Species: Mouse
Genes: APP
Modification: APP: Transgenic
Disease Relevance: Alzheimer's Disease, Cerebral Amyloid Angiopathy
Strain Name: N/A
Modification Details
A human APP minigene with the Swedish, Indiana, and Arctic mutations driven by the platelet-derived growth factor β-chain promoter.
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
Parenchymal neuritic plaques by 2 months with prominent plaque deposition in the hippocampus by 3-4 months. Abundant mature thioflavin-S positive plaques with dystrophic neurites by 10-12 months (Cheng et al., 2007).
Gliosis
Reactive astrocytosis at 3-4 months in the dentate gyrus as demonstrated by GFAP immunoreactivity (Cheng et al., 2007).
Cognitive Impairment
At 3-4 months the Arc48 mouse was able to learn a task involving escape to a cued platform in the Morris water maze, but were impaired in the ability to use extramaze cues to navigate to the hidden platform (Cheng et al., 2007).
Last Updated: 06 Mar 2018
Further Reading
No Available Further Reading
Species: Mouse
Genes: APP
Modification: APP: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Modification Details
Targeted knock-in of the V642I mutation into exon 17 of the mouse APP gene using homologous recombination and the Cre-loxP system.
Neuropathology
Increased Aβ42(43) relative to Aβ40 at 29 months, but without neuritic plaques, neurofibrillary tangles, massive neuronal loss, or brain atrophy.
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+.
Cognitive Impairment
Impairments at the water finding task at age 27-29 months, a test of long-term memory. No differences in the open field test of the elevated plus maze indicating no difference in general behavioral patterns, activity level, or emotional state.
Last Updated: 06 Mar 2018
Further Reading
No Available Further Reading
Species: Mouse
Genes: APP
Modification: APP: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Modification Details
These mice overexpress human APP695 with the Swedish (K670N/M671L) and Arctic (E693G) mutations.
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
Between 9 and 15 months of age β-amyloid plaques became prominent. Plaques had a characteristic dense core morphology which differed from the cotton wool-like structure of plaques seen with the Swedish mutation alone (Knobloch et al., 2007).
Changes in LTP/LTD
LTP is severely impaired in slices from 3.5 and 7.5 month old mice. LTP and basal synaptic transmission were normal in slices from one month old mice (Knobloch et al., 2007).
Cognitive Impairment
Cognitive impairment measured from the age of 6 months in the Morris water maze and Y-maze, as well as in active avoidance behavior (Knobloch et al., 2007).
Last Updated: 06 Mar 2018
Further Reading
No Available Further Reading
Species: Mouse
Genes: PSEN2
Modification: PSEN2: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Modification Details
Transgene containing human PSEN2 carrying the N141I mutation driven by the neuron-specific enolase (NSE) promoter.
Neuropathology
Not observed.
Cognition/Behavior
Behavioral deficits in the water maze at 12 months in mice expressing mutant as well as wild-type PSEN2, including longer escape latencies than wild-type mice, but no difference in swimming speed.
Last Updated: 06 Apr 2022
Further Reading
No Available Further Reading
Overview
Name: Brexpiprazole
Synonyms: Rexulti, OPC 34712
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease, Schizophrenia
U.S. FDA Status: Alzheimer's Disease (Approved), Schizophrenia (Approved)
Company: Lundbeck, Otsuka Pharmaceutical Co., Ltd.
Background
Brexpiprazole is an orally available dopamine receptor D2 partial agonist, and an atypical antipsychotic. This quinolinone derivative is a successor to aripiprazole (Abilify, Aripiprex), an approved, widely used drug that is also a dopamine D2 receptor partial agonist. Brexpiprazole is approved in the United States for the treatment of schizophrenia, and as an add-on therapy for depression. It was the first treatment approved for agitation associated with dementia in patients with Alzheimer's disease. In addition, it is being tested in people with bipolar and post-traumatic stress disorder.
In preclinical work with transgenic mouse models of AD, brexpiprazole reduced agitation-like behaviors including attacking intruder mice and nighttime activity (Amada et al. 2024).
Findings
In July 2013, Otsuka and Lundbeck started a Phase 3 study in the U.S., Europe, and Russia to evaluate brexpiprazole for the treatment of agitation in 560 patients with moderate to severe Alzheimer's dementia living in an institution or with a caregiver at home. The trial compared safety, efficacy, and tolerability of three months of 0.5, 1, and 2 mg of brexpiprazole or placebo once daily. The primary endpoint was change on the Cohen-Mansfield Agitation Inventory, but the trial also measured changes in aggression, global clinical status, and quality of life. In April 2015, this trial dropped the 0.5 mg dose and continued with a target enrollment of 420 patients. The trial offered a two-month safety follow-up study.
In September 2013, a second Phase 3 trial started enrolling an anticipated 230 patients. This trial explored brexpiprazole using a flexible dose titrated between 0.5 and 2 mg/day depending on efficacy and tolerability in a given patient, but is otherwise identical. In June 2014, Otsuka added a two-month follow-up study for participants in either of these two trials.
Top-line results of both trials were announced in May 2017 (see press release); more details were presented at the meeting of the American Association of Geriatric Psychiatry in March 2018 (press coverage). Results were later published after peer review (Grossberg et al., 2020). In the fixed-dose trial, patients on 2 mg daily were reported to have shown statistically significant improvement over placebo on the CMAI after three months. In the flexible-dose trial, the change in CMAI missed significance. A post hoc analysis of only the 2 mg/day group found a significant improvement in the CMAI compared to placebo. The full study group showed improvement on the Clinical Global Impression-Severity of Illness (CGI-S), a secondary measure of agitation.
Common adverse events were insomnia, residual agitation, and drowsiness in some patients. The investigators noted variability in data from different countries, which might be related to differences in standard of care. Patients in the U.S. responded well; patients from Russian sites did not.
Following discussions with the FDA, the sponsors started two new Phase 3 trials in 2018. In May, they initiated a three-month trial testing 2 and 3 mg daily doses of brexpiprazole or placebo in 345 Alzheimer's patients with agitation and aggression in the U.S. and Europe. In August, a similar trial started in Japan; it planned to treat 407 patients with 1 or 2 mg brexpiprazole per day or placebo for 10 weeks. For both, the primary endpoint is the change from baseline in CMAI at three months. The secondary endpoint is change in CGI-S. To monitor safety, the U.S. study offered a 12-week extension, the Japanese study a 14-week extension. The U.S. trial finished in June 2022, and met its primary endpoint. According to results presented at the 2022 CTAD conference (Dec 2022 news), either dose of brexpiprazole or placebo substantially reduced CMAI scores, but the drug did slightly better. The same pattern held for the key secondary endpoint, CGI-S. Brexpiprazole was generally well-tolerated and safe, with no increase in adverse events in treated patients compared to placebo. It was not sedating. There were more deaths in the treatment groups than placebo across three Phase 3 studies, but none were deemed related to drug. The companies planned to file for FDA approval by the end of 2022. Trial results were published after peer review (Lee et al., 2023; commentary by Ballard, 2023).
A subsequent analysis of adverse events reported, across indications, from 2015 to 2023 to the FDA Adverse Event Reporting System (FAERS) noted additional side effects (Jiang et al., 2024), whereas a meta-analysis of trial data found no adverse event signals but confirmed efficacy (Marinheiro et al., 2024).
On January 7, 2023, the company announced that brexpiprazole was granted priority review by the FDA for the treatment of agitation in Alzheimer's dementia. In April 2023, the FDA issued a briefing document that said the Phase 3 trials had provided substantial evidence of efficacy, and an outside advisory committee voted 9-1 in favor of approval (press release). On May 10, 2023, Rexulti was approved (May 2023 news). It carries a black box warning due to an observed increase in mortality associated with this class of antipsychotic agents in people with dementia (see Zhong and Cummings, 2024).
The study in Japan finished in May 2023, and results were published after peer review (Nakamura et al., 2024). Brexpiprazole 1 or 2 mg improved CMAI total scores after 10 weeks. Adverse events were mild to moderate, but occurred with a higher incidence in this population compared to previous studies. For all trials of brexpiprazole, see clinicaltrials.gov.
Clinical Trial Timeline
- Phase 3
- Study completed / Planned end date
- Planned end date unavailable
- Study aborted
| Sponsor |
Clinical Trial |
2011 |
2012 |
2013 |
2014 |
2015 |
2016 |
2017 |
2018 |
2019 |
2020 |
2021 |
2022 |
2023 |
2024 |
2025 |
2026 |
2027 |
2028 |
2029 |
2030 |
2031 |
2032 |
2033 |
2034 |
2035 |
| Otsuka Pharmaceutical Co., Ltd., Lundbeck |
NCT01862640 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
| Otsuka Pharmaceutical Co., Ltd., Lundbeck |
NCT01922258 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Last Updated: 18 Oct 2024
Further Reading
No Available Further Reading
Overview
Name: Idalopirdine
Synonyms: Lu AE58054, SGS 518
Chemical Name: 2-(6-fluoro-1H-indol-3-yl)-ethyl]-[3-(2,2,3,3-tetrafluoropropoxy)-benzyl]-amine
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease, Schizophrenia
U.S. FDA Status: Alzheimer's Disease (Discontinued), Schizophrenia (Inactive)
Company: Lundbeck, Otsuka Pharmaceutical Co., Ltd.
Background
This orally available drug is an antagonist of the serotonin 6 (5-HT6) receptor. This receptor subtype is expressed primarily in the brain, particularly in the cerebral cortex and hippocampus, where it has been proposed to play a role in cognitive impairments associated with schizophrenia and Alzheimer's disease. The 5-HT6 receptor antagonists are thought to enhance cholinergic, glutamatergic, noradrenergic, and dopaminergic neurotransmission. Apart from some affinity for adrenergic receptors, Lu AE58054 has been reported to be highly selective over other G-protein coupled receptors. The compound enters the brain and was able to dose-dependently reverse deficits in a rat model of cognitive impairment (Upton et al., 2008; Arnt et al., 2010).
Lu AE58054 was being developed as a symptomatic adjunct to cholinesterase inhibitor treatment in Alzheimer's disease. The compound was originally discovered by Lilly, which licensed it to the biotechnology company Saegis for clinical development in cognitive impairment in thinking disorders such as schizophrenia. In 2006, Saegis was acquired by Lundbeck, which in October 2013 launched a global Phase 3 program in AD. This program consisted of four trials that planned to enroll a total of nearly 3,000 patients (see company press release).
Findings
No Phase 1 trials on this drug are listed in publicly available databases. In 2005, Saegis conducted a Phase 2a trial in 20 schizophrenia patients in the United States, evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of giving this drug as an add-on to Risperidone (see company press release). In 2009 and 2010, Lundbeck conducted a Phase 2 trial in Europe and Asia to evaluate the compound as an adjunct to Risperidone for its effect on cognitive deficits in 124 patients with schizophrenia. Results were not published in the peer-reviewed literature, but development of Lu AE58054 for cognitive deficits in schizophrenia appears to have ended.
In 2010 and 2011, Lundbeck evaluated Lu AE58054 in a Phase 2 study in 278 patients with probable Alzheimer's disease. Conducted in Australia, Canada, and Europe, the trial compared the effects of a six-month course of 90 mg/day of Lu AE58054 with 10 mg/day of Donepezil to the same dose of placebo. In June 2012, the company announced that the trial had met its primary cognition endpoint as measured by the ADAS-cog. On secondary endpoints, such as measures of global status and activities of daily living, Lu AE58054 treatment showed trends for a benefit but fell short of achieving statistical significance. Elevated liver enzymes in the treatment group, and higher dropout than in the placebo group, were also noted in this trial (see Jun 2012 news).
In October 2013, the first of four Phase 3 studies began, called STARSHINE. All Phase 3 trials in this program enrolled patients with mild to moderate Alzheimer's disease who were already taking a stable dose of 10 mg/day of an acetylcholinesterase inhibitor; two studies required that patients be on donepezil, one allowed any of the three available drugs of that mechanism, the fourth is an extension study. All phase 3 trials dosed well below the 90 mg/day reported to be effective in phase 2. STARSHINE compared a six-month, adjunct course of once-daily 30 or 60 mg capsules of idalopirdine to placebo in 930 participants for added benefit on cognition as measured by the ADAS-cog as a single primary outcome. Secondary outcomes assessed various aspects of global clinical function and behavior. No biomarkers were embedded in this development program.
In spring 2014, Lundbeck started up three additional Phase 3 studies. STARBEAM compared a lower dose of 10 mg to 30 mg once daily for six months in 840 patients, STARBRIGHT was a worldwide study comparing 30 to 60 mg once daily for six months in 720 patients. The third was an open-label study to enroll 1,770 patients who completed one of the two trials comparing the higher two doses; it assessed safety, cognition, clinical, and psychiatric measures for another seven months. These studies were set to end between November 2015 and August 2016.
In 2013 and 2014, Phase 1 studies evaluating pharmacokinetics of single and multiple ascending doses in healthy volunteers and in people with liver impairment were added. In 2015, Lundbeck conducted four additional Phase 1 trials in France, Germany, and the United Kingdom. One evaluated the bioequivalence of two different formulations, the others investigated idalopirdine's effect on kidney function, excretion, and heart repolarization.
In July 2016, Idalopirdine received Fast Track designation by the FDA; however in September, Lundbeck announced that topline results showed weak efficacy: none of the two doses in the STARSHINE phase 3 trial reached the primary endpoint (see 30 Sept news). Negative findings from the STARBEAM and STARBRIGHT trials were presented at the 2017 AAIC (Aug 2017 conference news), and Lundbeck announced in its 2017 annual report that the results “did not demonstrate efficacy to support a regulatory submission” and removed the drug from its pipeline. Complete results of all three trials were published in JAMA (Jan 2018 news).
For listed trials on Lu AE58054, see clinicaltrials.gov; some of the 2015 Phase 1 studies are registered under idalopirdine at clinicaltrials.gov.
Clinical Trial Timeline
- Phase 2
- Phase 3
- Study completed / Planned end date
- Planned end date unavailable
- Study aborted
Last Updated: 27 Jan 2018
Further Reading
No Available Further Reading
Species: Mouse
Genes: PSEN1
Modification: PSEN1: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Summary
Last Updated: 06 Mar 2018
Further Reading
No Available Further Reading
Species: Mouse
Genes: PSEN1
Modification: PSEN1: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Summary
Last Updated: 06 Apr 2022
Further Reading
No Available Further Reading
Species: Mouse
Genes: BACE1
Modification: BACE1: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Modification Details
Transgene expressing wild-type human BACE1 driven by the mouse Thy1 promoter.
Neuropathology
Not observed.
Cognition/Behavior
Unknown.
Other Phenotypes
Transgene is expressed in neurons only. No change in the processing of endogenous murine APP.
Last Updated: 06 Mar 2018
Further Reading
No Available Further Reading
Species: Mouse
Genes: APP
Modification: APP: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Neuropathology
Increased Aβ42 in the cortex and hippocampus of 12 month-old mice, but no plaques. Increased tau phosphorylation and TUNEL-stained nuclei relative to control mice (Hwang et al., 2004).
Last Updated: 25 Nov 2019
Further Reading
No Available Further Reading
COMMENTS / QUESTIONS
No Available Comments
Make a comment or submit a question
To make a comment you must login or register.