic APP processing by ADAM10, thus reducing Aβ production (Corbett et al., 2015).
Two preclinical studies reported that treating AD mouse models with gemfibrozil decreased amyloid plaque accumulation in the cortex and hippocampus, and improved learning and memory in a PPARα-dependent pathway (Chandra and Pahan, 2019; Luo et al., 2019). The latter study also reported activated autophagy in plaque-associated microglia and astrocytes, suggesting gemfibrozil enhanced Aβ clearance.
Findings
In May 2014, an NIA-funded trial at the University of Kentucky started to evaluate whether gemfibrozil can safely modulate microRNA-107 levels for the prevention or early-stage treatment of AD. The study enrolled 48 cognitively normal and 24 mildly impaired (CDR 0.5) participants for a one-year, twice-daily course of 600 mg gemfibrozil or placebo. As primary outcomes, the trial assessed adverse events, blood and CSF gemfibrozil levels, and CSF Aβ40 and 42 levels. Secondary outcomes included two cognitive tests known to be sensitive at early stages, the Free and Cued Selective Reminding Test (FCSRT) and the Paired Associates Learning (PAL) tests.
Investigators presented results at the 2019 CTAD conference. Gemfibrozil appeared safe, and lowered the concentration of miR-107 in plasma. In CSF, miR-107 was undetectable. Changes over time in CSF Aβ42, p-tau, and p-tau/Aβ42 ratio trended in the right direction with treatment compared to placebo, but the differences were not statistically significant. Likewise, treatment-related trends toward less brain atrophy, reduced plasma TNF-α, and better scores on some memory tests did not reach statistical significance (Dec 2019 conference news).
For all trials on gemfibrozil, see clinicaltrials.gov.
Last Updated: 10 Jan 2020
Further Reading
No Available Further Reading
Species: Mouse
Genes: APP
Modification: APP: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: JU.Tg(NSE-APP751)Cordell
Summary
This model was the first reported APP transgenic mouse. It overexpressed the human APP751 isoform, which includes the Kunitz serine protease inhibitor domain. The transgene was expressed throughout the brain from a rat neural-specific enolase (NSE) promoter; expression levels varied between substrains.
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
Aβ deposits were observed as early as two months of age. These deposits were diffuse and extracellular and had a “cotton-like” appearance. Classic mature plaques were not observed.
Tangles
Classic tangles were not observed, but aberrant tau immunoreactivity was observed as early as two months.
Neuronal Loss
Cell death was not formally assessed, however, overt neuronal death was not seen.
Gliosis
Gliosis was noted in a single 22-month-old animal with extensive Aβ deposits (Higgins et al., 1994).
Cognitive Impairment
Deficits in spatial memory and learning appear as the mice age. At 12 months the mice demonstrate learning and memory deficits as measured by a water-maze task and in spontaneous alternation in a Y maze (Moran et al., 1995). At six months cognition is largely normal.
Last Updated: 02 Dec 2016
Further Reading
No Available Further Reading
Overview
Name: Lumateperone
Synonyms: ITI-007
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease, Schizophrenia, Bipolar Disorder
U.S. FDA Status: Alzheimer's Disease (Phase 3), Schizophrenia (Phase 3), Bipolar Disorder (Phase 3)
Company: Bristol-Myers Squibb, Intra-Cellular Therapies, Inc.
Background
This serotonin 5-HT2A receptor antagonist was originally developed by Bristol Myers Squibb and licensed to Intra-cellular Therapies in 2005. This company is testing ITI-007 clinically for schizophrenia, bipolar depression, and insomnia, as well as for the treatment of agitation in dementia, including Alzheimer's disease.
This compound is being studied at different dose levels. At low doses, it reportedly engages primarily the 5-HT2A receptor, whereas at higher doses it also affects dopamine receptors, enhances glutamatergic transmission, and inhibits serotonin reuptake (see see Davis et al., 2015; Snyder et al., 2015; Davis et al., 2016).
Findings
In 2014, Intra-Cellular Therapies ran a Phase 1/2 dose-escalation study of up to 30 mg/d in 30 old healthy volunteers and people with a clinical diagnosis of dementia. This trial measured safety, exposure and, as exploratory outcomes, cognitive function and sleep. Agitation was to be measured but did not occur in this patient sample. Results were presented at the 2014 CTAD conference (see Dec 2014 conference news; Dec 2015 conference news).
In June 2016, a Phase 3 study began enrolling an anticipated 360 participants with a clinical diagnosis of Alzheimer's and agitation. The study will evaluate a one-month course of 9 mg/d of ITI-007 against placebo on the Cohen-Mansfield Agitation Inventory-Community version (CMAI-C) and the Clinical Global Impression for Severity of Illness (CGI-S). This trial will run through August 2018.
For trials of this compound, see clinicaltrials.gov and WHO ICTRP.
Last Updated: 02 Dec 2016
Further Reading
No Available Further Reading
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