Overview
Name: Intranasal oxytocin
Synonyms: Syntocinon, Pitocin
Therapy Type: Other
Target Type: Other (timeline)
Condition(s): Frontotemporal Dementia
U.S. FDA Status: Frontotemporal Dementia (Phase 2)
Background
Oxytocin is a peptide hormone involved in social bonding, reproduction, and childbirth. Defects in oxytocin biology have been implicated in neurodegenerative disorders ranging from frontotemporal dementia to Huntington's disease (e.g. Bergh et al., 2022; Saiz-Rodgriguez et al., 2022).
Oxytocin therapy is approved for inducing labor, controlling postpartum bleeding, and aiding breastfeeding. It is given by injection, or as an intranasal spray. Low-dose oxytocin nasal sprays are available without prescription in the U.S.
Nasal oxytocin has been widely studied for its effects on social behavior. In healthy adults or people with autism, intranasal oxytocin acutely improves recognition of emotional and social cues, and enhances empathy and cooperative behavior. It can also stimulate aggressive behavior in some contexts. The nasal spray delivers oxytocin to the brain, where it is reported to last for several hours (see review by Quintana et al., 2021).
Oxytocin is proposed as a symptomatic treatment for people with frontotemporal dementia, where damage to the frontal and temporal lobes impairs emotional processing, social cognition, and behavior. Loss of empathy is a hallmark symptom of behavioral variant frontotemporal dementia. These patients also show deficits in recognizing facial expressions and verbal emotional cues, and lose insight into what others think or might do. Indifference to even close family members is a major challenge for caregivers. There are no treatments for these social behavioral problems in people with FTD. However, plasma levels of oxytocin have been reported to be unrelated to social cognition or behavior in these diseases (Johnson et al., 2022).
In Alzheimer’s disease, preclinical studies in mouse models have reported beneficial effects of nasal oxytocin on pathology and memory (Takahashi et al., 2022; El-Ganainy et al., 2022).
Findings
From September 2009 to November 2010, an academic-sponsored pilot study in Ontario, Canada, tested nasal oxytocin in 20 patients with a clinical diagnosis of behavioral variant FTD. Participants in the crossover trial received a single dose of 24 International Units of oxytocin or placebo, delivered intranasally. Eight hours and one week after dosing, they completed tasks related to recognition of emotional cues from others, and neuropsychiatric behaviors. Eight hours post-dose, patients had significant improvement in Neuropsychiatric Inventory scores, and trended toward improvement in the Frontal Behavioral Inventory, compared with baseline and with placebo. Oxytocin also reduced recognition of negative facial expressions of anger or fear (Jesso et al., 2011; Jun 2012 conference news). The investigators noted no effects on any endpoint after one week, and no significant adverse effects of the drug at any time.
Between June 2011 and October 2013, a Phase 1 study was completed at the same Canadian center. It enrolled 23 FTD patients to evaluate the safety and tolerability of 24, 48, or 72 IU of nasal oxytocin, given twice daily for one week. Results are published (Finger et al., 2015). All three doses were safe and well-tolerated. No serious adverse events occurred, although one-third of treated patients showed higher levels of inappropriate sexual behaviors. Efficacy outcomes suggested possible improvements in apathy and empathy, especially at the highest dose.
The same Canadian group performed a Phase 2 study between September 2013 and December 2017, measuring the effects of oxytocin on functional MRI imaging while participants viewed and imitated different facial expressions. The trial involved 28 FTD patients, who received a one-time dose of 72 IU intranasal oxytocin or placebo in a crossover design. According to published results, oxytocin treatment increased BOLD signals in regions of the brain associated with facial expression processing and empathy (Oliver et al., 2020).
In January 2018, a multicenter Phase 2 safety and efficacy trial called FOXY began. Initially, the study will compare daily and intermittent dosing in 112 patients. In the crossover design, participants will receive six weeks of 72 IU daily, every other day, or every third day, or placebo, against a primary outcome of change in the NPI apathy/indifference domain score. After that, an additional 40 patients will be enrolled to the most promising regimen for an efficacy assessment. Other endpoints include facial expression recognition, CSF oxytocin levels, and ratings of behavior based on videotaped interactions. The study, running at 11 centers across Canada and the U.S., is expected to wrap up in January 2023. The protocol is published (Finger et al., 2018).
Nasal oxytocin is under investigation for autism, schizophrenia, pain, substance use disorders, obesity, , personality disorders, PTSD and other conditions (e.g. see Guastella et al., 2022; Korann et al., 2022).
For details on nasal oxytocin trials in FTD, see clinicaltrials.gov.
Last Updated: 18 Jan 2023
Further Reading
No Available Further Reading
Overview
Name: Seltorexant
Synonyms: JNJ-42847922, MIN-202
Chemical Name: [5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-6-[1,2,3]triazol-2-yl-phenyl)-methanone
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: Janssen
Background
Seltorexant is a selective antagonist of the human orexin-2 receptor. The neuropeptide orexin regulates wakefulness; inhibiting orexin receptor signaling promotes sleep. This drug is in advanced clinical development for treating depression, where it is thought to be effective by improving sleep. It is being tested to treat agitation and aggression in people with AD.
In preclinical work in rats, orally administrated seltorexant rapidly entered the brain, and induced and prolonged sleep. In humans, it increased sleepiness after a single dose, with acceptable pharmacokinetics and safety (Bonaventure et al., 2015).
This compound was originally discovered at Minerva Neurosciences. That company was developing it in collaboration with Janssen, but their partnership ended in 2020, and now Janssen is solely responsible for its development.
Findings
Since 2009, Janssen has completed more than 20 Phase 1 studies of seltorexant. In people with insomnia, the drug reduced time to fall asleep and increased sleep time (van der Ark et al., 2018; De Boer et al., 2018). In patients with major depression and persistent insomnia, it eased core symptoms of depression, and improved sleep (Brooks et al., 2019; Recourt et al., 2019). In a Phase 2 trial, adding seltorexant improved depression in people who had responded poorly to serotonin reuptake inhibitors. The drug was most effective in people with the worst sleep problems at the start of the study (Savitz et al., 2021). The most common adverse effects were headache, sleepiness, and nausea. Two Phase 3 trials are now testing six weeks of suvorexant added on to antidepressants in people with major depression and insomnia. The studies, in a total of 1,270 patients, were anticipated to finish in 2023, with the company planning FDA submission later that year. In May 2024, Janssen’s parent company Johnson & Johnson announced that seltorexant had met all primary and secondary outcomes in one of the Phase 3 trails involving 588 people (press release).
In May 2022, Janssen began a Phase 2 trial of seltorexant in 86 people with probable Alzheimer’s disease and significant agitation or aggression. Patients will take a single 20 mg tablet or matching placebo daily for six weeks, against a primary outcome of the Agitation and Aggression domain scores of the Neuropsychiatric Inventory-Clinician rating. Secondary outcomes are change in Cohen-Mansfield Agitation Inventory, sleep, and plasma drug levels. The study ran at 25 locations in the U.S., and finished in November 2023 with a final enrollment of 70.
In mid-2024, Johnson & Johnson removed seltorexant’s Alzheimer indication from their pipeline. Development for depression will continue.
For details on seltorexant trials, see clinicaltrials.gov.
Last Updated: 09 Nov 2024
Further Reading
No Available Further Reading
Overview
Name: ION464
Synonyms: BIIB101, IONIS-BIIB6Rx
Therapy Type: DNA/RNA-based
Target Type: alpha-synuclein
Condition(s): Multiple System Atrophy
U.S. FDA Status: Multiple System Atrophy (Phase 1)
Company: Biogen, IONIS Pharmaceuticals
Background
ION464 is an antisense oligonucleotide targeting α-synuclein mRNA to block production of the protein. It is being developed as a potential therapy for Parkinson’s disease, multiple system atrophy, and related synucleinopathies. In these diseases, accumulation of aberrant forms of α-synuclein leads to neurodegeneration. By reducing synthesis of α-synuclein, ION464 is intended to prevent the toxicity of mutant or misfolded forms of the protein.
In preclinical models, Ionis’ α-synuclein ASOs inhibited protein production, and prevented neuronal death after exposure to toxic α-synuclein fibrils (Luna et al., 2018). The ASO similarly reduced α-synuclein production, and prevented development of pathology and motor deficits after injection of toxic fibrils in rodent models. When tested in a treatment paradigm, the ASO reduced levels of pre-existing α-synuclein pathology, and neuron loss. In nonhuman primates, intrathecal delivery of the ASO resulted in lowering of α-synuclein protein in brain and spinal cord (Cole et al., 2021). In another study involving a similar injection of preformed α-synuclein fibrils in mice, the ASO decreased α-synuclein protein levels and pathology, but was also associated with a decline in body weight and motor impairments (Boutros et al., 2021).
Findings
In July 2022, Ionis began a Phase 1 study of ION464 in 40 spinal muscular atrophy patients. Participants must have loss of dopamine nerve terminals detected on a DaTscan, and cognitive dysfunction. The first part of the study involves intrathecal injection of multiple ascending doses or placebo at regulator intervals over 12 weeks. In a second part, participants will receive a set dose multiple times over 72 weeks. The primary outcome is safety. Secondary outcomes include measures of CSF α-synuclein and blood ASO levels. The trial, at 10 sites in Austria, France, Germany, and the U.K., is expected to be complete by December 2025.
For details on ION464 trials, see clinicaltrials.gov.
Last Updated: 17 Jan 2023
Further Reading
No Available Further Reading
Overview
Name: Mirtazapine
Synonyms: Remeron, esmirtazapine, Org 50081
Chemical Name: (±)-2-Methyl-1,2,3,4,10,14b-hexahydropyrazino[2,1-a]pyrido[2,3-c][2]benzazepine
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 3)
Background
Mirtazapine is a tricyclic antidepressant. It inhibits central presynaptic α-2-adrenergic receptors, and increases the release of serotonin and norepinephrine. It produces sedation by antagonizing H1 histamine receptors. This drug is approved to treat major depressive disorder, and used off-label for insomnia, panic disorder, PTSE, anxiety, and headaches. Common side effects are sleepiness, dizziness, increased appetite, and weight gain. One study associated mirtazapine use in younger people with significantly increased mortality after one and five years, compared to other antidepressants (Coupland et al., 2018).
Between 2009 and 2014, mirtazapine was one of the most widely prescribed antidepressants for older people and those with dementia in Europe (Forns et al., 2019). However, in a placebo-controlled study of 218 people with Alzheimer’s dementia, the drug showed no efficacy for depression (Banerjee et al., 2011; Jul 2011 news). Mirtazapine also failed to improve nighttime sleep in a small study of 24 people with Alzheimer's disease, but caused more daytime sleepiness compared to placebo (Scoralick et al., 2016).
Secondary analyses of the depression trial data identified a possible benefit on neuropsychiatric symptoms, and improvement in caregivers’ experience (Banerjee et al., 2013; Romeo et al., 2013; Zuidersma et al., 2019).
Findings
In an open-label study in 16 Alzheimer’s patients with agitation, the Cohen Mansfield Agitation Inventory (CMAI) decreased by an average of 10 points after 12 weeks of mirtazapine at 15-30 mg per day. No significant side effects or cognitive deterioration were reported (Cakir and Kulaksizoglu, 2008).
From January 2017 to March 2020, the Study of Mirtazapine for Agitated Behaviors in Dementia (SYMBAD) evaluated 12 weeks treatment versus placebo in 204 people with Alzheimer’s. It enrolled patients from psychiatric outpatient services and nursing homes in the U.K., who had agitation that did not respond to nonpharmacological treatment. The study found no difference between drug and placebo in the primary outcome of the CMAI after 12 weeks, on an average dose of 30.5 mg per day. CMAI scores dropped by about 10 points in both groups by week six, and stayed below baseline in both at 12 weeks. The number of people with adverse events was similar between placebo and control, but there were seven deaths in the mirtazapine group compared to one in the placebo group, suggesting the possibility of higher mortality with mirtazapine use (Banerjee et al., 2021). The drug did not change the cost of health care, or caregiver burden, compared to placebo (Henderson et al., 2022).
A study of 52 Alzheimer’s patients in Iran is testing mirtazapine as an add-on to the antipsychotic medication quetiapine in people with aggression.
For details on studies of mirtazapine in dementia, see clinicaltrials.gov .
Last Updated: 13 Jan 2023
Further Reading
No Available Further Reading
Overview
Name: Bezisterim
Synonyms: NE3107, HE3286
Chemical Name: 3α-ethynyl-androst-5-ene-3β,7β,17β-triol
Therapy Type: Small Molecule (timeline)
Target Type: Inflammation (timeline), Other (timeline)
Condition(s): Alzheimer's Disease, Parkinson's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 3), Parkinson's Disease (Phase 1/2)
Company: BioVie Pharma
Background
NE3107 is a derivative of β-androstenetriol, a naturally occurring adrenal sterol metabolite. The parent compound has been chemically modified to increase oral bioavailability and stability. It has anti-inflammatory and insulin-sensitizing actions, and enters the brain. NE3107 binds to ERK1/2, kinases involved in inflammatory signaling and insulin responses. It does not interact with nuclear steroid hormone receptors, and has no androgenic or estrogenic function. It is not immunosuppressive.
In preclinical work, NE3107 demonstrated anti-inflammatory activity in vitro, and was neuroprotective in animal models of optic neuritis and glaucoma, where it reduced microglia activation (e.g., Lambert et al., 2017; Khan et al., 2014). In the glaucoma model, NE3107 selectively inhibited pro-inflammatory ERK/NK-kB signaling without affecting the enzyme’s homeostatic actions. It eased insulin resistance in diabetic rodents (Wang et al., 2010; Lu et al., 2010). In Parkinson’s disease mouse models, the compound was reported to protect against dopaminergic neuron loss (Nicoletti et al., 2012). The company claims that it improved the efficacy of L-dopa and decreased dyskinesia in Parkinsonian marmosets.
Multiple Phase 1 studies, and one Phase 2 study, have been completed in a range of indications including impaired glucose tolerance, Type 2 diabetes, ulcerative colitis, and rheumatoid arthritis. Where results were reported, the drug showed anti-inflammatory and insulin-sensitizing activities (Reading et al., 2013; Reading et al., 2013). Pharmacokinetics were dose-proportional from 2 to 100 mg. Most side effects were reported to be mild or moderate, and no serious adverse events were attributed to the drug.
Findings
In August 2021, BioVie began a Phase 3 trial in people with mild to moderate probable AD. The study planned to randomize 316 people to 20 mg NE3107 twice daily or placebo, for 30 weeks. The co-primary outcomes were change on the ADAS-Cog12 and ADCS-CGIC. Secondary endpoints include measures of neuropsychological deficits, functional performance, and glycemic control. A substudy will evaluate exploratory endpoints of volumetric magnetic resonance imaging and FDG-PET glucose uptake. The study, at 36 locations in the United States, finished in September 2023. The rationale and protocol are published (Reading et al., 2021).
In January 2022, an open-label, exploratory study began to examine changes in cognition and CNS biomarkers of AD, inflammation, and metabolic state in patients treated with NE3107. The 23 participants had MCI or mild dementia, with a primary complaint of memory impairment, and at least one abnormal brain imaging result. They took 20 mg twice a day for 12 weeks and were evaluated by multiple MRI modalities to assess brain glutathione levels, dendritic density, functional connectivity, and neurovascular coupling. Secondary outcomes were standard scales of cognition including the Quick Dementia Rating Scale, MoCA, ADAS-Cog12, MMSE, CDR, ADCOMS, and fasting glucose. The trial ran by invitation at a single center in Los Angeles, and finished in August 2022. According to results presented by the company at the 2022 CTAD, imaging studies showed normalization of cerebral perfusion, as well as increased functional connectivity in networks involving the nucleus basalis of Meynert, precuneus, and hippocampus after treatment. Imaging improvements were said to correlate with better ADCOMS scores. Increased brain glutathione suggested a lessening of oxidative stress. Participants' cognitive function was reported to have improved in four of six tests, with changes reaching statistical significance in a prespecified subgroup analysis of 17 patients with MMSE scores above 20. About 60 percent of participants were reported to have had reductions in the inflammatory serum biomarker TNFα, and CSF pTau and Aβ42, correlated with ADCOMS or ADAS-Cog12 scores. Results were published after peer review (Haroon et al., 2024). The reported increase in glutathione from baseline was not statistically significant. Several cognitive measures did reach significance, as did changes in CSF p-Tau and the p-Tau/Aβ ratio. TNFα was not significantly reduced. The company is planning a placebo-controlled Phase 2 trial in Parkinson’s disease, to begin in late 2024 (press release).
Also in January 2022, BioVie treated the first patient in a Phase 1/2 trial testing safety, tolerability, and pharmacokinetics of NE3107 in people with Parkinson’s disease. Forty participants on dopamine replacement were taking 20 mg NE3107 or placebo twice daily for 28 days. The primary objective was to evaluate drug-drug interaction with levodopa, as required by the U.S. FDA. A dozen other endpoints included the Unified Parkinson Disease Rating Scale Parts 1-3, total ON and OFF time, nonmotor symptoms, dyskinesia, and NE3107 pharmacokinetics. The study, at 16 centers in the U.S., was fully enrolled as of October 2022. On December 5, BioVie announced positive topline results on the UPDRS motor score. Additional data was presented at meetings in March and August 2023 (see 2022 Globe Newswire press release; 2023 BioVie press release; 2023 BioVie press release).
In December 2023, the company began an exploratory trial to assess the effects of NE3107 on sleep, fatigue, and cognition in five patients with traumatic brain injury.
In November 2023, BioVie announced results of the Phase 3 Alzheimer’s trial (press release; company slides). The analysis covered data from 57 patients out of the 439 enrolled. The company had to disqualify nearly half of the study sites for protocol violations, including suspected data falsification at some sites. In the resulting subset of patients, BioVie said that treatment resulted in trends toward improvement on co-primary endpoints of ADAS-Cog12 and CDR-CB, and multiple secondary endpoints. On biomarker measures, BioVie reported NE3107-treated patients to have shown a flattening of NfL and GFAP levels, compared to increases in placebo. Treatment also reportedly improved epigenetic/DNA methylation markers of aging. The company announced it would work with the FDA to use an adaptive trial design and continue enrolling patients to increase the trial's statistical power.
BioVie is planning another Phase 3 trial in AD, to start in 2025 and use a once-daily dosing formulation (Mar 2024 press release).
In April 2024, the company announced it received funding from the U.S. Department of Defense for a Phase 2 clinical trial testing NE3107 in long COVID patients (press release).
For details on NE3107/HE3286 trials, see clinicaltrials.gov.
Last Updated: 10 Sep 2024
Further Reading
No Available Further Reading
Overview
Name: TW001
Synonyms: FNP122, FAB122, oral edaravone
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease, Amyotrophic Lateral Sclerosis
U.S. FDA Status: Alzheimer's Disease (Phase 2), Amyotrophic Lateral Sclerosis (Phase 3)
Company: Treeway B.V.
Background
TW001 is a new oral formulation of edaravone, an antioxidant drug marketed in the U.S. and Japan to treat amyotrophic lateral sclerosis.
Oxidative stress plays a role in Alzheimer’s disease, and edaravone has shown beneficial effects in multiple cellular and animal models of Aβ toxicity (e.g., Feng et al., 2019; Feng et al., 2020; Jiao et al., 2015). An oral formulation of edaravone dose-dependently reversed behavior deficits in APP-PS-1 mice (Parikh et al., 2018).
Findings
In 2018, Treeway reported Phase 1 results in 18 healthy volunteers indicating that TW001 was safe and that the bioavailability of a single oral dose of 140 mg exceeded that of a one-hour infusion of 60 mg of Radicava, an FDA-approved oral edaravone.
TW001 received Orphan Drug Designation by the European Medicines Agency in 2014 and by the Food and Drug Administration in 2015.
In November 2021, Treeway, in collaboration with the Spanish company Ferrer, began a Phase 3 trial of TW001, now also called FNP122 or FAB122, in people with ALS. Called ADORE, it is enrolling 300 patients at 38 sites across Europe, to compare safety and efficacy of a 100 mg daily dose to placebo. The study will run until mid-2024, and offers an open-label safety extension.
In March 2023, Treeway began a Phase 2 trial of TW001 in Alzheimer's patients. It plans to enroll 60 people with early AD, defined as an MMSE score greater than 20, plus CSF or PET evidence of brain amyloid. Dosing will be 100 mg daily for three months, against primary outcomes of adverse events, and plasma and CSF biomarkers of oxidative stress. Other outcomes include pharmacokinetics, plasma biomarkers of AD pathology and neurodegeneration, and urine oxidative stress markers, as well as cognition, and function. The trial is running at five sites in the Netherlands and Croatia, with completion expected in June 2024. The design is published (Oosthoek et al., 2023).
For TW001/FNP122 trials, see clinicaltrials.gov
Last Updated: 02 Jan 2024
Further Reading
No Available Further Reading
Overview
Name: Benfotiamine
Synonyms: S-benzoylthiamine-O-monophosphate, Vitamin B1, Thiamine
Therapy Type: Supplement, Dietary (timeline)
Target Type: Inflammation (timeline), Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Background
Benfotiamine is a synthetic, fat-soluble precursor of Vitamin B1 with high bioavailability. Taken orally, benfotiamine produces supra-physiological blood levels of the active coenzyme form of thiamine. This supplement is available by prescription in some countries, and over the counter in the U.S. and other places. It is used to treat diabetic neuropathy at doses of 150-300 mg per day.
Thiamine-dependent enzymes function in glucose metabolism. Thiamine deficiency, and reduced activity of thiamine-dependent enzymes in the brain, have been documented in Alzheimer's disease patients (e.g. Gibson et al., 1998). This deficiency has been related to changes in brain glucose metabolism and cognitive function (Sang et al., 2018). Earlier trials of high-dose conventional thiamine demonstrated little or no benefit on cognition (e.g. Meador et al., 1993). A pilot trial of benfotiamine in five people with Alzheimer’s reported an increase of 3.2 points on the MMSE after 18 months of 300 mg daily, but it lacked a placebo group for comparison (Pan et al., 2016).
Preclinical work from two different groups showed that increasing thiamine to very high levels using benfotiamine supplementation diminished pathology, was neuroprotective, and improved behavior deficits in mouse models of amyloidosis and tauopathy (Pan et al., 2010; Tapias et al., 2018). In toxin-induced parkinsonism models, benfotiamine was neuroprotective and improved behavior and movement (Wang et al., 2024; Bashir et al., 2024). Benfotiamine and related thiamine prodrugs have antiinflammatory and antioxidant actions, which have been suggested to be independent of their function as coenzymes (reviewed in Bettendorff 2023).
Amyotrophic lateral sclerosis patients have impaired thiamine metabolism, and one patient reported greater muscle strength and energy after benfotiamine and Vitamin B12 treatment (Mann, 2023).
Findings
From February 2015 to July 2020, a Phase 2 pilot study in New York tested the ability of benfotiamine to improve cognition in people with mild cognitive impairment or mild AD dementia. Seventy-one participants with PET-confirmed brain amyloid took 600 mg benfotiamine or placebo daily for one year, against a primary outcome of change from baseline in the ADAS-Cog. Secondary outcomes were change in brain glucose metabolism in the posterior cingulate by FDG-PET, as well ADCS-Activities of Daily Living, Neuropsychiatric Inventory, Clinical Dementia Rating, and Buschke Selective Reminding test. According to published results, the trial missed its primary endpoint. The benfotiamine group had a 43 percent slowing in decline on the ADAS-Cog, which fell short of statistical significance. Decline on the CDR was significantly delayed by 77 percent; no differences were noted in other secondary outcomes (Gibson et al., 2020, reviewed in Gibson et al., 2022). An exploratory analysis suggested improvement in brain glucose utilization on FDG-PET, with a better response in ApoE4 noncarriers than carriers. Benfotiamine increased blood thiamine levels 161-fold and significantly decreased the levels of abnormally glycated fats and proteins in blood, indicating normalization of glucose metabolism. No treatment-related adverse events were reported. A separate serum metabolomic and lipidomic profiling analysis was published (Bhawal et al., 2021).
A poster presentation at the 2022 CTAD conference in San Diego reported on a trial in China that compared one year of 300 or 600 mg benfotiamine to placebo, as an add-on to donepezil in 302 clinically diagnosed AD patients. The study found no significant change in the primary outcome of ADAS-Cog in the group as a whole (Pan et al., 2022, CTAD poster). The authors did report a dose-dependent slowing of decline on ADAS-Cog in the subgroup of people with moderate AD (MMSE between 11 and 19), but not in those with mild AD (MMSE 20-24). Adverse events were similar between treatment and placebo. This group had previously published Phase 1 results, where benfotiamine had similar safety findings at these doses (Sheng et al., 2021).
In March 2024, the New York investigators began a follow-on Phase 2 trial to test 18 months of benfotiamine in 406 people with mild AD (Feldman et al. 2024). The adaptive design will initially compare safety of 600 or 1,200 mg to placebo, then randomize participants to the highest safe dose or placebo. The primary outcome will be within-person change from baseline in ADAS-cog and CDR-SB. Secondary outcomes include other measures of cognition, pharmacokinetics, safety and tolerability. Exploratory endpoints span MRI, plasma biomarkers of amyloid, tau and neurodegeneration, and age-related glycation end products. This multicenter study, coordinated by the ADCS in San Diego, is supported by National Institute on Aging (press release), and is planned to run at 24 locations in the U.S. until December 2027.
For details on benfotiamine trials, see clinicaltrials.gov.
Last Updated: 28 Jan 2025
Further Reading
No Available Further Reading
Overview
Name: MK-1942
Therapy Type: Small Molecule (timeline)
Target Type: Unknown
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: Merck
Background
Little is known about MK-1942, a small-molecule drug Merck began to develop for treatment-resistant depression in 2021. At that time, Merck partnered with Novamind, a company focusing on clinical applications of psychedelic compounds such as those derived from psilocybin mushrooms or LSD. This prompted media speculation that MK-1942 is a related therapy (e.g., see March 2021 Psychedlic Spotlight news and April 2021 TS news). As of February 2023, Merck had not disclosed the target of this drug.
Findings
In May 2022, Merck completed a Phase 1 drug interaction study to determine the safety of combining MK-1942 with donepezil in people with Alzheimer’s disease. Participants included 27 patients with mild to moderate dementia who were on a stable dose of donepezil. They were treated with escalating doses of MK-1942 from 8 mg twice daily for seven days, increasing to 15, 30, and up to 50 mg in seven-day increments, or placebo, in combination with donepezil up to 15 mg daily. The outcomes were the number of people with adverse events or abnormal clinical results, and pharmacokinetics.
In December 2022, the company began a Phase 2 efficacy and safety study of MK-1942 as an add-on to acetylcholinesterase inhibitor therapy in 408 people with mild to moderate Alzheimer’s dementia. Treatment was to be 12 weeks of either 5 or 15 mg twice daily, or placebo. Primary outcome is ADAS-Cog 11, plus adverse events and discontinuations. Secondary outcomes include the ADCS-CGIC and ADCS-ADL. The study ran at 20 sites in the U.S., Canada, Japan, and Korea; completion was anticipated in May 2026.
A Phase 2 trial for treatment-resistant depression, involving 140 patients at 40 locations in the U.S., was slated to finish in August 2024.
In September 2023, Merck terminated both Phase 2 trials and discontinued this program, due to potential liver toxicity (Oct 2023 Clinical Trials Arena news).
For details on MK1942 trials, see clinicaltrials.gov.
Last Updated: 19 Dec 2023
Further Reading
No Available Further Reading
Overview
Name: IBC-Ab002
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Amyloid-Related (timeline), Inflammation (timeline), Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: ImmunoBrain Checkpoint
Background
This humanized IgG1 antibody inhibits an immune checkpoint protein called programmed death ligand, aka PD-L1, stimulating the immune system. Checkpoint inhibitors, including other antibodies, are approved to treat cancer, where they release tumor-induced immunosuppression and allow immune attack on malignant cells.
The rationale for using PD-L1/PD-1 inhibitors to treat Alzheimer’s disease stems from research stimulating the peripheral immune system to recruit regulatory T cells and monocytes to the brain to improve amyloid clearance and quell inflammation (Baruch et al., 2015). Subsequent work showed that an antibody similar to the FDA-approved, anti-PD1 immunotherapy Keytruda increased infiltration of phagocytic monocytes in the 5xFAD mouse model, leading to reduced plaque load and better performance in the water maze (Baruch et al., 2016). The antibody reportedly had similar effects in the DM-HTau mouse model of tauopathy, though these findings were not corroborated (see news and commentary on Rosenweig et al., 2019; Latta-Mahieu et al., 2017; Obst et al., 2018).
In 2017, the Danish company Lundbeck announced it had acquired the rights to ImmunoBrain Checkpoint's program (press release).
According to company disclosures, IBC-Ab002 differs from other PD-L1/PD-1 antibodies in that it has a modified Fc effector region and is more rapidly cleared from the blood. Both modifications are designed to enhance safety, as checkpoint inhibitors can cause autoimmune side effects. At the 2020 AAIC, the company reported less induction of autoimmune diabetes in susceptible mice than the unmodified antibody. In preclinical efficacy studies, a single antibody dose improved cognitive performance one month later in 5xFAD, DM-HTau (K257T/P301S), and PS19 (p301S Tau) mice. Repeatedly dosed DM-HTau mice maintained improvements in T maze behavior for at least five months (see AAIC poster). In a poster at the 2023 AAIC, the company reported that the faster clearance of the modified antibody increased its safety in mice (Abstract).
Findings
In February 2023, IBC began a Phase 1, first-in-human study to evaluate the safety, tolerability, pharmacokinetics, and immunogenicity of intravenous IBC-Ab002. The single and multiple ascending dose study plans to enroll 40 people with Alzheimer's disease into five dose groups, with placebo controls. Funded by the U.S. National Institute On Aging and the Alzheimer’s Association, the trial is running at 10 sites in Israel, the Netherlands, and the United Kingdom, with completion set for late 2025.
For details on IBC-Ab002 trials, see clinicaltrials.gov.
Last Updated: 02 Jan 2025
Further Reading
No Available Further Reading
Overview
Name: PRX012
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: Prothena
Background
PRX012 is a humanized monoclonal IgG1 antibody to an N-terminal epitope on Aβ. The company reports a 70 picomolar affinity for Aβ fibrils, or about 10-fold greater binding avidity than aducanumab. The antibody is given by subcutaneous injection.
According to preclinical data presented at conferences, PRX012 binds plaque in mouse and human brain tissue preparations, and mediates microglial phagocytosis of Aβ1-42 fibrils from these tissues. It reportedly blocks binding of soluble Aβ oligomers to rat neurons (CTAD 2020 poster).
The antibody does not bind to synthetic pyroglutamate-modified Aβ42, yet it still promoted microglial clearance of this form from plaques in brain tissue (Aug 2021 conference news; AAIC 2021 poster; Tam et al., 2021).
At the April 2023 AD/PD conference in Gothenburg, additional preclinical data showed PRX012 bound Aβ protofibrils with 20-fold higher affinity than lecanemab, and cleared pyroglutamate-modified Aβ42 from brain tissue with three to eight times the potency of donanemab (April 2023 conference news; slides).
Findings
No trials are registered but, according to company information, PRX012 began a single-ascending-dose Phase 1 study in March 2022 (press release). Approximately 50 healthy controls and AD patients will receive a single subcutaneous injection at up to six dose levels, to determine safety, tolerability, immunogenicity, and pharmacokinetics. In April 2023, the company announced it was partnering with a U.S. national drug store chain to accelerate enrollment in an ongoing multiple-ascending-dose study (press release). In January 2024, the company claimed that amyloid reduction was seen following six months of treatment with 70 mg PRX012, with ARIA-E frequency similar to placebo (press release). Doses of up to 400 mg injected once a month are being tested. Top-line data is expected in 2024.
In April 2022, PRX012 received Fast Track designation from the U.S. FDA (press release).
Last Updated: 07 Feb 2024
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