Overview
Name: Metformin
Synonyms: Glucophage, Glucophage XR
Chemical Name: N,N-Dimethylimidodicarbonimidic diamide
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2/3)
Approved for: Type 2 Diabetes
Background
Metformin is a prescription drug widely used to treat Type 2 diabetes. It lowers blood glucose and restores insulin sensitivity. Type 2 diabetes is a risk factor for dementia, and insulin sensitivity may be altered in Alzheimer's patients.
Metformin has been reported to reduce inflammation and oxidative stress, and to promote neurogenesis. Its ability to stimulate AMP-activated protein kinase (AMPK) has been linked to anti-aging activity in animal models, but also to increased Aβ generation via upregulation of BACE1. In people, metformin use is associated with reduced mortality, cardiovascular disease, and cancer, independent of its effects on diabetes (Campbell et al., 2017). This has led some to promote it as a potential anti-aging drug in people (Barzilai et al., 2016).
Some epidemiological studies suggest metformin reduces Alzheimer's risk in people using it to treat diabetes, but others have found long-term use may increase it. Long-term metformin use can lead to vitamin B12 deficiency, which can cause symptoms of dementia (Campbell et al., 2018; Chin-Hsiao, 2019; Sluggett et al., 2020; Imfeld et al., 2012; Porter et al., 2019). More recent, and larger, studies bear out a reduction in all-cause dementia in people with diabetes who use metformin, and indicate a dose-response relationship (e.g., Doran et al., 2024; Sun et al., 2023; Zimmerman et al., 2023). This finding is not universal (see Wu et al., 2024). In one study, metformin effects varied among subgroups defined by use of antidepressants, NSAIDs, or with neuropsychiatric disorders (Tang et al., 2024).
Likewise, results for studies of metformin in Alzheimer’s disease are mixed. One meta-analysis of published studies suggested a reduced risk of cognitive decline, but not of Alzheimer’s, in people with diabetes who used metformin (Zhang et al., 2022). Other studies found no reduction of AD risk or slowing of decline in people with AD (Luo et al., 2022; Wu et al., 2020; Xue and Xie, 2023). One study reported the potential for a higher risk of AD among Asians using metformin (Ha et al., 2021). In an autopsy study of 1,584 participants, there was no difference in the level of AD pathology or evidence of strokes between metformin users and non-users (Sood et al., 2024).
Among positive studies, metformin was associated with a reduced risk of all types of dementia, but only if it was initiated before dementia began (Ji et al., 2022). In the Alzheimer's Disease Neuroimaging Initiative study, metformin was associated with better cognitive performance, and CSF and imaging biomarkers in AD patients, if treatment started early (Pomilio et al., 2022). In the same study population, non-demented metformin users had less atrophy in some brain regions (Nabizadeh et al., 2022). A Swedish study found slower cognitive decline in people with AD who took metformin (Secnik et al., 2021).
A genetic analysis of variants in genes that affect blood sugar levels and metformin target genes linked several variants to a reduction in the risk of AD (Zheng et al., 2022). This and other studies support the idea that metformin prevents cognitive aging by mechanisms other than glycemic control (e.g., see Charpignon et al., 2022; Zheng et al., 2023; Chen et al., 2023).
In multiple preclinical models of Alzheimer’s and Parkinson’s diseases, metformin was reported to improve behavioral phenotypes while decreasing Aβ pathology and tau phosphorylation (for a meta-analysis of animal results, see Craig et al., 2019; Chen et al., 2021; Lu et al., 2020; Zhao et al., 2023). Metformin was reported to normalize expression of some genes in the brain, induce the Aβ protease IDE, and activate chaperone-mediated autophagy of APP to reduce Aβ levels (Qiu-Yue et al., 2022; Lu et al., 2020; Xu et al., 2021). Not all studies were positive: One found that metformin treatment in the P301S mouse tauopathy model reduced hyperphosphorylated tau but increased tau aggregation (Barini et al., 2016). In a study of long-term treatment in 3XTG-AD mice, one year of metformin led to memory impairment, and increased Aβ plaques and tau pathology (Cho et al., 2024).
In people with Huntington's disease, metformin treatment was linked to better cognitive function and, in mouse models of HD, to longer survival and milder symptoms (Hervás et al., 2017; Arnoux et al., 2018; Sanchis et al., 2019). Metformin was claimed to reduce production of toxic peptides from the C9orf72 expansion, and mitigate symptoms in a mouse model of ALS/FTD (Zu et al., 2020). In C9orf72-expressing cells, metformin protected against mitochondria damage (Feng et al., 2024).
An intranasal formulation improved cognitive function in a streptozotocin-induced diabetes-like AD mouse model (Kazkayasi et al., 2022).
Findings
From 2008 to 2012, a pilot study was conducted at Columbia University, New York City, in 80 people with amnestic mild cognitive impairment. Participants were overweight but did not have diabetes. They received a maximum of 2,000 mg metformin per day, split into two doses, or placebo for one year. Primary outcomes were the Selective Reminding Test (SRT) for memory, and the ADAS-Cog. Glucose uptake in the posterior cingulate/precuneus by FDG-PET was the secondary outcome; plasma Aβ42 was also measured. After one year, the metformin group scored significantly better on the SRT than the placebo group. The ADAS-Cog, glucose uptake, and plasma Aβ42 did not differ between groups (Luchsinger et al., 2016). Only 10 percent of people tolerated the highest metformin dose, with most taking 1,000 or 1,500 mg daily. There were no serious adverse events.
In 2013 to 2015, a small trial at the University of Pennsylvania investigated the effect of metformin on biomarkers of AD in 20 non-diabetic people with mild cognitive impairment or dementia due to AD. Diagnosis of AD was confirmed by MRI, FDG-PET, or amyloid biomarkers. In a crossover design, each participant received metformin at a maximum dose of 2,000 mg/day for eight weeks, then placebo for eight weeks, or vice versa. Outcomes included cognitive testing in multiple learning and memory domains, executive functioning, attention, language, and motor speed using the ADAS-Cog and CANTAB batteries; CSF concentration of Aβ, total tau, and phosphorylated tau; and blood flow in the brain as measured by arterial spin labeling. The trial found a statistically significant increase in the Trails B measure of executive function, and trends toward improvement on learning, memory, and attention in the treated group. Metformin did not change blood flow in prespecified regions of interest. The drug was detectable in CSF, but AD biomarkers were unchanged (Nov 2015 conference news; Koenig et al., 2017).
Starting in October 2019, a small imaging study embedded in the long-running Diabetes Prevention Program Outcomes Study (DPPOS) in New York City was recruiting 10 people on metformin and 10 on placebo for amyloid plaque and neurofibrillary tangle PET imaging. The participants were to be scanned with 11C-PIB and 18F-MK-6240, and undergo MRI measurement of hippocampal volume and cortical white-matter lesions. As of July 2021, the study was enrolling; its current status is unknown.
In October 2020, Swedish investigators started evaluating the effect of one year of metformin plus exercise and diet on memory in 80 people with Type 2 diabetes and mild cognitive impairment. Primary outcomes are recruitment, adherence, and retention rates, while secondary measures are metabolic change and memory function. The study was to run through March 2022. As of March 2021, the enrollment was reduced to 10.
A multicenter, Phase 2/3 prevention trial began in March 2021. The Metformin in Alzheimer’s Dementia Prevention (MAP) study is enrolling 326 people at more than 20 academic medical centers in the U.S. Participants must be between 55 and 90, be overweight or obese without diabetes, and have early or late MCI. People of normal weight are less likely to have a metabolic response to metformin, and will be excluded. Participants were to take up to 2,000 mg per day extended-release metformin or placebo for two years; this was shortened to 18 months mid-trial. The primary outcome is change on the Free and Cued Selective Reminding Test; secondary outcomes are change on the Alzheimer's Disease Cooperative Study Preclinical Alzheimer's Cognitive Composite (PACC-ADCS), hippocampal volume, white-matter hyperintensity volume, and plasma measures of amyloid, tau, and neurofilament light. Half the participants will have amyloid and tau PET scans at baseline and after treatment. The trial will run through 2026.
In January 2020, a small, open-label study began to assess safety and efficacy of metformin in people with amyotrophic lateral sclerosis due to C9ORF72 expansions. It has recruited 18 participants, and expects to finish in early 2024.
In December 2021, a Phase 3 trial began testing one year of daily 1,700 mg metformin against cognitive decline in 60 people with Huntington's. The trial is running at multiple sites in Spain through August 2024.
In February 2022, the MetMemory trial began recruiting 242 people with mild cognitive impairment to test three years of metformin for its effects on cognitive decline and neuroimaging biomarkers. Participants who are overweight or obese, without diabetes, will be randomized to 500-2000 mg daily metformin, against primary outcomes of changes in memory and executive function. Thirteen secondary outcomes span measures of other cognitive domains, changes in total brain and hippocampal volume, white-matter hyperintensities, cerebral blood flow, cerebral amyloid, fMRI, and biomarkers of glucose and insulin status. The trial, in two sites in Australia, is expected to finish in December 2027.
In January 2023, a trial began testing metformin in the context of the FINGER study of multidomain lifestyle interventions to reduce the risk of dementia in older adults. FINGER 2.0 is enrolling 600 people age 60-79, with a CAIDE Dementia risk score greater than six, and average to slightly low cognitive performance for their age. Participants will be randomized to a structured, intensive lifestyle intervention including diet, physical activity, cognitive training, and cardiovascular/metabolic risk monitoring, or a program that gives only lifestyle advice. Within the intervention group, participants at increased risk of diabetes will be assigned randomly to metformin 2000 or 1000 mg daily, or placebo. The intervention lasts for two years, with a primary outcome of change in a z score for cognition based on an extended Neuropsychological Test Battery. The list of 39 secondary and exploratory outcomes includes other cognitive measures, CDR-SB and measures of function, blood lipids, diabetes, hypertension, blood biomarkers of amyloid, tau, and neurofilament light. The trial is to run in Finland, Sweden, and the United Kingdom through December 2026. The protocol is published (Barbera et al., 2024).
Metformin is also being studied for Fragile X Syndrome, age-related macular degeneration, various types of cancer, and other conditions. For details on metformin trials for dementia, see clinicaltrials.gov.
Last Updated: 23 Feb 2024
Further Reading
No Available Further Reading
Overview
Name: Semaglutide
Synonyms: Ozempic, Wegovy, Rybelsus
Therapy Type: Other
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease, Parkinson's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 3), Parkinson's Disease (Phase 2)
Company: Novo Nordisk A/S
Approved for: Type 2 Diabetes, Obesity, Protection against myocardial infarction and stroke
Background
Semaglutide is a synthetic, long-acting analog of glucagon-like peptide-1, used to treat diabetes. OzempicTM is a once-per-week injection formulation, while RybelsusTM is is a daily pill. RybelsusTM was approved by the U.S. FDA in September 2019 as the first GLP-1 analog that does not need to be injected. It is also approved for use in Japan and the European Union.
GLP-1 is a hormone produced in the gut that activates receptors in the gut, liver, and pancreas to stimulate insulin release, and restore insulin sensitivity (for review, see Knudsen and Lau, 2019). In some people with Alzheimer’s disease, there is evidence for insulin resistance in the brain, providing a rationale for testing semaglutide as a potential therapeutic for AD. In addition, GLP-1 receptors expressed in the brain are involved in learning and neuroprotection (During et al., 2003). Other GLP-1 analogs, for example exendin-4, liraglutide, and lixisenatide, are currently in clinical trials for Parkinson’s or Alzheimer’s diseases.
There are several published preclinical studies for semaglutide in Alzheimer’s. A cell-based study implicated the drug in enhanced autophagy and reduced apoptosis (Chang et al., 2020). In a 3xTg mouse model of AD, semaglutide improved brain glucose uptake, improved learning and memory, and decreased Aβ plaques and tau tangles (Wang et al., 2023). An independent study using the APP/PS1 model reported similar positive results (Zhang et al., 2024). In contrast, other researchers found that although semaglutide caused weight loss and improved glucose tolerance in 5XFAD and APP/PS1 mice, it did not change amyloid plaque density, inflammation markers, or cognitive function (Germano et al., 2024).The drug is reported to be active in rodent models of Parkinson’s (Zhang et al., 2019; Zhang et al., 2018) and stroke (Yang et al., 2019). In rats or mice, semaglutide did not readily cross the blood brain barrier, although it did appear in the hypothalamus (Salameh et al., 2020; Lee et al., 2023). It is thought to act by lowering peripheral blood sugar, and reducing peripheral and central inflammation. It is suggested to act by lowering peripheral blood sugar, and reducing peripheral and central inflammation (e.g. De Paiva et al., 2024). In APP/PS1 mice, intranasal application did not result in brain entry (Abdulhameed et al., 2024).
Findings
In September 2018, researchers at the University of Oslo registered a Phase 2 trial of semaglutide for Parkinson’s disease. The study aims to enroll 120 newly diagnosed PD patients who will receive 1 mg drug or placebo by weekly injection for two years, followed by an additional two years of open-label administration. Per the registration entry, the trial has not begun recruiting.
In 2020, a Phase 2a trial of semaglutide tablets in 60 people with mild Alzheimer's disease received funding from the Alzheimer's Association's Part the Cloud program; no such trial is registered.
On December 16, 2020, Novo Nordisk announced it would begin development of semaglutide in people with early Alzheimer’s disease (see press release). Beginning in the first half of 2021, the Phase 3a program planned to enroll 3,700 people for a planned two-year course of a once-daily 14 mg semaglutide pill or placebo. The company said the decision was based on evaluation of GLP-1 data from preclinical models, real-world studies involving patient registry and insurance claims databases, and post hoc analysis of data from three large cardiovascular outcome trials of semaglutide and liraglutide. That analysis reportedly found a 53 percent reduction in the risk of developing dementia in people with Type 2 diabetes who took either GLP-1 agonist compared to placebo (see Nørgaard et al., 2022). An independent study using electronic health records found that, in people with Type 2 diabetes, those using semaglutide reduced their risk of an AD diagnosis by 40 to 70 percent, compared those using insulin or other diabetes drugs (Wang et al., 2024).
In May 2021, the company began two Phase 3 trials, each enrolling 1,840 people with mild cognitive impairment or mild dementia due to Alzheimer’s disease, confirmed by amyloid PET or CSF Aβ42. The trials are identical, except that one allows participants with subcortical vascular disease, and one does not. The sole primary outcome is change in CDR-SB. Secondary outcomes include other standard cognitive and functional scales, as well as cardiovascular events and stroke. The trials include a one-year extension. By mid-2023, both studies were fully enrolled and running at more than 400 centers worldwide, to be completed in October 2026.
In August 2022 enrollment began on a study evaluating the effect of semaglutide on tau accumulation in the brains of people who are amyloid-positive, with or without diabetes, and with no or mild cognitive impairment (Koychev et al., 2024). The study at the University of Oxford in the U.K. will treat 88 participants with a dose of 14 mg once daily oral semaglutide or placebo for one year, against a primary outcome of change in tau-PET. Secondary outcomes address potential mechanism of semaglutide action, including brain inflammation measured by TSPO-PET and GFAP protein levels, and blood biomarkers of Aβ, phosphorylated tau and neurofilament light. Other outcomes are hippocampal volume by MRI, cognition, quality of life, physical activity, and circadian rhythms. Supported by Novo Nordisk, the trial is expected to finish in March 2026.
In June 2023, Novo Nordisk began a small study on how semaglutide affects the immune system in people with Alzheimer’s. Twenty-four participants will receive 12 weekly subcutaneous injections with a pen injector, titrating to a final dose of 1 mg per week. After a 12-week placebo-controlled period, all participants will receive 1 mg/week for one year open-label. The primary endpoint is changes in gene expression in immune cells in blood and CSF, assessed by single-cell RNA sequencing. Secondaries are safety, and semaglutide concentration in blood. Study completion is anticipated in September 2025.
In January 2024, investigators at Sheba Medical Center in Israel began a study of the combination of semaglutide pills and intranasal insulin in people with mild cognitive impairment and metabolic syndrome. The trial will enroll 80 participants in four groups, who will receive each treatment with appropriate placebo, both treatments, or placebo only for one year. Primary outcomes are cognitive function, cerebral blood flow, and brain glucose uptake. Completion is expected in December 2027. The trial protocol is published (Davidy et al., 2024).
For details on these semaglutide trials, see clinicaltrials.gov and the WHO registry.
Last Updated: 27 Oct 2024
Further Reading
No Available Further Reading
Overview
Name: Nilotinib
Synonyms: Tasigna, AMN107
Chemical Name: 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)- 5-(trifluoromethyl)phenyl]-3- [(4-pyridin-3-ylpyrimidin-2-yl) amino]benzamide
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Parkinson's Disease, Dementia with Lewy Bodies, Alzheimer's Disease
U.S. FDA Status: Parkinson's Disease (Phase 2), Dementia with Lewy Bodies (Phase 2), Alzheimer's Disease (Inactive)
Company: KeifeRx
Approved for: Chronic myeloid leukemia
Background
Nilotinib is an oral Abl tyrosine kinase inhibitor used to treat chronic myeloid leukemia. Nilotinib induces autophagy, leading to death of rapidly dividing cells (Salomoni and Calabretta, 2009). The drug carries a black-box warning of sudden death due to cardiac arrythmia. It also can cause myelosuppression.
Nilotinib (and another Abl kinase inhibitor cancer drug, bosutinib) has been proposed for repurposing as a disease-modifying treatment for synucleinopathies including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Abl kinase phosphorylates α-synuclein and prevents its degradation. By inhibiting Abl, nilotinib promotes α-synuclein clearance by autophagy (Mahul-Mellier et al., 2014). Nilotinib has also been reported to increase toxicity of α-synuclein in Neuro2A cells (Shaker et al, 2013) and to induce apoptosis and autophagic cell death in cultured liver cells (Eteläinen et al., 2022).
Additional targets of nilotinib are the discoidin domain receptor (DDR) tyrosine kinases, which have been implicated in cancer, fibrotic disorders, and inflammatory diseases. DDR1 is claimed to be elevated in AD brain. In models of protein toxicity, DDR1 or DDR2 knockdown reduced levels of α-synuclein, tau, and Aβ, and inflammation (Hebron et al., 2017). Inhibition of DDR2 may account for some aspects of nilotinib’s cardiac toxicity (Carracedo et al., 2022).
Nilotinib has been tested in preclinical models of PD and DLB. In the MPTP toxicity model of parkinsonism, nilotinib prevented dopaminergic cell death and behavioral deficits (Karuppagounder et al., 2014). In α-synuclein-overexpressing mice, nilotinib lowered levels of α-synuclein and phosphorylated tau in brain. Treatment was reported to increase brain dopamine and improved animals’ motor skills and cognition (Hebron et al., 2013; Hebron et al., 2013; Hebron et al., 2014). In other models, nilotinib was reported to improve tau clearance and astrocytic function in tau P301L mice and to promote amyloid clearance in TgAPP mice (Hebron et al., 2018; Lonskaya et al., 2013). In addition, it reportedly protected against TDP-43 toxicity in mice (Heyburn et al., 2016; Wenqiang et al., 2014). Much of this preclinical work came from one group at Georgetown University.
In independent studies, nilotinib failed to lessen synuclein accumulation and cell death in mice expressing mutated α-synuclein in oligodendrocytes to model multiple systems atrophy (Lopez-Cuina et al., 2020). In a different proteinopathy model, nilotinib did not improve autophagy, pathology, survival, or motor behaviors in mice expressing mutated Huntingtin protein (Kumar et al., 2021). The drug did inhibit microglia-mediated dopaminergic death induced by LPS injection in an inflammatory model of PD (Wu et al., 2021).
In AD models, nilotinib prevented degeneration of dopamine neurons and improved memory performance in Tg2576 mice (La Barbera et al., 2021; see also Nobili et al., 2021). It also improved mitochondrial function and energetics in astroglia isolated from 3xTg AD mice (Adlimoghaddam et al., 2021).
Findings
In November 2014, Georgetown University investigators began evaluating nilotinib in cognitively impaired patients with PD or DLB. In the first Phase 1 study, 12 participants took 150 or 300 mg nilotinib daily for six months, a dose one-half to one-fifth of that used for cancer. There was no placebo group. Because nilotinib can cause irregular heart rhythms, people with abnormal cardiac rhythms were excluded from this and subsequent trials. The drug was generally safe and tolerable. Nilotinib crossed into the brain and was detectable in the CSF, albeit at 1 percent of plasma levels. Treatment resulted in inhibition of tyrosine phosphorylation of Abl kinase and raised CSF levels of the dopamine metabolite homovanillic acid (HVA). In exploratory endpoints, both dose groups were reported to improve motor and non-motor symptoms assessed by the Unified Parkinson’s Disease Rating Scale (UPDRS) and PD questionnaire, and cognitive symptoms assessed by the MMSE and Scales for Outcomes in Parkinson’s disease-Cog. The gains reversed when drug was discontinued (Pagan et al., 2016).
Presentation of these data at the 2015 Society for Neuroscience conference (Nov 2015 conference news) stimulated initiation of two Phase 2, placebo-controlled studies. A single-site study at Georgetown began in January 2017. It enrolled 75 patients with PD or PD dementia to receive 150 or 300 mg nilotinib or placebo once daily for 12 months, with a three-month follow-up. The primary outcome was safety. The nilotinib group had more serious adverse events than the placebo group. The nilotinib group had no significant improvement on exploratory motor or cognitive measures over placebo. The 300 mg group showed a worsening of activities of daily living from baseline to 12 months on the Movement Disorders Society–Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part 2 and the Montreal Cognitive Assessment score, which was not seen in the other groups. In exploratory biomarker measurements, the 150 mg dose was reported to be associated with higher CSF concentration of a dopamine metabolite and lower CSF concentration of α-synuclein oligomers and phosphorylated tau; there was no comparison between baseline and subsequent time points (Pagan et al., 2019; editorial by Espay et al., 2019; NPR news). After this trial, 63 participants entered an open-label safety and tolerability extension. Ninety percent were able to complete one year of dosing at 150 or 300 mg, with no adverse events deemed to be drug-related by the investigators (Pagan et al., 2021). An analysis of CSF miRNA expression in trial participants found changes in pathways related to angiogenesis, extracellular matrix, and autophagy over one year on placebo, some of which were modified by nilotinib (Fowler et al., 2021). A continuation of this study reported that nilotinib treatment reduced miRNAs involved in inflammation, vascular fibrosis, and DDR1 kinase expression, and changed others related to autophagy and dopamine metabolism, compared to placebo (Stevenson et al., 2023). DDR1 kinase activity in CSF rose over time in placebo-, but not in nilotinib-treated patients.
The second trial started in October 2017. Called NILO-PD, it was a multicenter Phase 2a funded by the Michael J. Fox Foundation. It enrolled 76 people with moderate PD at 25 academic centers in the U.S. Participants were strictly screened for heart and other health problems. They were assigned to 150 or 300 mg nilotinib daily or placebo for six months, with two months of follow-up. The primary outcome was safety and tolerability; secondary outcomes included measures of motor and cognitive symptoms. The study finished in September 2019. In December 2019, the study organizers announced the drug was safe in this select study population, but did not improve motor or cognitive function over placebo (press release). According to published results, the full data show a trend toward worsening motor function in the treated groups. Nilotinib concentrations in CSF were less than 0.3 percent of plasma, and one-tenth of the levels expected to inhibit Abl. The investigators found no drug effect on dopamine biomarkers (Simuni et al., 2021).
In January 2017, the Georgetown University group began a single-center, Phase 2 safety study in Alzheimer’s disease. It enrolled 37 participants with mild to moderate AD confirmed by CSF Aβ levels or amyloid PET scan, or both. They took 150 mg nilotinib daily for six months, followed by 300 mg for six months, or matching placebo. According to published data, the total number of side effects was the same for drug and placebo, but people on the high dose experienced significantly more instances of agitation, aggression, and irritability (Turner et al., 2020; see also Tan et al., 2021). Drug concentrations in CSF reached 3.5 and 4.7 nM on the low and high doses, respectively, and did not result in detectable inhibition of Abl kinase. CSF Aβ42 was significantly reduced in the treated group compared with placebo at 12 months, and accumulation of amyloid in the frontal lobe was slowed. Tau and phospho-tau were unchanged. No differences were seen in exploratory clinical, cognitive, functional, or behavioral measures.
Another Phase 2 trial at Georgetown University tested nilotinib in patients with DLB. Beginning in July 2019, this study planned to compare 200 mg daily of nilotinib or placebo taken for six months, followed by a one-month washout in 60 participants. The primary outcome was safety and tolerability; secondary outcomes were drug levels in CSF and plasma, changes in HVA in CSF, amyloid burden by PET, and other, unspecified surrogate and exploratory biomarkers for DLB, as well as measures of cognition, behavior, and motor function. The trial finished in December 2023, and results were presented at the October 2024 CTAD conference in Madrid. Due to the COVID pandemic, only 43 people enrolled, fewer than expected. No one dropped out due to side effects, and there were no serious adverse events related to drug. Overall, the treated group had fewer adverse events, including falls, than placebo. In exploratory endpoints, nilotinib improved the ADAS-Cog14 and the MDS-UPDRS cognition scale. Treatment did not change motor function, but reduced measures of irritability and apathy, and cognitive fluctuations.
The Georgetown investigators founded the company KeifeRx. In December 2021, KeifeRx registered a Phase 3 clinical trial for a new, low-dose formulation of nilotinib in AD. In 50 centers across the U.S., the study is to enroll 1,275 patients diagnosed with early AD, defined as a CDR of 0.5 or 1, MMSE scores between 20 and 27, and PET or CSF evidence of brain amyloid. The study will test 84 or 112 mg daily of the company’s Nilotinib BE against placebo for three years. The primary outcome is CDR-SB after 18 months. Secondary outcomes include ADAS-Cog14, MMSE, ADCS-ADL-MCI, and ADCOMS. Substudies will analyze CSF and imaging biomarkers at baseline and 18 months. The study was planned to run from February 2022 to June 2026, but according to clinicaltrials.gov has not started recruiting. Nilotinib no longer appears on the company’s pipeline.
A Phase 1 in Huntington’s disease began in 2018; its current status is unknown. A Phase 2 study in cerebellar ataxia was completed in Korea in August 2020. For all nilotinib trials, see clinicaltrials.gov.
Last Updated: 09 Nov 2024
Further Reading
No Available Further Reading
Overview
Name: Bosutinib
Synonyms: BOSULIF®, PF-5208763, SKI-606
Chemical Name: 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease, Dementia with Lewy Bodies
U.S. FDA Status: Alzheimer's Disease (Phase 2), Dementia with Lewy Bodies (Phase 2)
Company: Pfizer
Approved for: Chronic myeloid leukemia
Background
Bosutinib is an oral inhibitor of Abl and Src tyrosine kinases that has been approved since 2012 for the treatment of chronic myeloid leukemia. At the therapeutic dose of 500 mg/day, its common side effects are diarrhea, nausea, and vomiting. The drug can also cause myelosuppression.
Bosutinib and another Abl inhibitor, nilotinib, are candidates for repurposing to treat the α-synucleinopathies Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), and other neurodegenerative conditions. The inhibitors promote autophagy, which facilitates clearance of neurotoxic protein aggregates in neurons.
In preclinical work, bosutinib reduced levels of α-synuclein in mice expressing the human A53T α-synuclein pathogenic mutation. Bosutinib was reported to enhance dopaminergic neuron survival, and modulated the immune response to α-synuclein (Lonskaya et al., 2013; Hebron et al., 2014).
In other mouse models, bosutinib treatment facilitated α-amyloid and tau clearance, changes in immune markers, and cognitive improvement (Lonskaya et al., 2013; Lonskaya et al., 2015; Hebron et al., 2018). The drug also protected against TDP-43 toxicity in mice (Heyburn et al., 2016; Wenqiang et al., 2014).
In cell and animal models of amyotrophic lateral sclerosis, bosutinib enhanced survival and function of motor neurons (Imamura et al., 2017; Osaki et al., 2018).
Findings
In September 2016, a Phase 1, open-label study began to evaluate bosutinib’s tolerability in people with mild cognitive impairment or dementia. The single-center study at a private neurological practice in Santa Monica, California, has enrolled 71 volunteers between age 45 and 89 with a Clinical Dementia Rating from 0.5 to 2. Participants start out on 100 mg bosutinib daily, with the dose increasing monthly to a top dose of 300 mg as tolerated. Total treatment time is one year, and the primary outcome is the number of patients who discontinue treatment due to side effects. A publication describes results of dementia evaluation on 31 participants who completed one year of treatment and one year of follow-up (Mahdavi et al., 2021). The patients had probable AD dementia or Parkinson's dementia. During the year of treatment, participants declined less according to the Quick Dementia Rating System and the Repeatable Battery Assessment of Neuropsychological Status, than expected from population estimates. No difference was found on the MoCA. Sixteen patients reached one year of follow-up; as a group, their worsening was no different than the population-based estimate. The trial will run through December 2023.
In April 2019, a Phase 2 trial began testing bosutinib in people with DLB. The single-center study at Georgetown University, Washington, D.C., would enrolled 26 patients for a 12-week regimen of 100 mg drug or placebo per day, followed by a four-week follow-up. The primary outcome was safety and tolerability. Secondary measures included plasma and CSF bosutinib levels and changes in a panel of plasma and CSF biomarkers including dopamine metabolites, Aβ, total and phosphorylated tau, oligomeric α-synuclein, as well as additional markers of cell death and inflammation. The trial finished in August 2021, and results were published after peer review (Pagan et al., 2022). Among the 25 men and one woman in the trial, there were no serious adverse events and no dropouts. CSF drug concentrations reached 2 percent of plasma, and were adequate to inhibit the kinase. Treatment reduced phosphorylation of the Abl protein in CSF compared to placebo, and lowered CSF α-synuclein. Plasma markers of dopamine breakdown were reduced. Exploratory efficacy assessments revealed improvement in activities of daily living after 12 weeks of treatment, but no change in cognitive measures.
An open-label Phase 1 study in ALS patients is underway in Japan. In March 2019, Kyoto University investigators began recruiting 24 patients to compare treatment with 100, 200, 300, or 400 mg/day bosutinib for 12 weeks, with a four-week follow-up (Imamura et al., 2019). The primary outcome is the occurrence of dose-limiting toxicity during treatment or follow-up. The trial will also measure change from baseline in lung function and grip strength, and blood levels of neurofilament proteins. The study will finish in 2022.
Bosutinib is also being evaluated in other types of cancer. For details on bosutinib trials, see clinicaltrials.gov.
Last Updated: 27 Jul 2022
Further Reading
No Available Further Reading
Overview
Name: Vascepa
Synonyms: Icosapent ethyl (IPE), Ethyl eicosapentaenoic acid (E-EPA), AMR101, Miraxion
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2/3)
Approved for: Severe hypertriglyceridemia, and to lower risk of cardiovascular events in people with elevated triglycerides
Background
Vascepa is a prescription formulation of omega-3 fat ethyl eicosapentaenoic acid (ethyl-EPA) purified from fish oil. Liquid-filled capsules are taken twice a day with food, at a dose of 4 g per day.
This drug is approved to lower triglycerides in adults with severe hypertriglyceridemia. Vascepa is also used along with statins to reduce risk of heart attack or stroke in people with more modestly elevated serum triglycerides, or in people with diabetes plus additional cardiovascular risk factors. In trials, side effects included increased risk of arrhythmia and bleeding events. The most common side effects were musculoskeletal pain, swelling of hands and legs, atrial fibrillation, and joint pain. Unlike DHA or fish oil supplements, Vascepa does not raise LDL (bad) cholesterol.
Clinical studies of omega-3 supplements for AD have yielded negative results. Daily DHA/EPA for six months did not slow cognitive decline in people with mild to moderate AD, although there was a benefit for subjects with very mild disease (Freund-Levi et al., 2006). In other trials, 1.5 years of daily DHA did not affect cognition in people with AD (Quinn et al., 2010), and three years of DHA/EPA had no effect on cognitive decline in older people with memory complaints (Andrieu et al., 2017). No AD study to date has tested EPA alone, or at a dose above 650 mg/day.
In a Phase 3 trial in 300 people with Huntington’s disease, 2 g per day of ethyl-EPA for six months did not improve motor symptoms (HD Study Group TREND-HD Investigators, 2008). Prior trials of EPA in depression, schizophrenia, and a cognition outcome measure in an age-related macular degeneration trial were negative, as well (Chew et al., 2015).
Findings
In a pilot study of 22 patients with mild to moderate AD, ethyl-EPA at 1 gram daily for 12 weeks did not alter cognitive decline, compared with a 12-week untreated baseline period (Boston et al., 2004).
In June 2017, scientists at the Veteran’s Administration and the University of Wisconsin, Madison, began a Phase 2/3 proof-of-concept prevention trial to assess the effects of Vascepa on brain amyloid and vasculature. The single-center study is enrolling 150 cognitively healthy military veterans, aged 50 to 75, to receive 4 g of Vascepa daily or matching placebo for 18 months. The primary endpoint is change in regional cerebral blood flow, measured by atrial spin-labeling MRI. Secondary endpoints are changes in CSF Aβ, total tau, and phospho-tau, and cognitive performance on the Preclinical Alzheimer’s Cognitive Composite (PACC). As a group, veterans have a higher prevalence of dementia risk factors such as head trauma, post-traumatic stress, and hypertension; however, the trial is not requiring that participants have specific AD risk factors such as family history or ApoE4. The study will run through November 2021.
Vascepa is being clinically evaluated primarily for lipid and cardiovascular disorders and colon cancer. For details on the Vascepa trial for Alzheimer’s disease, see clinicaltrials.gov.
Last Updated: 07 Feb 2020
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Overview
Name: GV1001
Synonyms: RIAVAXTM, Tertomotide
Therapy Type: Immunotherapy (active) (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 3)
Company: GemVax & KAEL Bio
Approved for: Pancreatic cancer (Korea)
Background
Originally developed as a cancer vaccine, GV1001 is a 16-amino-acid peptide comprising a sequence from the human enzyme telomerase reverse transcriptase (TERT). Most cancers highly express TERT, and immunization with GV1001 aims to activate the immune system to recognize and kill cancer cells. GV1001 was approved in Korea for immunotherapy of pancreatic cancer, but failed to show efficacy in two international pancreatic cancer trials (Middleton et al., 2014; Clinicaltrials.gov).
The peptide reportedly penetrates cells, interacts with HSP70 and HSP90, and displays direct anti-cancer and anti-viral activity independent of an immune response (Kim et al., 2018; Kim et al., 2016).
In non-cancer cells, GV1001 has anti-inflammatory and antioxidant activity. In rat neuronal stem cells, GV1001 blocked Aβ oligomer-induced toxicity, and increased survival of cells exposed to oxidative stress (Park et al., 2014; Park et al., 2016). The authors attribute these actions to GV1001’s ability to mimic TERT’s antioxidant, anti-apoptotic, and pro-survival functions.
Beneficial effects have been reported in rodent models of hearing loss, macular degeneration, and stroke (Kim et al., 2018; Kim et al., 2018; Lee et al., 2020; Kwon et al., 2021).
Findings
In 2017, GemVax and Kael began a Phase 2 trial to assess safety and efficacy of GV1001 in people with moderate to severe Alzheimer’s disease at 13 sites in Korea. The study enrolled 96 clinically diagnosed patients, who were randomized equally to receive four weekly subcutaneous injections of 0.56 mg or 1.12 mg of GV1001, or placebo, followed by biweekly injections for 24 weeks, for a total of 14 injections. All participants were taking donepezil. The primary outcome at 24 weeks was change on the Severe Impairment Battery; secondary outcomes included the Korean-MMSE and standard measures of cognition and function, i.e., the CDR-SB, Neuropsychiatric Inventory, Global Deterioration Scale, ADCS-Activities of Daily Living and Clinician Interview-Based Impression of Change.
The company presented top-line trial results at CTAD 2019 (Dec 2019 conference news). The study met its primary endpoint, with treated participants holding steady on the SIB (0.12 point drop) whereas those on placebo dropped by 7.23 points. A dose response was not shown; results for secondary endpoints were not shown. Adverse events were similar across all three groups. Results were subsequently published after peer review (Koh et al., 2021). In the full analysis, only the higher-dose group met the primary endpoint. They declined 0.3 points on the SIB compared to 6.9 for the placebo group. The ADCS-ADL and CDR-SB showed a similar pattern, but did not reach statistical significance. Other secondary outcomes were negative at 24 weeks.
In May 2021, a Phase 2 trial of similar size and design as the Korean study was registered to be conducted in the U.S. According to the company, the trial was delayed by the COVID pandemic (press release). It was ultimately withdrawn in early 2022 with no patients enrolled.
Instead, in October 2022, GemVax and Kael began a larger and longer Phase 2 study, also in the U.S. It plans to randomize 180 people with mild to moderate Alzheimer’s to four weekly subcutaneous injections of 0.56 mg or 1.12 mg of GV1001, or placebo, followed by biweekly injections for one year. Participants must have an MMSE score between 13 and 24. The primary outcome will be the change on the ADAS-Cog; secondary outcomes are changes in measures of cognition and function, similar to the Korean study. Completion is anticipated in September 2024.
In March 2022, the company registered a Phase 3 study in 936 Korean patients with moderate to severe Alzheimer’s. Participants must have a Korean-MMSE of 19 or less, and will be randomized to six months of 0.56 mg or 1.12 mg GV1001, or placebo, against primary outcomes of the SIB and CDR-SB. Secondary outcomes include the Neuropsychiatric Inventory, Global Deterioration Score, and ADCS-Study Activities of Daily Living Inventory for Severe Alzheimer's Disease. A six-month open-label extension is planned, with completion slated for April 2026.
This drug has also been trialed in cancers of the prostate, lungs, liver, skin, intestine.
For details on GV1001 trials, see Clinicaltrials.gov.
Last Updated: 24 Jan 2023
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