Overview
Name: MW150
Synonyms: MW01-18-150SRM
Chemical Name: 6-(4-methylpiperazin-1-yl)-3-naphthalen-2-yl-4-pyridin-4-ylpyridazine
Therapy Type: Small Molecule (timeline)
Target Type: Inflammation (timeline), Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Neurokine Therapeutics
Background
MW150 is a CNS-penetrant, selective inhibitor of the alpha isoform of the mitogen-activated serine/threonine protein kinase p38 MAPK. It is taken by mouth.
p38α MAPK is expressed in microglia and neurons. In microglia, the enzyme stimulates release of pro-inflammatory cytokines such as TNFα and IL-1β in response to a variety of stressors including Aβ42; in neurons, signaling via p38α MAPK has been implicated in tau localization and neuronal plasticity (Yasuda et al., 2011; Bachstetter et al., 2011; Corrêa and Eales, 2012). In addition, p38α MAPK regulates Ras-related protein Rab5, a key regulator of early endosomes whose role in endolysosomal and synaptic vesicle function has made it a target in neurodegenerative disease drug development (Germann and Alam, 2020).
MW150 is one of a series of compounds co-developed by investigators at Northwestern University in Chicago and Columbia University in New York (Jan 2002 news; May 2017 conference news; Jun 2018 conference news).
For MW150, a kinase inhibitor fragment was built out to achieve isoform specificity and brain penetration. In the APP/PS1 mouse model of amyloidosis, treatment from an early age prevented the development of memory deficits, without affecting amyloid plaque accumulation. In APP/PS knock-in mice, treatment of older mice suppressed memory deficits (Roy et al., 2015; Roy et al., 2019). MW150 inhibited the release of proinflammatory cytokines from glia, and rescued synaptic dysfunction in the entorhinal cortex of these models (Zhou et al., 2017; Rutigliano et al., 2018).
In a mouse model of autism spectrum disorder, MW150 normalized poor social behaviors and physiological disturbances stemming from excess serotonin activity (Robson et al., 2018).
A related preclinical p38MAPKα inhibitor, MW181, was reported to reduce tau pathology in a mouse model of tauopathy (Maphis et al., 2016).
Findings
In 2018, the Alzheimer’s Association funded a Phase 1 study of MW150. According to information on the company’s web site, the drug was safe, well-tolerated, and reached promising blood levels after daily oral administration to healthy volunteers.
In January 2022, the company listed a Phase 2 study in people with mild to moderate AD. Beginning in May 2022, the 24 participants will take one 10 mg capsule of MW150 or placebo daily for 12 weeks. Primary outcomes are safety and adverse events. Secondary outcomes include measures of cognition, daily function, neuropsychiatric symptoms, and blood levels of cytokines, tau, and neurofilament light. The trial is expected to run until August 2024.
MW150 is one of two p38α MAPK inhibitors in development for Alzheimer’s; the other is neflamapimod.
For details on MW150 trials, see clinicaltrials.gov.
Last Updated: 13 May 2022
Further Reading
No Available Further Reading
Overview
Name: Baricitinib
Synonyms: Olumiant®, NCB28050, LY3009104
Chemical Name: 2-[1-ethylsulfonyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]azetidin-3-yl]acetonitrile
Therapy Type: Small Molecule (timeline)
Target Type: Inflammation (timeline)
Condition(s): Alzheimer's Disease, Amyotrophic Lateral Sclerosis
U.S. FDA Status: Alzheimer's Disease (Phase 2), Amyotrophic Lateral Sclerosis (Phase 1)
Company: Eli Lilly & Co.
Approved for: Rheumatoid arthritis, Eczema (Europe, Japan only)
Background
Baricitinib is an inhibitor of Janus kinase (JAK). It is approved in the U.S. and many other countries for the treatment of rheumatoid arthritis and severe COVID, approved in Japan and Europe but not yet the U.S. for atopic dermatitis, and used for alopecia areata. Baricitinib suppresses the immune system and reduces inflammation by interfering with cytokine signaling induced via the JAK/STAT, i.e., signal transducer and activator of transcription pathway.
The repurposing of baricitinib for neurodegeneration rests on studies from Massachusetts General Hospital that uncovered a role for JAK-mediated innate immunity in neuronal cell death in amyotrophic lateral sclerosis. In cells bearing the causative c9ORF72 gene hexanucleotide expansions, double-stranded RNA products of the expanded repeats triggered the Type I interferon inflammatory response, which caused neuron death. Baricitinib or other FDA-approved JAK inhibitors blocked this interferon response and rescued cell death (July 2021 news). In a separate study, the same investigators identified baricitinib as a candidate for repurposing for Alzheimer disease, based on a computational biology analysis of gene expression changes in AD brain, and reversal of these changes in drug-treated cells (Rodriguez et al., 2021).
Baricitinib carries box warnings for increased risk of serious infections, cancer, major cardiovascular events, blood clots, and death. In clinical trials, the most common side effects were upper respiratory tract infections, nausea, and shingles or herpes flare-ups. The drug is taken in tablet form, in doses of 2 mg per day for arthritis, and 4 mg per day for COVID.
Findings
In December 2022, a trial began to test baricitinib in people at risk for, or with, Alzheimer’s disease or ALS. The open-label study aims to enroll 20 participants with subjective cognitive decline, mild cognitive impairment, Alzheimer’s disease, or ALS, or asymptomatic carriers of a C9ORF72 gene expansion. Participants must have elevated levels of the inflammatory cytokine CCL2 in CSF. Dosing will be 2 mg daily for eight weeks, then 4 mg for 16 weeks. Primary outcomes are CSF concentration of baricitinib and CCL2. Secondary outcomes include CSF biomarkers of inflammation and neurodegeneration, plasma levels of the RNA-binding protein TDP-43, and adverse effects. The study, at Massachusetts General Hospital and Holy Cross Hospital in Florida, will finish in mid-2024. For details on this study, see clinicaltrials.gov.
In Phase 3 trials, baricitinib reversed autoimmune hair loss (King et al., 2022). Trials are ongoing for a range of autoimmune conditions; see clinicaltrials.gov.
Last Updated: 21 Sep 2023
Further Reading
No Available Further Reading
Overview
Name: Trazodone
Synonyms: Trazodone hydrochloride, Oleptro, Desyrel
Chemical Name: 2-{3-[4-(3-Chlorophenyl)piperazin-1-yl]propyl}[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease, Mild Cognitive Impairment, Amyotrophic Lateral Sclerosis
U.S. FDA Status: Alzheimer's Disease (Phase 3), Mild Cognitive Impairment (Phase 3), Amyotrophic Lateral Sclerosis (Phase 2/3)
Approved for: Depression
Background
Trazodone is a phenyl piperazine derivative with agonist and antagonist activity at serotonin receptors, in addition to adrenergic and histaminergic activity and serotonin uptake inhibition. It was approved more than 40 years ago to treat major depressive disorder. It is widely used off-label for insomnia and anxiety disorders, and to treat agitation and sleep disturbances in people with Alzheimer’s disease. Taken as a tablet, trazodone is available as a generic.
Recent interest in trazodone is focused on its potential to slow cognitive loss by improving sleep in people with early stage memory loss or dementia. Compared to other sleep medications, trazodone has a unique effect of prolonging and deepening slow-wave sleep. Disruption of slow-wave sleep by amyloid and tau deposition appears to contribute to cognitive problems (e.g., Mander et al., 2015; Lucey et al., 2019).
In an observational study of people with AD, MCI, or normal cognition but attending a sleep clinic, those using trazadone showed significantly slower decline in MMSE scores over four years than a matched group who did not take the drug (La et al., 2019; commentary by Ashford, 2019; also Burke et al., 2018). Slowing of cognitive decline was associated with subjective reports of sleep improvement.
There is also emerging evidence from preclinical studies for a possible disease-modifying effect due to trazodone’s ability to enhance proteostasis and protect against neurodegeneration in models of prion disease and frontotemporal dementia (Halliday et al., 2017; also see review by Sidhom et al., 2022). In rTg4510 tau mice, it reduced neuroinflammation and tau pathology, and improved sleep and olfactory memory (de Oliveira et al., 2022).
For treatment of depression, doses range from 150-300 mg per day, and can go up to 600 mg. Common side effects include dry mouth, feeling faint, hypotension, vomiting, and headache. Trazodone is moderately sedating. This drug can increase the risk of falling, but is nonetheless used for older people with depression, and for severe agitation or insomnia in AD patients (e.g. see Ringman and Schneider 2019).
A placebo-controlled study at Colorado State University Veterinary Teaching Hospital is evaluating trazodone for age-related cognitive dysfunction in dogs (TRAC study).
Findings
Following anecdotal reports of trazodone’s effectiveness for agitation in people with AD, a Phase 3 trial was run in the late 1990s at 21 sites in the U.S. It compared 16 weeks of trazodone (average mean dose 200 mg daily) to haloperidol, behavior management techniques, or placebo in 149 AD patients with moderate to severe cognitive impairment and agitation. Participants had to be living at home, or not in an institution. None of the interventions changed agitation compared to placebo. There was a slight worsening of cognition and function in medicated groups (Teri et al., 2000; Feb 2001 news). Side effects in the trazodone group were similar to placebo, with few dropouts in the trazodone arm.
In other, smaller trials, trazodone did improve agitation better than placebo in institutionalized AD dementia patients (Sultzer et al., 2001), and reduced irritability, agitation, depression, and disordered eating in people with frontotemporal dementia (Lebert et al., 2004).
Between 2010 and 2012, a low dose of trazodone was tested to treat sleep disorders in people with AD at a single center in Brasilia, Brazil. The trial randomized 36 patients with dementia and sleep problems to 50 mg trazodone or placebo at bedtime for two weeks. The primary outcome was change from baseline in total sleep time; secondary outcomes measured nighttime waking and daytime sleep, as well as cognitive function, dementia rating, and functional and behavioral measures. According to published results, the trazodone group slept 42.5 minutes longer than the placebo group at night, with no increase in daytime sleepiness or naps. The study found neither improvement nor impairment in cognition (Camargos et al., 2014; Carmargos et al., 2105).
In March 2022, Johns Hopkins investigators registered a Phase 2 clinical trial, called REST, to evaluate trazodone for its ability to improve sleep and cognition in people with mild cognitive impairment. Participants will have a subjective memory complaint and/or evidence of memory problems, a Clinical Dementia Rating of 0.5, and sleep complaints. In a crossover design, 100 participants will get 50 mg trazodone or placebo at bedtime for four weeks, separated by a four-week washout period. Primary outcomes are measures of sleep duration, slow-wave sleep duration and intensity, time to sleep onset, sleep fragmentation, self-reported sleep quality, and sleepiness. Secondary measures are memory performance and fMRI measures of hippocampal activation. The trial is to run from June 2022 to May 2028.
In May 2022, a one-year trial is to start in Hong Kong, enrolling 124 people with mild cognitive impairment due to AD and sleep apnea, to evaluate effects of 50 mg trazodone daily or placebo on plasma biomarkers of inflammation and neurodegeneration, and CDR global score. Completion is expected for December 2026.
A Phase 2/3 study in the U.K. is comparing trazodone or memantine to placebo in people with amyotrophic lateral sclerosis or other motor neuron disease. Called MND-SMART, the multicenter, adaptive trial is enrolling 750 patients for 18 months of treatment. Results are expected in 2026.
Other ongoing studies are assessing the ability of trazodone to enhance overnight memory consolidation in healthy or depressed people, to treat insomnia or sleep apnea in a variety of settings, and to treat delirium in intensive care. A small study in Brazil is assessing the effects on motor symptoms in 30 people with Parkinson’s disease.
For details on trazodone trials, see clinicaltrials.gov.
Last Updated: 06 May 2022
Further Reading
No Available Further Reading
Overview
Name: Vodobatinib
Synonyms: K0706, SCC-138, SCO-088
Chemical Name: 2-chloro-6-methyl-N'-{4-methyl-3-[(quinolin-3-yl)ethynyl]benzoyl}benzohydrazide
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Parkinson's Disease, Dementia with Lewy Bodies
U.S. FDA Status: Parkinson's Disease (Phase 2), Dementia with Lewy Bodies (Phase 2)
Company: Sun Pharma Advanced Research Company Ltd.
Background
Vodobatinib is a third-generation c-Ableson tyrosine kinase inhibitor. It is structurally similar to the commercial anticancer agents Dasatinib and Ponatinib (Antelope et al., 2019). Abl kinase inhibitors induce autophagy, leading to the death of rapidly dividing cells (Salomoni and Calabretta, 2009).
Some drugs in this class have been proposed for repurposing as a disease-modifying treatment for synucleinopathies including Parkinson’s disease and dementia with Lewy bodies (e.g., see nilotinib, bosutinib). The rationale is based on the finding that activated Abl kinase contributes to pathogenesis by phosphorylating α-synuclein and promoting its aggregation and toxicity, and by inhibiting neuroprotective effects of the parkin protein (e.g., Ko et al., 2010). In cells, nilotinib promoted α-synuclein degradation by autophagy (Mahul-Mellier et al., 2014). Abl kinase inhibitors prevented loss of dopaminergic neurons in mouse models of Parkinson's disease (Karuppagounder et al., 2014; Imam et al., 2013; Hebron et al., 2013).
No preclinical work is published to date for Vodobatinib. The company claims it is neuroprotective in two mouse and one rat model of PD (investor presentation, slides 8 and 9). K0706 has a reported IC50 for c-Abl of 0.9 nM.
Findings
From 2017-2019, the company conducted three Phase 1 studies relevant to the PD indication. A bioavailability study compared different formulations in healthy adults. A second study compared two weeks of daily doses from 6 to 384 mg or placebo in 60 people with Parkinson’s disease. Another Phase 1 study in 2018-2019 assessed brain penetration of the drug, by measuring CSF drug levels after seven days of 48, 192 or 384 mg daily in 18 healthy men. According to results presented at the 2019 AAN meeting, no serious adverse events were observed in the PD patients (Goldfine et al., 2019). Blood levels increased with dose and reached estimated therapeutic levels based on PD animal models. Observed blood and CSF drug concentrations guided the choice of dose for subsequent Phase 2 trials.
In February 2019, the company began a Phase 2 study in Parkinson’s disease, called PROSEEK. It planned to enroll 504 people with early Parkinson’s who were not taking dopamine therapy, and randomizing them to high or low dose K0706, or placebo, once a day for 40 weeks. The primary outcome was change from baseline on the MDS-UPDRS Parts 2 and 3, with secondary outcomes of change in MDS-UPRDS all parts, time to start symptomatic medication, health-related quality of life, clinical impression of change, and autonomic symptoms. Exploratory outcomes include DAT-Spec brain dopamine scans, blood and CSF drug levels, and α-synuclein deposition in skin. The trial, at 77 sites in the U.S., Hungary, India, Poland, Slovakia, and Spain, would run through March 2023.
In September 2019, a single-center Phase 2 study at Georgetown University Hospital began testing vodobatinib in dementia with Lewy Bodies. The plan was to randomize 45 participants to 96 or 192 mg K0706 or placebo daily for 12 weeks. The primary outcome is adverse events; secondaries are pharmacokinetics, and CSF and plasma biomarkers of kinase inhibition. The study will also assess cognition, behavioral symptoms, and motor function using standard scales, with a planned end date of October 2023.
K0706 is also being tested for chronic and acute myeloid leukemia. The drug reportedly was well tolerated at doses up to 204 mg in a Phase 1 study in people with chronic AML (meeting abstract), and a larger phase 1/2 trial is ongoing.
For details on K0706 trials, see clinicaltrials.gov.
Last Updated: 03 May 2022
Further Reading
No Available Further Reading
Overview
Name: CST-2032
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Mild Cognitive Impairment, Parkinson's Disease
U.S. FDA Status: Mild Cognitive Impairment (Phase 2), Parkinson's Disease (Phase 2)
Company: CuraSen Therapeutics, Inc.
Background
CST-2032 is a proprietary, brain-penetrant β2-adrenergic receptor agonist. Like clenbuterol, CST-2032 activates norepinephrine receptors in cortical and limbic brain regions to compensate for the loss of this neurotransmitter in neurodegenerative diseases. The sole source of norepinephrine in the brain is the locus coeruleus, and those neurons die early in AD and PD (e.g., Jacobs et al., 2021).
Multiple lines of research implicate the loss of norepinephrine in the progression of AD and PD pathology and symptoms (e.g., Dec 2010 conference news). β2-adrenergic agonists were reported to suppress α-synuclein expression, show neuroprotective effects, and be associated epidemiologically with lower PD incidence (Sep 2017 news). β2 agonists were reported to show activity in mouse models of AD and ALS (Chai et al., 2017; Teng et al., 2006). The effects may stem from their anti-inflammatory actions (e.g., Evans et al., 2021; O’Neill et al., 2020).
No preclinical work is published on CST-2032 by name. CuraSen was founded by Stanford researchers who have published on a novel, brain permeable, β1-receptor partial agonist with anti-inflammatory, anti-amyloid, and pro-cognitive actions in mouse models of AD and Down’s syndrome (Yi et al., 2017; Ardestani et al., 2017; Salehi et al., 2009).
CuraSen has presented data at conferences that β2-receptor agonists increase regional blood flow in the brain, a marker of metabolic health. At the March 2021 AD/PD meeting, company scientists reported that salbutamol (albuterol) significantly increased thalamic perfusion measured by arterial spin labeling-MRI in 12 healthy people (press release). A second study, presented at CTAD 2021, used clenbuterol, which the company is developing under the name CST-103. In eight people with MCI or PD, a single clenbuterol dose significantly increased perfusion in the hippocampus, thalamus, and amygdala (see poster, press release). In both studies, administration of the non-brain penetrant β-blocker nadolol (aka CST-107) mostly eliminated adrenergic side effects like increased heart rate, tremor, and palpitations, but did not change clenbuterol’s effect on brain perfusion.
Findings
In September 2020, CuraSen began a first-in-human study in New Zealand and Belgium to assess the safety and pharmacokinetics of CST-2032 in 118 healthy subjects and people with PD or MCI (ANZCTR). Dosing began at 1 mg, with or without concomitant CST-107/nadolol. In addition to safety outcomes, the single- and multiple-ascending dose design also included neuroimaging for blood flow, autonomic function tests, and cognition. The trial was stopped early in January 2021, with data on 79 participants. According to information in the registry, the company stopped the study for business reasons, and there were no safety concerns with the drug. According to a presentation at the 2023 AD/PD conference, the drug increased regional brain blood flow, similar to clenbuterol. Adverse events were typical for β2 agonists and inhibited by naldolol.
A Phase 1 trial, set to begin in October 2021, was withdrawn for business reasons. The study had intended to enroll 16 people with mild cognitive impairment or PD.
A Phase 2 trial began in April 2022, recruiting 60 participants with mild dementia or MCI due to AD or PD. The crossover trial tests two weeks of 3 or 6 mg CST-2032 plus 3 mg CST-107/nadolol, and two weeks of placebo, against primary outcomes of adverse events, vital signs, and ECG. Secondary outcomes include CANTAB tests of attention, memory, and learning, and a test of facial emotional expression recognition. The study, at 15 sites in the U.S. and New Zealand, is expected to finish in November 2023.
For details on CST-2032 trials, see clinicaltrials.gov.
Last Updated: 07 Nov 2023
Further Reading
No Available Further Reading
Overview
Name: CST-103
Synonyms: Clenbuterol
Chemical Name: (RS)-1-(4-Amino-3,5-dichlorophenyl)-2-(tert-butylamino)ethan-1-ol
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Mild Cognitive Impairment, Parkinson's Disease, Amyotrophic Lateral Sclerosis
U.S. FDA Status: Mild Cognitive Impairment (Phase 2), Parkinson's Disease (Phase 2), Amyotrophic Lateral Sclerosis (Phase 2)
Approved for: Asthma, in countries outside the U.S.
Background
CST-103 is CuraSen’s name for clenbuterol, a β2-adrenergic receptor agonist. Clenbuterol is related to common asthma drugs such as albuterol but is not approved for use in the U.S. It is abused by athletes and others for its steroid-like actions, to increase muscle mass, and for weight loss.
Its repurposing for neurological disorders stems from its ability to activate norepinephrine receptors in the brain, in an effort to compensate for the loss of this neurotransmitter in neurodegenerative diseases. The sole source of brain norepinephrine is the locus coeruleus, and those neurons die early in AD and PD (e.g., Jacobs et al., 2021). Multiple lines of research implicate the loss of norepinephrine in the progression of AD and PD pathology and symptoms (e.g., Dec 2010 conference news).
β2-adrenergic agonists were reported to suppress α-synuclein expression, show neuroprotective effects, and be associated epidemiologically with lower PD incidence (Sep 2017 news). Clenbuterol likewise reduced synucleinopathy, mitochondrial damage, and memory deficits in mice with post-surgical cognitive deficits (Li et al., 2021). In aged mice, the β2 agonist mabuterol decreased inflammation in the hippocampus and locus coeruleus, and improved learning and memory (Evans et al., 2021). A more recent study found clenbuterol had only a transient effect on α-synuclein mRNA, and no effect on protein levels in mice (Patterson et al., 2022). Clenbuterol was reported to reduce microglia activation, immune cell infiltration, and dopamine neuron degeneration in a mouse model of α-syn neurotoxicity (Torrente et al., 2023).
In the APP/PS1 mouse model of amyloid accumulation, clenbuterol was reported to lessen plaques, increase neurogenesis and synapse formation, and improve memory deficits (Chai et al., 2016; Chai et al., 2017). It prevented mitochondrial dysfunction and tau pathology after brain infusion of Aβ in mice (Chai et al., 2022). Clenbuterol slowed disease progression in a mouse model of amyotrophic lateral sclerosis (Teng et al., 2006). In a model of inflammation-induced Parkinson’s disease, it prevented dopamine neuron loss and loss of motor function (O’Neill et al., 2020).
Anti-inflammatory effects of clenbuterol have been reported in mouse and rat brain, as well as a rat excitotoxicity model (McNamee et al., 2010; Ryan et al., 2011; Gleeson et al., 2010). A controlled-release formulation was reported to deliver clenbuterol for two weeks after intramuscular injection (Lin et al, 2023). It reduced inflammation and improved behavior in a rat model of aluminum-induced cognitive impairment.
CuraSen has presented data at conferences that β2-receptor agonists increase regional blood flow in the brain, a marker of metabolic health. At the March 2021 AD/PD meeting, company scientists reported that salbutamol (albuterol) increased thalamic perfusion measured by arterial spin labeling-MRI in 12 healthy people (press release). Co-administration of the peripherally restricted β-blocker nadolol largely eliminated adrenergic side effects of increased heart rate and tremor, but did not affect brain perfusion.
Findings
At the November 2021 CTAD conference, CuraSen reported findings of a Phase 1 study with clenbuterol. In eight people with MCI or PD, a single 80 microgram dose increased perfusion in the hippocampus, thalamus, and amygdala (see poster, press release). Consistent with earlier work, co-administration of nadolol (CST-107) mostly eliminated the adrenergic side effects of increased heart rate, tremor, and palpitations, but did not alter clenbuterol’s ability to increase brain perfusion.
In 2019-2020, CuraSen ran a Phase 2 trial in the Netherlands to evaluate central nervous system effects of single or multiple doses of clenbuterol in healthy people or people with PD. The primary outcome was the NeuroCart battery, which includes physiological and cognitive measures. Secondary outcomes included heart rate and blood pressure. A substudy evaluated the feasibility of smartwatch-based heart rate monitoring in 12 patients with PD; published results document average increases of 3.79 and 8.79 bpm during sleep or wake times, respectively (Elzinga et al., 2021).
In June 2021, CuraSen began a Phase 2 study in 38 patients with mild cognitive impairment or Parkinson’s disease with rapid-eye-movement sleep disorder (RBD). Run at sites in Australia, New Zealand, the U.K., and Belgium, the crossover study compared two weeks of clenbuterol plus nadolol to two weeks of placebo on outcomes related to cognitive and executive function, mood, attentiveness, arousal, and activity. At the March 2023 AD/PD conference in Gothenburg, Sweden, the company presented results, claiming rapid improvements in cognition and mood with a daily dose of 80 micrograms clenbuterol and 1 mg nadolol (press release). The regimen was well tolerated, with no serious adverse events and no side effects associated with peripheral activation of β2-ARs.
A Phase 2 study is planned to begin in June 2024, to evaluate the effects of clenbuterol plus nadolol on walking in people with Parkinson’s. The single-center trial at the University of Sydney will enroll 25 participants for a two-week crossover treatment of drug or placebo. The primary outcome will be a measure of gait freezing, i.e., the number of times participants interrupt normal foot progression while walking, based on analysis of video recordings. Other endpoints include cognitive tests and tracking of physical activity and sleep. The study will finish in March 2025.
Clenbuterol was tested in an open-label pilot trial to improve motor function in people with amyotrophic lateral sclerosis. It ended in March 2021, and results were published after peer review (Li et al., 2023). Clenbuterol was safe at the dose of 80 microgram twice daily, but 13 of 25 patients withdrew from the trial due to adverse events. Clenbuterol appeared to slow progression during treatment. In a previous study, clenbuterol was reported to have improved the efficacy of enzyme replacement therapy for the lysosome storage disorder Pompe disease (Koeberl et al., 2018).
CuraSen is also evaluating a related, proprietary β2-receptor agonist (see CST-2032).
For details on CST-103 trials, see clinicaltrials.gov.
Last Updated: 07 Nov 2023
Further Reading
No Available Further Reading
Overview
Name: Cannabidiol
Synonyms: CBD, Epidiolex
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Approved for: Seizures in Dravet syndrome, Lennox-Gastaut syndrome or tuberous sclerosis complex
Background
Cannabidiol is a major active compound of the cannabis plant. It is structurally related to tetrahydrocannabinol (THC), but does not produce a high. CBD is also abundant in hemp plants, which have little to no THC, making industrial hemp the usual source of THC-free CBD oil. In many locales, hemp-derived CBD is not subject to cannabis laws, and is freely available as capsules, drops or oil suspensions, or in transdermal patches, topical lotions, or salves. CBD has been studied in clinical trials for anxiety, addiction, cognition, movement disorders, pain, and other conditions, with no strong evidence yet for its effectiveness. Nonetheless, it is widely promoted and used for these and other maladies.
In 2018, an oral solution of CBD was approved in the U.S. to treat rare forms of severe childhood epilepsy. Common side effects include sleepiness, poor sleep, decreased appetite, diarrhea, and fatigue. This formulation can also cause an increase in liver enzymes, and interferes with metabolism of other medications.
Like the THC formulations nabilone and dronabinol, in Alzheimer's, CBD is mainly being evaluated for treatment of agitation and aggression with this disease.
In preclinical work, extensive studies with CBD in cell and animal models of Aβ-induced neurotoxicity found it had multiple actions on Aβ production, tau phosphorylation and aggregation, oxidative stress, inflammation, and neurogenesis (reviewed by Watt and Karl, 2017; also see Khodadadi et al., 2021). A combination of CBD and THC was reported to preserve memory function and reduced astrogliosis and inflammation in APP/PS1 mice, with the combination more effective than either alone (Aso et al., 2015). CBD is reportedly neuroprotective in models of tauopathy and stroke (e.g. see Kreilaus et al., 2022; Ceprian et al., 2017).
CBD’s mechanism of action is unclear. It has low affinity for the cannabinoid receptors CB1 and CB2; instead, it has been proposed to act through TRPV cation channels, the peroxisome proliferation receptor gamma (PPARγ), novel G protein coupled receptors, and serotonin receptors (reviewed by Vitale et al., 2021).
Previous small trials of CBD in Parkinson’s and Huntington’s diseases found no improvement in symptoms, but the PD patients on treatment reported higher quality of life (Chagas et al., 2014; Consroe et al., 1991).
Findings
From 2017-2019, Tikun Olam Pharmaceuticals ran a 64-person Phase 2 trial in Israel testing Avidekel oil, a high CBD/low THC cannabis extract, for the treatment of agitation and aggression in dementia patients. The oil contains 30 percent CBD and 1.5 percent THC. Participants received active or placebo drops under the tongue three times a day for 16 weeks. The primary outcome was a reduction of four points on the Cohen-Mansfield Agitation Inventory; secondary was change on the Neuropsychiatric Inventory-Nursing Home version. According to a published abstract, 72 percent of participants taking CBD oil achieved the primary outcome versus 30 percent on placebo. The average reduction on CBD was 13.3 points versus 2.3 points on placebo. NPI-NH scores were reported to be significantly better with treatment (Hermush et al., 2020; 68, see (Suppl 1):S86 abstract A202 page 86).
In January 2021, an open-label Phase 1 trial began testing an eight-week course of high CBD/low THC oil in 12 people with mild to moderate AD and anxiety and aggression. The custom-formulated hemp extract is given under the tongue twice a day. A target dose of 45 mg CBD per day also delivers approximately 1 mg THC. The primary endpoint is the clinician impression of anxiety from the Neuropsychiatric Inventory-C; other endpoints are additional measures of anxiety, as well as safety and side effects, cognition, and caregiver burden. An optional 12-month extension with similar, commercially available CBD products is offered. According to a presentation at CTAD in November 2021, one person had completed the single-center study at McLean Hospital in Massachusetts. The trial was planned to end in January 2022.
In February 2021, a Phase 2 trial started to assess the effectiveness of a THC-free CBD oil to treat agitation in people with AD dementia or mixed AD dementia. The trial will enroll 40 participants for a six-week regimen of hemp-derived CBD oil capsules or a matching placebo. The dose begins at 30 mg daily, titrating up to 90 mg, or the highest tolerated dose. Primary outcomes are change in Cohen-Mansfield Agitation Inventory, caregiver burden, and quality of life of patient and caregiver. Secondary measures include the Neuropsychiatric Inventory, MMSE, and sleep quality. The single-center study at Eastern Virginia Medical School in Norfolk is expected to finish in June 2022
In April 2021, a study began enrolling older people with mild cognitive impairment who carry the ApoE4 allele, to compare the effects of a CBD or homotaurine on cognition, daily function, and depression. The single-center, Phase 4 study is ongoing in Greece. It will randomize 90 patients to 5 percent CBD oil, homotaurine, or no intervention. Twenty primary outcomes include the MMSE, MoCA, a cognitive battery, dementia ratings, measures of anxiety and depression, and CSF biomarkers of BDNF, tau, inflammation, and oxidative stress. The trial will run through December 2022.
CBD is also being tested for motor symptoms and pain in Parkinson’s disease. Other active studies include amyotrophic lateral sclerosis, psychosis, anxiety, autism, insomnia, pain conditions, and substance use disorders, among others.
For details on cannabidiol trials, see clinicaltrials.gov.
Last Updated: 10 Mar 2022
Further Reading
No Available Further Reading
Overview
Name: Dronabinol
Synonyms: THC , Marinol, Syndros, delta-9-tetrahydrocannabinol, delta-9-THC
Chemical Name: (6aR,10aR)-6,6,9-Trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: AbbVie, Others
Approved for: Anorexia and weight loss in people with AIDS; Second-line treatment of nausea and vomiting due to chemotherapy
Background
Dronabinol is synthetic delta-9-tetrahydrocannabinol, aka THC, the major psychoactive compound of cannabis. It is an agonist of CB1 and CB2 cannabinoid receptors found in the brain and in peripheral tissues. Taken in capsule or liquid form, dronabinol has the same central actions as THC. It was approved by the FDA in 1985 for the treatment of nausea and vomiting associated with cancer chemotherapy, and in 1992 for the treatment of anorexia and weight loss in people with AIDS. The term dronabinol refers to generic versions of Abbvie's brand Marinol.
In trials, the most frequent side effects were euphoria, dizziness, sleepiness, nausea and vomiting, abnormal thinking, paranoia, and abdominal pain. Risks of dronabinol in older people include delirium, sedation, seizures, blood pressure changes, and increased heart rate. It has a low potential for abuse or dependence.
The dose for appetite stimulation is 5 to 10 mg per day, reached after gradual titration and taken as two divided doses. For nausea, the maximum dose is 15 mg, four to six times daily. Older people are started on lower doses to minimize CNS symptoms.
The primary interest in repurposing dronabinol and other cannabinoids (see nabilone, cannabidiol) for Alzheimer's disease currently focuses on the symptomatic treatment of agitation and aggression. Cannabinoids are mildly sedative and anxiolytic, and may act by reducing neuroinflammation, regulating neurotransmission, and improving sleep and circadian rhythms (reviewed in Outen et al., 2021). These compounds also increase appetite and decrease pain, which may benefit people with dementia.
There is a large body of preclinical research on cannabinoids’ disease-modifying actions, in particular their effects on microglia. In short, multiple receptor agonists have been shown to protect against Aβ-induced neural toxicity in AD animal models, by inhibiting inflammation, excitotoxity, mitochondrial dysfunction, oxidative stress, and tau hyperphosphorylation, and facilitating Aβ removal (reviewed by Cristino et al., 2020).
Findings
An early dronabinol study evaluated effects of a six-week course on appetite and agitation in 15 patients with severe AD dementia who refused to eat (Volicier et al., 1997). In the crossover trial, 5 mg dronabinol daily was better than placebo at improving body weight and decreasing symptom severity on the Cohen Mansfield Agitation Inventory and other scales. Side effects were euphoria and sleepiness; one patient suffered a grand mal seizure after the first dose of dronabinol.
In a small, open-label pilot study, 2.5 mg dronabinol given in the evening reduced nighttime agitation in six severely demented patients with day/night rhythm disturbances and evening agitation, aka sundowning (Walther et al., 2006).
A review of off-label use of dronabinol in 40 severely demented patients with agitation in a geriatric neuropsychiatric inpatient unit reported that adding it to regular psychiatric medications was associated with improvement on the Pittsburg Agitation Scale, the Clinical Global Impression of Change, sleep duration, and eating after one week (Woodward et al., 2014). The average dose taken was 7 mg/day, for an average of 17 days. The most frequent side effects were sedation and delirium, although neither was clearly related to the drug. No severe adverse events were reported. Thirteen of the 40 participants were diagnosed with AD; the others had vascular or mixed dementia, or FTD, or were unspecified.
Between 2011 and 2014, an alternative formulation of delta-9-THC was tested. Namisol (Echo Pharmaceuticals) is a proprietary tablet designed to give quicker onset of action. Initial work in the Netherlands found its pharmacokinetics varied between people, but side effects were negligible after doses of 1.5 or 3 mg per day in older people with dementia (Ahmed et al., 2015). A subsequent Phase 2, placebo-controlled pilot trial found no effect of three days of these doses on daily on neuropsychiatric symptoms in 22 people with severe dementia, mainly due to Alzheimer’s. No adverse events were reported. Five patients completed an optional six-month open-label extension; the low doses of THC appeared safe but did not improve behavioral symptoms (van den Elsen et al., 2015; van den Elsen et al., 2017). In 2012-2014, the same group conducted a second study with a higher dose. Fifty participants with AD or vascular dementia and moderate agitation/aggression or motor disturbances took 4.5 mg Namisol daily, divided in three doses, or placebo, for three weeks. The primary outcome of Neuropsychiatric Inventory scores after two or three weeks showed reduced symptoms in both groups, with no difference between placebo and Namisol. Side effects were similar between drug and placebo (Van den Elsen et al., 2015). A systematic review of these trials of THC, plus studies of dronabinol, and nabilone, found insufficient evidence for benefits on cognition or behavior (Bosnjak Kuharic et al., 2021).
In March 2017, a Phase 2 pilot trial began testing three weeks of 10 mg daily dronabinol added to usual medications in 160 AD patients with severe agitation. Treatment starts at 5 mg daily for one week, then increases to 10 mg for two weeks. Participants take half at 8 am and 2 pm, to maximize daytime coverage and minimize sundowning. The coprimary outcomes are scores on the Pittsburgh agitation scale and NPI-Clinician agitation and aggression subscales, with a secondary of the Cohen-Mansfield Agitation Inventory. The study will also assess function, cognition, sleep and safety. Of the first 44 participants, three quarters are women, most are white and in good health (Cohen et al., 2021). The trial is running at three U.S. hospitals until May 2023. The trial uses Abbvie's brand Marinol but is sponsored by Johns Hopkins University; Abbvie does not list Marinol in its development pipeline for this indication.
In December 2021, a Phase 2 study started in Israel to test a combination of dronabinol plus the endogenous cannabinoid palmitoylethanolamide (PEA) in 20 people with AD and agitation severe enough to require medication. The single center, open label study begins with a two to three-week titration of dronabinol from 2.5 mg to 12.5 mg daily, or the highest tolerated dose, plus 800 mg PEA, then 10 days at that dose. Dosing is twice daily, added on to existing medications. The primary outcomes are dropouts and adverse events. The study will finish in June 2023.
Dronabinol has also been tested in Huntington's disease.
For details on these trials, see clinicaltrials.gov.
Last Updated: 10 Mar 2022
Further Reading
No Available Further Reading
Overview
Name: Nabilone
Synonyms: Cesamet
Chemical Name: (±)-trans-3-(1,1-dimethylheptyl)- 6,6a,7,8,10,10a-hexahydro-1-hydroxy-6-6-dimethyl-9H-dibenzo[b,d]pyran-9-one
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease, Parkinson's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 3), Parkinson's Disease (Phase 2)
Company: Bausch Health Companies Inc.
Approved for: Nausea associated with cancer chemotherapy (US and other countries); pain spasticity in multiple sclerosis (Canada and other countries).
Background
Nabilone is a synthetic compound sold by Bausch Health, formerly Valeant Pharmaceuticals. Nabilone is related to delta-9-tetrahydrocannabinol, aka THC, the major psychoactive compound of cannabis. It is a partial agonist of CB1 and CB2 cannabinoid receptors found in the brain and in peripheral tissues. It is currently being tested to treat agitation in people with advanced AD dementia.
Nabilone crosses the blood-brain barrier, and has central actions similar to THC's. In trials, the most frequent side effects were drowsiness, dizziness, dry mouth, and euphoria. This drug has a high abuse potential. It causes mood and memory changes, and even psychosis, in some people (e.g. Udow et al., 2018). In a meta-analysis of clinical trials, nabilone was generally safe and well-tolerated in people over 50, but raised concerns because of increased alterations in thinking, as well as dizziness and lightheadedness (Velayudhan et al., 2021; Velayudhan et al., 2021; commentary by Fick, 2021).
For nausea associated with chemotherapy, the dose is 1 to 2 mg, taken in capsule form multiple times a day, up to a total of 6 mg. Because of its psychoactive effects and other adverse effects, it is a second-line treatment, used only when people do not respond to other anti-emetics.
The primary interest in nabilone and other cannabinoids (see dronabinol, cannabidiol) for Alzheimer's disease currently focuses on symptomatic treatment of agitation and aggression. Cannabinoids are mildly sedative and anxiolytic, and may act by reducing neuroinflammation, regulating neurotransmission, and improving sleep and circadian rhythms (reviewed in Outen et al., 2021). These compounds also increase appetite and decrease pain, which may benefit people with dementia.
There is a large body of preclinical research on cannabinoids’ disease-modifying actions, in particular the role of CB2 receptors on microglia. In short, multiple receptor agonists have been shown to protect against Aβ-induced neural toxicity in AD animal models, by inhibiting inflammation, excitotoxity, mitochondrial dysfunction, oxidative stress, and tau hyperphosphorylation, and facilitating Aβ removal (reviewed by Cristino et al., 2020).
Findings
In a published case study, an advanced AD patient with agitation and aggressiveness who had not responded to anti-psychotic or anti-anxiety medications showed rapid and dramatic improvement on nabilone (Passmore, 2008).
In 2015-2019, a pilot Phase 2/3 safety and efficacy study ran at Sunnybrook Health Sciences Center in Toronto. The crossover design trial enrolled 38 patients with moderate to severe AD and agitation, who were in a nursing home or outpatients at a geriatric psychiatric facility. Participants received 1 to 2 mg daily nabilone or placebo sequentially for six weeks, and were assessed for agitation and other behaviors, adverse events, cogntition, overall clinical status, pain, nutritional status, caregiver distress, and blood-based biomarkers. The protocol and results are published (Ruthirakuhan et al., 2019; Herrmann et al., 2019; and commentary by Rosenberg et al., 2019). Nabilone moderately improved the primary outcome of the Cohen-Mansfield Agitation Inventory by four points, compared to placebo. Scores on the Neuropsychiatric Inventory, caregiver distress, and MMSE improved, but the Severe Impairment Battery worsened on drug. Treatment improved nutrition, with no change in weight or pain. Nearly half of people experienced sedation on nabilone, compared to a quarter of those on placebo, but in most sedation lessened when the dose was lowered, while agitation still improved. Falls and serious adverse events were similar in nabilone and placebo phases. Data on biomarkers related to oxidative stress and inflammation in this trial were separately published, and showed that proinflammatory cytokine TNFα levels correlated with agitation severity at baseline, and with treatment (Ruthirakuhan et al., 2020). A blood biomarker reflecting elevated brain cholesterol, serum 24-S-hydroxycholesterol, was associated with agitation severity, but did not change with nabilone treatment (Ruthirakuhan et al., 2019).
A meta-analysis including this trial and five others using dronabinol or natural THC found no overall benefit on agitation or aggression, but suggested a greater signal for a potential benefit in synthetic cannabinoids than natural THC (Ruthirakuhan et al., 2019). All forms caused sedation. A Cochrane review of four trials of nabilone, dronabinol, or THC in people with AD found insufficient evidence for benefits on cognition or behavior (Bosnjak Kuharic et al., 2021).
In February 2021, the Ontario investigators began a Phase 3 trial. Called NAB-IT, the study plans to enroll 112 people with a clinical diagnosis of AD and agitation. They will take 1-2 mg nabilone or placebo daily for nine weeks, followed by eight weeks of observation. The primary outcome is the Cohen-Mansfield Agitation Inventory, with secondaries including other neuropsychiatric measures, cognition, global clinical change, caregiver distress, and safety. Exploratory measures include pain, nutritional status and blood biomarkers of inflammation and oxidative stress, and 24-S-hydroxycholesterol. The study will run through October 2025 at five locations in Ontario and Alberta, Canada.
Nabilone has been studied in Parkinson’s disease. An early study in seven patients found it could lessen levodopa-induced dyskinesia (Sieradzan et al., 2001). More recently, in a single-center Phase 2 study of 47 people with Parkinson's, doses from 0.25 to 2 mg daily reduced the disease's non-motor symptoms, mainly by reducing anxiety and sleep disturbances (Peball et al., 2020). Most participants tolerated the treatment well, with typical side effects of mild fatigue, dizziness, dry mouth, and sleepiness. No severe adverse events were reported. A six-month open-label extension was completed in January 2020, and results are posted on clinicaltrials.gov.
Nabilone has also been tested for cannabis dependence, fibromyalgia, spasticity due to nerve damage, motor symptoms of Huntington disease, and neuropathic pain conditions. Trials are ongoing for obsessive compulsive disorder, obesity, inflammatory bowel disease, and neuropathic itching due to kidney disease.
For details on nabilone trials, see clinicaltrials.gov.
Last Updated: 11 Mar 2022
Further Reading
No Available Further Reading
Overview
Name: Protollin
Therapy Type: Immunotherapy (active) (timeline)
Target Type: Inflammation (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: I-MAB Biopharma Co., Ltd., Jiangsu Nhwa Pharmaceutical Co., Ltd
Background
Protollin is a nasal vaccine composed of the outer membrane proteins of bacteria complexed with lipopolysaccharides. It was developed as an adjuvant to enhance mucosal immune responses to intranasal flu and other vaccines (Jones et al., 2004). Protollin stimulates the innate immune system through toll-like receptors.
The rationale for its use as an Alzheimer’s vaccine comes from preclinical work in APP-transgenic mice, where nasal Protollin stimulated clearance of brain amyloid, apparently by activating peripheral monocytes to enter the brain and phagocytose Aβ (Frenkel et al., 2005; Frenkel et al., 2008). Removal of brain amyloid did not require an antibody response. Protollin was shown to elevate expression of the Aβ scavenger receptor Scara1 on mouse microglia (Frenkel et al., 2013); in human microglia cultures, it slightly increased phagocytosis of Aβ42 (Hjorth et al, 2010).
In a mouse model of cerebral vascular amyloidosis, nasal vaccination with Protollin reduced amyloid in blood vessels, prevented microhemorrhages, and improved cognition (Lifshitz et al., 2012).
Protollin was tested, and appeared safe, in humans as part of an experimental intranasal shigella vaccine (Fries et al., 2001).
Findings
In December 2021, I-Mab Biopharma announced dosing of the first patient in a Phase 1 Alzheimer's disease trial (press release). The study, at Brigham and Women’s Hospital in Boston, involves 16 participants between 60 and 85 years old who have early symptomatic AD (BWH press release). They will receive two doses of Protollin, one week apart. The primary outcomes are safety and tolerability, and the study will also assess immune responses.
No registration for this trial appears in clinicaltrials.gov.
Last Updated: 16 Feb 2022
Further Reading
No Available Further Reading
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