Species: Mouse
Genes: FUS
Mutations: FUS Δ14
Modification: FUS: Virus
Disease Relevance: Frontotemporal Dementia, Amyotrophic Lateral Sclerosis
Strain Name: N/A
Summary
This model uses adeno-associated virus (AAV) to introduce cDNA encoding mutant human FUS into the brains of wild-type mice. It is considered a model of the neuronal pathology observed in FUS proteinopathies, such as ALS and FTD (Verbeeck et al., 2012).
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+.
Cytoplasmic Inclusions
Neuronal cytoplasmic inclusions were present by 3 months of age in the cerebral cortex. Inclusions occurred in about 20% of neurons and often co-labeled with ubiquitin.
Gliosis
No obvious astrogliosis or microglial activation at 3 months of age in the cerebral cortex.
Motor Impairment
When the mice were sacrificed at 3 months of age, they appeared healthy and displayed no obvious motor phenotype.
Last Updated: 06 Mar 2018
Further Reading
No Available Further Reading
Overview
Name: SUVN-G3031
Synonyms: Samelisant, 17v
Chemical Name: N-[4-(1-Cyclobutylpiperidin-4-yloxy)phenyl]-2-(morpholin-4-yl)acetamide Dihydrochloride
Therapy Type: Small Molecule (timeline)
Target Type: Cholinergic System (timeline), Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: Suven Life Sciences Ltd
Background
SUVN-G3031 is an orally active histamine H3 receptor antagonist being developed to treat cognitive deficits in Alzheimer's disease and schizophrenia. Histamine H3 receptors are widely expressed in healthy and Alzheimer's disease brains (Medhurst et al., 2009). They exert neuromodulatory functions on the cholinergic, adrenergic, and dopaminergic neurotransmitter systems. Preclinically, inhibiting this receptor has been shown in mice and rats to enhance cholinergic signaling, reduce tau phosphorylation, and reverse behavioral deficits (Medhurst et al., 2007; Bitner et al., 2011). Previous histamine H3 receptor antagonists that were in Phase 2 clinical development for cognition in Alzheimer's include Servier's S 38093, ABT 288, and GSK239512. SUVN-G3031 was described to have nM potency as an inverse against at H3 receptors, and marked wake-promoting activity in rats (Nirogi et al., 2019).
No peer-reviewed scientific studies have been published for SUVN-G3031. At the 2014 AAIC conference, Suven Life Sciences reported positive data on exposure, safety, pharmacokinetics, and behavioral assays in rats. The poster claimed an increase in cortical histamine and acetylcholine levels as well as reversal of memory deficits (Babu et al., 2014). Further preclinical data were presented at AAIC in 2015 (Benade et al., 2015). This work was later published, detailing procognitive effects in tests of social recognition and object recognition. SUVN-G3031 increased brain acetylcholine levels, and acted synergistically with suboptimal doses of donepezil to improve performance in the Morris water maze (Nirogi et al., 2021). At 10 times higher doses, it increased cortical levels of histamine, norepinephrine and dopamine in rats, and promoted wakefulness in rats and mice (Nirogi et al., 2021). The potential for drug-drug interactions was judged to be low, based on in vitro predictive assays (Nirogi et al., 2020).
Findings
Between September 2014 and August 2017, the CRO Quintiles conducted two Phase 1 safety, tolerability, and pharmacokinetics studies in 108 healthy people, mostly men, in the state of Kansas. Results of both trials were published (Nirogi et al., 2020). Single doses up to 20 mg and multiple does up to 6 mg were safe and well-tolerated. The most frequent adverse events were abnormal dreams, trouble falling or staying asleep, and hot flushes. Pharmacokinetics were dose-proportional, and not affected by food, sex, or age.
No trials are currently registered for cognitive disorders. A Phase 2 study for narcolepsy completed enrolling 190 participants in June 2023, and results are expected in mid-2024.
For registered trials on this compound, see clinicaltrials.gov.
Last Updated: 21 Sep 2023
Further Reading
No Available Further Reading
Overview
Name: Masupirdine
Synonyms: SUVN-502
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 3)
Company: Suven Life Sciences Ltd
Background
Developed by Suven Inc., the Delaware-based subsidiary of Indian company Suven Life Sciences, SUVN-502 is an orally available, brain-penetrant, selective antagonist of the 5-HT6 serotonin receptor (Nirogi et al., 2017). This G protein-coupled receptor is expressed mostly in the brain, where it mediates neurotransmission for functions including cognition and memory. Blocking this receptor increases cholinergic and glutamatergic signaling, and other 5-HT6 receptor antagonists have been reported to improve cognition. Several were being developed as treatments for Alzheimer's, and all were discontinued due to lack of efficacy (Upton et al., 2008; Intepirdine; Idalopirdine; Dimebon; PF-05212377).
In preclinical work, one rat study reported that masupirdine had procognitive effects, reversed age-related memory decline, increased brain acetylcholine and glutamate levels, and potentiated the effects of memantine and donepezil on brain neurotransmitters and electrical activity (Nirogi et al., 2018).
Findings
According to the company's website, Phase 1 studies were conducted in Switzerland in 2008. Suven scientists reported positive safety and pharmacokinetic data from single and multiple doses in healthy young adults and elderly volunteers (Nirogi et al., 2018).
In September 2015, a Phase 2a proof-of-concept trial began enrolling what would be 564 patients with probable Alzheimer's disease as diagnosed by the 1984 NINCDS-ADRDA criteria and an MMSE of between 12 and 20. The trial compared 26 weeks of treatment with 50 or 100 mg of SUVN-502 daily to placebo, all given in addition to donepezil and memantine. Conducted at 57 sites in the United States, this trial measured change on the ADAS-Cog11 as primary, and change on the CDR and various clinical and functional scales as secondary outcomes. The trial missed its primary outcome, according to data presented at the 2019 CTAD (Dec 2019 conference news, slide presentation, Nirogi et al., 2022). After 26 weeks, there was no difference between groups on the ADAS-cog, nor were there changes in any secondary measures.
The company stated in a Nov 2019 press release that it would continue developing masupirdine based on subgroup analyses indicating potential benefit in some patients. Suven provided masupirdine to eligible trial participants under an expanded access protocol, without evaluation for efficacy or safety, but had ended this program by September 2020.
In June 2022, Suven began a Phase 3 trial for the treatment of agitation in people with Alzheimer’s dementia. This was based on a subgroup analysis that claimed improvement in the agitation/aggression domain of the Neuropsychiatric Inventory scores in the Phase 2 study presented at CTAD 2021. The new trial is enrolling 375 Alzheimer’s patients with agitation for 12 weeks of 50 or 100 mg daily masupirdine or placebo, against a primary outcome of the Cohen-Mansfield Agitation Inventory. The secondary outcome will be a modified ADCS-CGIC focusing on agitation. Running at 18 sites in the U.S. and Poland, the trial is set to run until January 2025.
For 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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Clinical Trial |
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2015 |
2016 |
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2018 |
2019 |
2020 |
2021 |
2022 |
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2024 |
2025 |
2026 |
2027 |
2028 |
2029 |
2030 |
2031 |
2032 |
2033 |
2034 |
2035 |
| Suven Life Sciences Ltd |
NCT02580305 |
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Last Updated: 08 Feb 2023
Further Reading
No Available Further Reading
Overview
Name: ALZT-OP1
Synonyms: Cromolyn sodium, Intal, Ibuprofen
Therapy Type: Combination, Small Molecule (timeline)
Target Type: Amyloid-Related (timeline), Inflammation (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 3)
Company: AZTherapies, Inc.
Background
ALZT-OP1 is a combination regimen of two FDA-approved drugs, cromolyn (designated ALZT OP1a) and ibuprofen (designated ALZT OP1b). In the ALZT-OP1 regimen, cromolyn is delivered via an oral, dry-powder inhaler; ibuprofen is swallowed separately as an oral tablet.
Ibuprofen is a nonsteroidal anti-inflammatory with an extensive history of preclinical and clinical evaluation in AD (see Ibuprofen). Widely used to treat asthma, cromolyn is a prescription drug. It is a mast-cell stabilizer that acts as an anti-inflammatory compound by suppressing cytokine release.
One study conducted at Massachusetts General Hospital reported that cromolyn inhibits aggregation of Aβ monomers in vitro, and decreased soluble Aβ levels in the brains of APPswe/PS1ΔE9 mice after peripheral administration in vivo (Hori et al., 2015). In Tg2576 AD mice, three months’ dosing with cromolyn alone, or in combination with ibuprofen, prevented accumulation of insoluble brain Aβ42 and Aβ40. Cromolyn alone or with ibuprofen promoted microglia recruitment to plaques, and phagocytosis of β-amyloid deposits. Ibuprofen alone had no effect (Zhang et al., 2018).
Cromolyn acted synergistically with two other drugs, bromocriptine and topiramate, to diminish Aβ42 and Aβ40 production, and the Aβ42/20 ratio, in neurons derived from induced pluripotent stems cells from Alzheimer’s patients (Kondo et al., 2017).
For details on the proposed mechanism of action of this combination therapy, cromolyn delivery via the lungs, and preclinical treatment experiments, see patent WO 2014066318 A1.
Findings
In June and July 2015, AZTherapeutics compared two dosing regimens of ALZT-OP1, each lasting two days, in a Phase 1 plasma/CSF pharmacokinetic crossover study conducted with 26 healthy volunteers at Panax Clinical Research in Florida. The combination appeared safe, with mild to moderate adverse events reported in three subjects. Both drugs achieved CSF concentrations judged sufficient to reduce amyloid production and inflammation (Brazier et al., 2017).
In September 2015, the company started an 18-month Phase 3 study. It aimed to enroll 600 people with early AD as verified by subjective memory complaint, impairment on a logical memory test, abnormally low CSF Aβ levels, and a CDR of 0.5. The trial compares four groups: cromolyn active plus ibuprofen active, cromolyn active plus ibuprofen placebo, cromolyn placebo plus ibuprofen active, cromolyn placebo plus ibuprofen placebo. The primary outcome is change on the CDR-sum of boxes; secondary outcomes are treatment-emergent adverse events. The study listing contains no additional outcome measures such as psychometric tests or biomarkers. Conducted at 90 trial sites in North America, Australia, and Eastern European countries, this study aims for 100 completers per group and is set to run until December 2020. This trial completed enrollment of 620 participants in July 2019.
For all clinical trials on this combination therapy, see clinicaltrials.gov.
Clinical Trial Timeline
- Phase 3
- Study completed / Planned end date
- Planned end date unavailable
- Study aborted
| Sponsor |
Clinical Trial |
2013 |
2014 |
2015 |
2016 |
2017 |
2018 |
2019 |
2020 |
2021 |
2022 |
2023 |
2024 |
2025 |
2026 |
2027 |
2028 |
2029 |
2030 |
2031 |
2032 |
2033 |
2034 |
2035 |
| AZTherapies, Inc. |
NCT02547818 |
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Last Updated: 29 Nov 2019
Further Reading
No Available Further Reading
Species: Mouse
Genes: MAPT
Modification: MAPT: Transgenic
Disease Relevance: Alzheimer's Disease, Frontotemporal Dementia
Strain Name: N/A
Summary
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
Amyloid plaques were absent.
Tangles
Neurofibrillary tangles were not observed; however, hyperphosphorylated tau occurred early in the form of oligomers and aggregates.
Synaptic Loss
Reduced levels of synaptic proteins as early as 1.3 months, including synaptophysin. Further reductions in 3 and 6-month-old animals.
Neuronal Loss
No significant neurodegeneration by 12 months of age.
Gliosis
No significant astrogliosis in the hippocampus or cortex by 12 months of age.
Cognitive Impairment
Learning and memory impairments as early as 1.3 months in several behavioral tests including the Y-maze, passive avoidance, and novel object recognition.
Last Updated: 08 Jan 2016
Further Reading
No Available Further Reading
COMMENTS / QUESTIONS
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