Species: Mouse
Genes: MAPT, MAPT-AS1, Mapt
Modification: MAPT: Knock-In; MAPT-AS1: Knock-In; Mapt: Knock-Out
Disease Relevance: Frontotemporal Dementia
Strain Name: B6(Cg)-Tc(HSA17*)1Mdk/J
Summary
MAPT 10IVS+16 C>T mice are among a series of models developed by Michael Koob and colleagues at the University of Minnesota, collectively referred to as Gene Replacement – Alzheimer’s Disease (GR-AD) mice. In GR-AD mice, “genes of interest are precisely and completely replaced in the mouse genome by their full human orthologs, along with all known overlapping, co-regulated non-coding RNAs (Benzow et al., 2024).”
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+.
Last Updated: 13 Feb 2024
Further Reading
No Available Further Reading
Species: Mouse
Genes: MAPT, MAPT-AS1, Mapt
Modification: MAPT: Knock-In; MAPT-AS1: Knock-In; Mapt: Knock-Out
Disease Relevance: Frontotemporal Dementia
Strain Name: B6J.B6N-Tc(HSA17*P301L)1Mdk/J
Summary
MAPT(H1.0)-GR mice are among a series of models developed by Michael Koob and colleagues at the University of Minnesota, collectively referred to as Gene Replacement – Alzheimer’s Disease (GR-AD) mice. In GR-AD mice, “genes of interest are precisely and completely replaced in the mouse genome by their full human orthologs, along with all known overlapping, co-regulated non-coding RNAs (Benzow et al., 2024).”
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+.
Last Updated: 13 Feb 2024
Further Reading
No Available Further Reading
Overview
Name: ACP-204
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2/3)
Company: Acadia Pharmaceuticals
Background
ACP-204 acts as an inverse agonist at the 5-HT2A serotonin receptor. It is currently being developed for the treatment of Alzheimer’s disease psychosis. Acadia’s previous 5-HT2A inverse agonist Nuplazid is approved for Parkinson’s disease psychosis. In 2022, the FDA declined to approve Nuplazid for Alzheimer’s disease, citing a lack of evidence for its effectiveness.
According to the company website, ACP2-4 is a next-generation 5-HT2A blocker designed to mitigate Nuplazid’s shortcomings. These include the heart rhythm disturbance of QT prolongation, which can be lethal, as well as dosing limitations and delayed onset of action.
Findings
No Phase 1 trials are registered. In investor presentations, Acadia claims that in Phase 1, ACP-204 caused no QT wave prolongation, was able to be dosed to twice the levels of Nuplazid, and reached steady-state pharmacokinetics in half the time (slides 18/19 JPM24.pdf).
In November 2023, the company began a Phase 2/3 program. The initial Phase 2 study evaluates the efficacy and dose response of six weeks of 30 or 60 mg ACP-204, or placebo, in approximately 1,074 participants with Alzheimer’s disease and psychosis. The primary endpoint is change in the Scale for the Assessment of Positive Symptoms–Hallucinations and Delusions subscales (SAPS-H+D) at week six; clinician-rated improvement in symptoms serves as a secondary endpoint. Based on the results, two Phase 3 studies will each enroll 378 patients with Alzheimer’s disease and psychosis, for six weeks of treatment at one or both doses, against the same endpoints. Patients who complete the study will have the option of enrolling in a long-term open-label extension. The trial will enroll worldwide, and finish in February 2028.
For details on these trials, see clinicaltrials.gov.
Last Updated: 05 Feb 2024
Further Reading
No Available Further Reading
Overview
Name: Focused Ultrasound – Blood-Brain Barrier
Synonyms: FUS-BBB, MRgFUS, MRI-Guided Focused Ultrasound, FUS+MB
Therapy Type: Procedural Intervention
Target Type: Amyloid-Related (timeline), Other (timeline)
Condition(s): Alzheimer's Disease, Amyotrophic Lateral Sclerosis, Mild Cognitive Impairment, Parkinson's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1), Amyotrophic Lateral Sclerosis (Phase 1), Mild Cognitive Impairment (Phase 1), Parkinson's Disease (Phase 1)
Background
Focused ultrasound with microbubbles is a noninvasive procedure that transiently opens the blood-brain barrier (BBB) using low-intensity sound waves. The openings reseal within 24 hours. Using MRI to guide the ultrasound enables targeted opening of precise brain regions to facilitate drug delivery. In the case of Alzheimer’s disease, opening the BBB appears to promote amyloid removal.
More than 20 years ago, researchers discovered that low-energy ultrasound waves paired with intravenous microbubbles routinely used as contrast agents temporarily loosened the BBB in rabbits (Hynynen et al., 2001). The procedure has since been widely explored as a way to enable drug delivery to the brain. In mice, FUS-BBB was shown to elicit transient opening of the hippocampal blood-brain barrier, allowing entry of antibodies and larger molecules that normally would be excluded (Choi et al., 2007; Choi et al., 2010). Optimized parameters for sonication energy, time, and microbubble dose were studied in mice and rats, to maximize safety while minimizing tissue damage and hemorrhaging (Baseri et al., 2010; Choi et al., 2011; O’Reilly and Hynynen, 2012; Hsu et al., 2022). This led to studies in nonhuman primates (McDannold et al., 2012), and in pigs with human skull implants (Huang et al., 2017). In both, the ultrasound/microbubble combination appeared to cause no apparent tissue damage or long-term neurological effects. Work to optimize FUS-BBB protocols in humans continues (Meng et al., 2021).
A large body of preclinical work underpins the use of this intervention to treat neurodegenerative disease. In Alzheimer's mouse models, targeted ultrasound reversibly opened the hippocampal BBB similarly to normal mice (Choi et al., 2008; Raymond et al., 2008). BBB opening by itself, in the absence of adjunct drugs, was subsequently shown to activate microglia, stimulate neurogenesis, clear Aβ in targeted regions, improve synaptic long-term potentiation, and restore memory (Jordão et al., 2013; Burgess et al., 2014; Scarcelli et al., 2014; Kong et al., 2023). In the rTg4510 amyloidosis mice, focused ultrasound reduced the levels of phosphorylated tau, when done before the onset of tau pathology (Karakatsani et al., 2019). A modified technique that uses scanning ultrasound to produce widespread BBB opening was found to activate microglia, reduce cortical plaques and improve cognition in APP23 mice (Mar 2015 news on Leinenga and Götz, 2015). Aging and amyloid pathology enhanced BBB opening, and delayed closing, in mice (Noel et al., 2023). The procedure is claimed to enhance glymphatic clearance of proteins from the mouse brain (Ye et al., 2023).
In a safety study using aged dogs with naturally occurring amyloid, four weekly treatments produced no changes on MRI, histology or neurologic exams. One adverse event of vomiting and bloody urine was possibly related to anesthesia or contrast agent injections (O’Reilly et al., 2017).
Animal studies in tauopathy models gave inconsistent results. In K391I mutant tau transgenic mice, repeat ultrasound was reported to reduce tau pathology and improve motor and cognitive behaviors (Pandit et al., 2019). A different group reported no effect of ultrasound treatment on tau pathology in P301S tau mice (Geraudie et al., 2023).
In preclinical drug delivery studies, FUS-BBB was shown to increase brain concentrations and efficacy of amyloid and tau antibodies, neurotrophic factors, IvIG, a GSK-3 inhibitor, and viral vectors, in mouse models of AD and PD (Jordao et al., 2010; Samiotaki et al., 2015; Nisbet et al., 2017; Janowicz et al., 2019; Karakatsani et al., 2019; Hsu et al., 2018; Ji et al., 2019; Dubey et al., 2020; Xhima et al., 2021; Antoniou et al., 2023). One paper reported FUS-enabled transplantation of neural stem cells in rats (Burgess et al., 2011). FUS-BBB paired with an antibody to pyroglutamated Aβ resulted in fivefold higher brain antibody levels, greater plaque removal, synapse sparing, and improved cognitive function compared to antibody alone, in part due to enhanced recruitment of peripheral monocytes to plaques (Sun et al., 2021; Bathini et al., 2022). Ultrasound reportedly enhanced brain levels of a new tau monoclonal antibody, but not its efficacy (Bajracharya et al., 2022). FUS-BBB boosted delivery of GDNF gene therapy in a mouse model of Huntington’s disease and of edaravone in a model of ALS (Lin et al., 2019; Shen et al., 2023).
Several studies have examined the response to FUS-BBB at the tissue and cell level. Transcriptional analysis, including single-cell sequencing of brain tissue after the procedure, showed upregulated phagosome pathway genes, microglial proliferation, more of the disease-associated microglia phenotype, and recruitment of central nervous system macrophages in targeted areas (Kline-Schoder et al., 2023; Leinenga et al., 2023; Mathew et al., 2021). FUS-BBB enhanced aducanumab delivery, but did not change the endothelial cell transcriptome, endothelial or astrocyte viability, or inflammatory responses in an in-vitro BBB model generated from AD patient-derived cells (Wasielewska et al., 2022).
Most clinical studies to date use InSightec’s ExAblate® Neuro device. This helmet-mounted array of 1,200 probes is used with a stereotactic frame to deliver focused, low-intensity sound waves to defined brain regions while the patient is undergoing MRI. The device is approved in the U.S. and other countries for high-intensity surgical ablation of tissue, including to treat essential tremor and Parkinson’s disease. Temporarily opening the BBB requires 100-fold lower energy than tissue ablation. Other devices, including a frameless version, and an implantable sonicator, are in development (e.g. Epelbaum et al., 2022).
Findings
In 2016-2017, a feasibility trial in Ontario enrolled five people with mild Alzheimer’s disease for two rounds of focused ultrasound, spaced one month apart and targeting a small region of the frontal lobe. BBB opening was detected with the MRI contrast agent gadolinium. The procedure produced no adverse events, hemorrhages, or brain swelling, and BBB opening was reversed after 24 hours (Aug 2018 conference news; Lipsman et al., 2018). A transient decrease in functional connectivity occurred after BBB opening, which also resolved by 24 hours (Meng et al., 2019). This academic trial, using the ExAblate device, was sponsored by InSightec.
In September 2018, an InSightec-sponsored safety trial began at West Virginia University, enrolling 10 patients with mild AD for three serial treatments targeting the hippocampus/entorhinal cortex. The study was later expanded to two more sites, and enrollment increased to 50. Interim results on six patients were published, reporting rapid BBB opening in the targeted regions, which reversed in 24 hours (Rezai et al., 2020). Participants had no adverse events, and neither cognitive nor neurological worsening after the procedure. Opening of the BBB was seen in 95 percent of the targeted area the hippocampus, covering one-third of the hippocampal volume. Amyloid PET scans revealed an average 5 percent reduction in probe uptake one week after the third treatment (D’Haese et al., 2020). Published data on three women in this study reported no gadolinium contrast agent entering the brain parenchyma after 24 hours, consistent with BBB closure. However, contrast agent was detected in the perivenous space of the blood-meninges barrier, away from the target opening sites, for up to 48 hours. This blood-meninges opening resolved by one week, and no adverse effects were reported in these patients (Mehta et al., 2021, commentary by Klibanov, 2021). The perivenous appearance of contrast agent was proposed to be evidence of glymphatic efflux (Meng et al., 2019).
Additional data was published on 10 patients who had received three treatments targeting brain regions containing the highest amyloid loads, including the hippocampus/entorhinal cortex, and parietal and frontal lobes, and had at least six months of followup (Rezai et al., 2022). Patients were tested on cognition and memory using the ADAS-Cog and MMSE one week after treatment, and intermittently thereafter. Participants declined comparably to an ADNI reference group on the ADAS-Cog and MMSE after six months. Reduction in amyloid plaque averaged 14 percent in the targeted regions. Completion of this trial is planned by December 2024.
In December 2018, another safety trial began enrolling 30 patients to a course of three treatments. The endpoints are device- and procedure-related adverse events through six months, with secondary outcomes of BBB disruption and closure, change in ADAS-Cog, and amyloid tracer uptake by PET. The trial, sponsored by InSightec at the Sunnybrook Health Sciences Centre in Ontario, Canada, is anticipated to end in December 2024. Results on the first nine patients were published (Meng et al., 2023). All showed BBB opening in the targeted areas of the default mode network, which included the bilateral precuneus, anterior cingulate cortex, and the hippocampus, with no serious adverse events or deleterious cognitive effects. After treatment, patients had a modest reduction of amyloid on PET scans, and stable biomarkers of AD pathology and BBB integrity; they also had a transient elevation of NfL.
From 2018-2021, the company sponsored pilot studies demonstrating the safety and feasibility of focused ultrasound to the primary motor cortex in eight patients with ALS, and to the posterior putamen in seven people with Parkinson’s disease and cognitive impairment (Abrahao et al., 2019; Pineda-Pardo et al., 2022). In the PD patients, there was a small but significant reduction in Aβ tracer uptake in the targeted region and no change in FDOPA PET. An additional company-sponsored pilot assessed the use of focused ultrasound-BBB disruption to deliver Cerezyme® β-glucocerebrosidase enzyme in four people with Parkinson’s disease. The trial was supposed to finish in December 2022; no further information has been made public.
A 2020 pilot study in six mild AD patients in Korea found repeated opening of volumes up to 30 ml in frontal lobe regions was safe and tolerable (Park et al., 2021). In 2022, the same investigators began a new trial with six additional patients, offering a higher number and more frequent treatments.
In August 2020, a Phase 2a trial at Columbia University began testing a portable ultrasound transducer that does not require patients to be immobilized in an MR machine (see Wu et al., 2018 and Pouliopoulos et al., 2020). This NIA-funded study plans to enroll six people with AD, and includes outcomes of successful opening of BBB, safety, and change in amyloid PET and MMSE scores. Completion was planned in December 2023. Results in a single patient were published, showing a 1.8 percent reduction in amyloid PET SUVr 3 weeks after treatment, but a 5.9 percent increase after three months (Karakatsani et al., 2023).
In July 2022, a Phase 1 trial began to test the effects of FUS-BBB opening in AD patients treated with an anti-amyloid antibody. Five participants with mild cognitive impairment or mild dementia will receive aducanumab infusions monthly for six months at a top dose of 6 mg/kg, below the effective dose of 10 mg/kg established in Phase 3 trials. After each infusion, participants will undergo BBB opening with the ExAblate protocol. The primary outcome is safety; secondary is change in brain amyloid, ADAS-Cog, and MMSE. According to interim results on three patients presented at the October 2023 CTAD conference, the procedure cleared about half of baseline amyloid in the targeted regions in six months (Nov 2023 conference news). Clearance in ultrasound-targeted regions was greater than in non-targeted areas. No ARIA was noted, but none of the patients carried the ApoE4 gene. The most common adverse event was headache, and one patient experienced cognitive worsening during follow-up. Results were published after peer review (Rezai et al., 2024). The study, at West Virginia University, is planned to run until summer of 2029.
Use of focused ultrasound for BBB opening is also being tested to improve delivery of chemotherapeutic agents to glioblastoma and other brain cancers (e.g., Carpentier et al., 2016).
Other studies are evaluating targeted low-intensity ultrasound, without bubbles, as a means of noninvasive neuromodulation of deep brain structures in the absence of BBB opening (for preclinical evaluation, see Jun 2021 news). This procedure in healthy adults has been shown to increase blood flow, neural activity and functional connectivity (Kuhn et al., 2023). An open-label trial is enrolling 100 patients with PD or AD with MCI or dementia, to receive short-term, transcranial focused ultrasound to the putamen and substantia nigra or the hippocampus, depending on their diagnosis. Preliminary results on 22 participants have been reported, claiming safety and possible cognitive improvements (Nicodemus et al., 2019). The trial is expected to end in early 2025. A 40-patient, sham-controlled trial of ultrasonic neuromodulation in people with cognitive impairment and confirmed AD biomarkers is registered to begin in April 2024. Two smaller studies are also registered, testing single sessions of neuromodulation for safety and cognitive effects in people with AD.
For details on focused ultrasound trials, see clinicaltrials.gov.
Last Updated: 16 Jan 2024
Further Reading
No Available Further Reading
Overview
Name: NYX-458
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): PD-MCI
U.S. FDA Status: PD-MCI (Discontinued)
Company: Aptinyx Inc.
Background
NYX-458 is an oral NMDA receptor modulator with pro-cognitive and antidepressant actions. It was being developed to treat cognitive impairment in people with Parkinson’s disease, where it was intended to mitigate NMDA receptor dysregulation caused by a lack of dopamine.
With a novel spiro-β-lactam-based chemical structure, NYX-458 differs from other NMDA agonists such as ketamine and MK-801. It was designed to mimic the activity of rapastinel, a peptide drug and NMDA partial agonist given by intravenous infusion. In Phase 2 trials, rapastinel elicited rapid and long-lasting improvements in people with treatment-resistant depression, but failed to replicate that result in large, pivotal Phase 3 studies (Moskal et al., 2017; 2019 Allergan press release).
In a nonhuman primate model of Parkinson’s disease, NYX-458 caused rapid cognitive improvements that persisted for three months across domains of attention, working memory, and executive function. It did not change motor symptoms, levodopa efficacy, or the occurrence of dyskinesias (Barth et al., 2020). The related NMDA modulator NYX-2925 showed little off-target activity, and enhanced NMDA receptor currents and long-term synaptic potentiation in rat hippocampus. This compound entered the CSF and enhanced cognitive performance in rodent models of learning and memory (Khan et al., 2018).
Findings
In November 2019, Aptinyx began a Phase 2 study in people with Parkinson’s disease or Lewy body disease with mild cognitive impairment or mild dementia. The 99 participants took 30 mg NYX-458 or placebo daily for 12 weeks. Primary outcomes were safety including adverse events, changes in vital signs or lab results, and neuropsychiatric or motor symptoms. Secondary outcomes assessed efficacy on scales of daily function and cognitive symptoms, and a battery of computerized cognitive tests.
On February 27, 2023, Aptinyx announced negative top-line results (press release). NYX-458 did not demonstrate clinically meaningful improvements over placebo on any efficacy endpoints. The company stopped development.
In March 2023, the company submitted trial results to clinicaltrials.gov. In June the company was liquidated.
Last Updated: 04 Jan 2024
Further Reading
No Available Further Reading
Overview
Name: NA-831
Synonyms: Traneurocin
Therapy Type: Small Molecule (timeline)
Target Type: Cholinergic System (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Biomed Industries, NeuroActiva™ Inc.
Background
This small molecule is claimed to activate AMPA receptors and increase the production of brain-derived neurotrophic factor in neurons. According to company information, it promotes neurogenesis and cognitive function. It is given orally, and is said to cross into the brain. It is being developed to treat Alzheimer’s disease, and also for the treatment and prevention of COVID19.
The NA-831 structure has not been disclosed. A patent application suggests it may be a cyclic prolyl glycine peptide or related structure. These molecules are naturally present in the brain, and positively modulate AMPA receptors (e.g. see Gudasheva et al., 2016).
No preclinical work is published on NA-831.
Findings
In Phase 1, 32 healthy volunteers in four cohorts received multiple doses of NA-831 ranging from 5 to 50 mg daily over one week. At AAIC 2018, the compound was shown having had dose-linear pharmacokinetics, low variability between people, and no adverse effects up to the highest dose tested (abstract). Additional Phase 1 results presented at CTAD 2021 established that doses up to 100 mg/day were well tolerated in healthy volunteers.
According to information on clinicaltrials.gov, a Phase 2 study began in September 2018, enrolling 126 participants with mild cognitive impairment due to AD, defined as an MMSE of 23 or greater. Treatment was to be 10, 20, or 40 mg per day or placebo for 24 weeks, against a primary outcome of change from baseline on the CDR-SB. Other outcomes were ADCS-ADL MCI version and the CIBIC-Plus. The trial took place in New Zealand, and is listed as having been completed in September 2019.
At the 2019 CTAD meeting, the company presented results of a Phase 2 trial that differed in its details from the registered trial (LB14 in CTAD abstracts). This study enrolled 112 people for six months treatment. Sixty-four were classified as having MCI, with an MMSE of 20 or greater, and received 10 mg NA-831 or placebo daily. The remaining 48 were defined as early onset AD with mild to moderate dementia, with MMSE scores greater than 17. They took 30 mg/day or placebo. The primary outcomes were the ADAS-Cog13, the brief cognitive rating scale (BCRS) and the CIBIC-plus. The company reported that NA-831 improved several domains on the BCRS starting at 12 weeks, including fatigue, anxiety, irritability, affective lability, disturbance to waking, daytime drowsiness, headache, and nocturnal sleep. ADAS-Cog scores declined 4.1 points less than on placebo in the mild to moderate group, and 3.4 points less in MCI group after treatment. More patients were reported to have improved on the CIBIC-Plus in the drug group versus placebo. No adverse events were reported.
At the October 2023 CTAD conference, the company presented protocols for a Phase 2 trial testing NA-831 in combination with aducanumab, and a Phase 3 with lecanemab. Neither trial is registered yet.
NA-831 is also in trials for depression and COVID-19 disease. In August 2023, the company announced positive top-line results for a small study in people with major depressive disorder (press release). A Phase 3 for the treatment of COVID-19 disease in combination with dexamethasone or the antiviral atazanavir is ongoing. A Phase 2 trial testing a combination with the polio vaccine for COVID was completed.
No peer-reviewed papers are available for this compound.
For details on NA-831 trials, see clinicaltrials.gov.
Last Updated: 28 Nov 2023
Further Reading
No Available Further Reading
Overview
Name: NTRX-07
Synonyms: MDA7
Chemical Name: 1-[(3-benzyl-3-methyl-2,3-dihydro-1-benzofuran-6-yl)carbonyl]piperidine
Therapy Type: Small Molecule (timeline)
Target Type: Inflammation (timeline), Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: NeuroTherapia, Inc.
Background
NTRX-07 is a cannabinoid receptor agonist. It enters the central nervous system and activates receptors on microglia, reportedly to reduce neuroinflammation. It is specific for the cannabinoid receptor type 2 (CB2) and does not alter mood or behavior as do CB1 receptor agonists.
This compound emerged from an academic lab and was subsequently explored by its discoverer. Studies reported activity in animal models of neuropathic pain (Naguib et al., 2008; Diaz et al., 2009). In a model of chemotherapy-induced nerve pain, it altered pathways involved in inflammation and microglia dysregulation (Xu et al., 2014; Wu et al., 2019; see also Naguib et al., 2012). Neuroprotective and anti-inflammatory effects were reported in a model of complex regional pain syndrome (Xu et al., 2016).
Preclinical work related to Alzheimer’s disease was conducted by the same group. In rats injected with Aβ40 fibrils, NTRX-07 was reported to prevent microglial activation, promote Aβ clearance, restore synaptic plasticity, and improve cognition and memory (Wu et al., 2013). In the APP/PS1 mouse, NTRX-07 suppressed neuroinflammation, improved amyloid clearance, synaptic function, and markers of neurogenesis in the hippocampus, and restored behavior in the Morris water maze (Wu et al., 2017).
Findings
From October 2019 to December 2020, NeuroTherapia conducted a Phase 1, single-ascending-dose study in 48 healthy volunteers. Six cohorts received oral doses from 0.3 to 8 mg/kg, with placebo control. Results from the first three cohorts were presented at the July 2020 AAIC (Foss et al., 2020). The drug attained blood levels better than expected from animal studies, and reached concentrations predicted to be efficacious based on preclinical animal models. No adverse effects were reported at the highest dose tested, 2 mg/kg. In December 2020, the company reported results on all cohorts, claiming no dose-limiting side effects (press release). The two highest doses induced lightheadedness and flushing.
At the October 2023 CTAD conference, NeuroTherapia presented data on a Phase 1b study, which involved administration of 10, 30, or 90 mg NTRX-07 daily for seven days to healthy older adults (press release). The drug was reported to induce mild and transient adverse effects, and no safety concerns. A high-fat meal before dosing not change drug exposure. The study went on to evaluate a cohort of eight mild AD patients given 90 mg daily for one week or placebo. The company claimed a trend toward improvement in the ADAS-Cog, with all six treated patients but not the two on placebo scoring better. They also claimed normalization of quantitative electroencephalogram (EEG) outcomes in treated patients. There were no significant changes in biomarkers. This trial does not appear in registries.
For details on NTRX-07 trials, see clinicaltrials.gov.
Last Updated: 10 Nov 2023
Further Reading
No Available Further Reading
Overview
Name: E2511
Therapy Type: Small Molecule (timeline)
Target Type: Cholinergic System (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: Eisai Co., Ltd.
Background
E2511 is Eisai’s positive allosteric modulator of the tropomyosin receptor kinase A. TrkA activation by nerve growth factor is required for the survival and function of cholinergic neurons. Loss of these neurons early in Alzheimer’s disease contributes to cognitive decline. This small molecule, taken in tablet form, aims to preserve cholinergic nerve function and improve cognition.
No preclinical work on E2511 is published. At meetings, the company has presented evidence that it binds TrkA, activates kinase activity, and boosts expression of genes involved in cholinergic function in neurons. Chronic administration in Tau P301S transgenic mice prevented loss of cholinergic neurons and increased the number of cholinergic synapses (Tomioka et al., 202; Tomioka et al., 2023).
Findings
In September 2020, a Phase 1 study began assessing safety, pharmacokinetics, and food effects of single ascending doses in 40 healthy adults and five elderly participants. Safety endpoints spanned adverse events, physical exams, clinical laboratory tests, vital signs, electrocardiograms and electroencephalograms. According to results presented at the 2023 AAIC, E2511 produced no dose-dependent or severe adverse events, or changes in safety parameters (abstract). The drug reached maximum blood concentrations after one hour, and had a half-life of 3.2 hours. Pharmacokinetics were linear with dose, and comparable in elderly and younger adults.
A multiple-ascending-dose trial began in December 2021. It enrolled 32 healthy, non-Japanese adults to receive 10, 20, 40, or 80 mg tablets once daily for 14 days. CSF was collected on day 13. An additional three cohorts totaling 15 Japanese adults received 20, 40, or 80 mg daily for two weeks. One group of older adults was given 40 mg per day.
According to results presented at the 2023 CTAD conference, no dose-related adverse events or safety signals were observed. One Japanese participant, treated with the highest dose, had a serious event of mania, and was withdrawn from the study. Blood pharmacokinetics were as expected from the previous trial, and similar between Japanese and non-Japanese participants. The drug entered the brain, achieving CSF-to-plasma ratios ranging from 15 to 32 percent, depending on dose. Proteomic analysis of CSF found that treatment resulted in changes in multiple axonal and synaptic markers, consistent with E2511’s presumed mechanism of action. The company is planning a Phase 1b dose-finding trial.
For details on E2511 trials, see clinicaltrials.gov.
Last Updated: 09 Nov 2023
Further Reading
No Available Further Reading
Overview
Name: Obicetrapib
Synonyms: TA-8995
Therapy Type: Small Molecule (timeline)
Target Type: Cholesterol
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: NewAmsterdam Pharma
Background
This cholesteryl ester transfer protein (CETP) inhibitor is being developed primarily as a cholesterol-targeted therapy to reduce cardiovascular disease. CETP inhibitors block the transfer of cholesteryl esters from high-density lipoprotein (HDL) into other lipoproteins, and thus promote removal of cholesterol by HDL. Drugs of this class were initially developed to increase “good” high-density lipoprotein (HDL) cholesterol, and were shown to also reduce “bad” low-density lipoprotein (LDL) cholesterol in people. Previous CETP inhibitors were discontinued when they showed little or no improvement in cardiovascular outcomes, or even increased deaths, despite raising HDL (see review by Nurmohamed et al., 2022; also Oct 2021 news). Obicetrapib is claimed to be more potent and specific than these failed candidates.
The rationale for testing this CETP inhibitor for Alzheimer’s disease stems from work linking high levels of HDL to longer life and preserved cognition (Barzilai et al., 2006; Lewis et al., 2010). By its ability to elevate HDL, obicetrapib increases cholesterol efflux from cells, a process which may mitigate the risk of AD due to ApoE4, and help clear Aβ from brain (van Capelleveen et al., 2016; Van Valkenburgh et al., 2021). However, low-activity CETP gene variants that mimic inhibition do not decrease the risk of AD (Nordestgaard et al., 2022; Peloso et al., 2018). In one study, genetic variants associated with higher HDL actually raised AD risk (May 2023 news). High HDL is also linked to an elevated risk of age-related macular degeneration (Burgess and Davey Smith, 2017).
No preclinical work is published on obicetrapib in Alzheimer’s models. Mice lack a CETP gene, but a recently produced transgenic animal may be useful for such studies (Oestereich et al., 2022).
Findings
In Phase 1 evaluation in healthy subjects, single and multiple oral doses of obicetrapib from 2.5 to 25 mg daily were well-tolerated and nearly completely inhibited CETP (Ford et al., 2014). The treatment increased high-density lipoprotein-cholesterol (HDL-C) by 96 to 140 percent and decreased low-density lipoprotein-cholesterol (LDL-C) by 40 to 53 percent. No significant effects of age, gender, ethnicity, or food were found. There was no evidence of off-target effects seen with earlier inhibitors, such as changes in blood pressure, serum electrolytes, or aldosterone.
In January 2022, NewAmsterdam Pharma began a Phase 2, open-label proof-of-concept study in 13 patients with a clinical diagnosis of Alzheimer's disease who carried one or two ApoE4 alleles. Treatment consisted of 10 mg obicetrapib daily for 24 weeks. Primary outcomes were concentration of apolipoproteins and high-density lipoprotein particles in plasma and CSF. Other outcomes were pharmacokinetics including CSF levels of drug. The study was completed in June 2023. In September, the company announced top-line data, saying that obicetrapib had been well-tolerated (company press release). No data on lipoprotein levels was reported; instead, the company claimed 10 and 11 percent reductions in CSF 24- and 27-hydroxycholesterol, respectively. This was interpreted as evidence of normalization of cholesterol metabolism in the brain. The treatment nudged up the CSF Aβ42/40 ratio by 8 percent.
Three large, worldwide Phase 3 trials of obicetrapib are ongoing, testing it as an add-on to statins to further lower cholesterol and improve cardiovascular outcomes in people with familial high cholesterol or atherosclerotic cardiovascular disease. In a Phase 2 study, 10 mg obicetrapib added to high-intensity statin treatment decreased LDL and increased HDL (Nicholls et al., 2022). Obicetrapib additively lowered cholesterol when given with statins and ezetimbe, a drug that blocks intestinal cholesterol absorption (Ballantyne et al., 2023). Even though CETP inhibitors raise HDL, their cardiovascular benefits are now attributed to their ability to lower LDL and apolipoprotein B (see Nelson et al., 2022; Mehta et al., 2023).
For details on this study, see clinicaltrials.gov.
Last Updated: 07 Nov 2023
Further Reading
No Available Further Reading
Species: Mouse
Genes: Plcg2, App
Modification: Plcg2: Knock-In; App: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: B6.Cg-Plcg2em1Msasn/J x Apptm3.1Tcs/Apptm3.1Tcs
The PLCG2 gene encodes the enzyme phospholipase C gamma 2 (PLCγ2), a mediator of transmembrane signaling in microglia that acts downstream of TREM2.
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
ThioflavinS-positive amyloid plaques observed in mice studied at 6 months of age. Higher plaque burdens than APPNL-G-F.
Gliosis
Microgliosis observed in mice studied at 6 months of age. Attenuated microglia-plaque interactions in the hippocampus, compared with APPNL-G-F.
Synaptic Loss
The P522R variant attenuated the synapse loss observed in APPNL-G-F mice with wild-type PLCγ2.
Complementary Models
Microglial-like cells derived from human induced pluripotent stem cell lines (hIPSCs) have been used to study PLCγ2 biology in human cells in vitro and in vivo after transplantation into mouse brains.
CRISPR/Cas9 gene editing was used to introduce the PLCG2 P522R mutation into hIPSCs derived from skin cells of an apparently healthy, middle-aged Caucasian male. Isogenic clones homozygous for the wild-type P522 allele or mutant R522 allele were differentiated into microglia-like cells (Maguire et al., 2021). Stimulation of PLCγ2 by Fc receptor ligation led to a greater increase in intracellular Ca2+ in cells carrying the mutant allele, consistent with a hypermorphic effect of the mutation. Similar to microglia and macrophages isolated from Plcg2*P522R knock-in mice (Maguire et al., 2021), hIPSC-derived microglia carrying the mutant allele showed decreased phagocytosis (uptake of E. coli particles or zymosan) and increased endocytosis (uptake of Aβ42 oligomers or Dextrans), compared with isogenic hIPSC-derived microglia expressing wild-type PLCγ2.
A second study compared isogenic hIPSC-derived microglia that differed with regard to P522R gene dose—wild-type (PLCγ2WT), heterozygous for the P522R mutation (PLCγ2HET), and homozygous for the mutation (PLCγ2HOM) (Solomon et al., 2022). In this case, the parental hIPSC line was derived from skin fibroblasts donated by a teenaged male (APOE3/4) of black or African-American ancestry with no diagnosed diseases. Here, too, CRISPR gene editing was used to introduce the PLCG2 P522R mutation. IPSC-derived microglia contained similar levels of PLCγ2 protein, regardless of PLCG2 genotype. However, the genotypes differed with regard to functional properties and gene expression—with PLCγ2HET showing more pronounced differences than PLCγ2HOM on several measures (compared with PLCγ2WT). PLCγ2HOM and PLCγ2HET showed increased uptake of fluorescently labeled Aβ42, but only PLCγ2HET cells showed increased uptake of Dextrans. Uptake of synaptosomes was reduced in P522R carriers, regardless of gene dose. LysoTracker staining—a marker for lysosomes—was elevated in P522R carriers, slightly more so in heterozygotes than homozygotes. When co-cultured with IPSC-derived neurons (heterozygous for the PLCG2 P522R mutation), PLCγ2HET microglia engaged in less synaptic pruning—as measured by PSD95 engulfment—than PLCγ2WT microglia, while PLCγ2HOM did not significantly differ from PLCγ2WT. When levels of expression of selected genes related to microglial function were compared between P522R carriers and wild-type cells, several genes were found to be upregulated in PLCγ2HET—in pathways related to lipid metabolism, lysosomal biogenesis, and immune function—while only APOE was upregulated in PLCγ2HOM. Microglial motility and intracellular Ca2+ levels were also greater in PLCγ2HET compared with the other two PLCG2 genotypes. Physiological studies showed a gene-dose-dependent increase in oxidative phosphorylation with PLCγ2HOM > PLCγ2HET > PLCγ2WT.
A third study focused on the effects of the P522R mutation on the transcriptomes of human microglia-like cells in vivo, in the context of amyloidosis (Claes et al., 2022). Once again, CRISPR gene editing was used to introduce the P522R mutation into the PLCG2 gene, this time in an (RFP)-α-tubulin expressing hIPSC line derived from fibroblasts donated by an apparently healthy 30-year-old Japanese man. IPSCs homozygous for the PLCG2 P522R mutation or isogenic hIPSCs with wild-type PLCG2 were differentiated into microglia-like cells in vitro, then grafted into the brains of neonatal immune-deficient 5xFAD or non-transgenic mice. Mice were aged to 7 months, a time when plaque deposition is well underway in 5xFAD brains, and the human cells were harvested for RNA sequencing. PLCG2 P522R microglia from 5xFAD brains showed increased levels of expression of multiple HLA and interferon genes and of genes encoding chemokines that mediate T-cell recruitment to the brain, compared with microglia expressing wild-type PLCG2. Gene Ontology analysis highlighted MHC class II antigen presentation, cytokine/chemokine signaling, interferon signaling, and regulation of T cell proliferation as pathways affected by the P522R mutation. PLCG2 P522R microglia isolated from non-transgenic hosts also showed increased expression of HLA genes, compared with microglia carrying wild-type PLCG2.
Chimeric 5xFAD brains were also examined histologically, and no differences were seen between those transplanted with P522R and wild-type PLCG2 hIPSC-derived microglia in the following measures: amyloid plaque burden, number, or size; microglial morphology, number of plaque-associated microglia, or microglial amyloid internalization; “amount” of plaque-associated dystrophic neurites; or numbers of total or plaque-associated astrocytes.
The lack of an effect of the P522R mutation on amyloid-related pathology in chimeric mice contrasted with findings in 5xFAD mice in which the P522R mutation was knocked into the endogenous Plcg2 gene. In the knock-in mice, the P522R mutation reduced amyloidosis, enhanced microglia-plaque interactions, and protected against plaque-associated pathology. The chimeric and knock-in models differ in several aspects that could potentially contribute to these discrepant findings, including intrinsic differences between human and mouse microglia, expression of P522R PLCγ2 in cells other than microglia in the knock-in mice, and lack of immune responses in chimeric hosts.
Last Updated: 27 Oct 2023
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