Overview
Name: CHF 5074
Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline), Inflammation (timeline), Other (timeline)
Condition(s): Mild Cognitive Impairment, Alzheimer's Disease
U.S. FDA Status: Mild Cognitive Impairment (Phase 2), Alzheimer's Disease (Inactive)
Company: CereSpir™ Incorporated, Chiesi Pharmaceuticals Inc.
Background
This compound was initially reported as a γ-secretase modulator but is now portrayed as acting on multiple targets, particularly microglia. Long-term use of NSAIDs confers some protection against incident Alzheimer’s, and a widely noted finding that certain NSAIDs lower Aβ42 production independent of their action on the Cox enzymes prompted widespread research into NSAID derivatives of similar function (see Weggen et al., 2001). From 2007–2011, CHF5074 was being reported as a γ-secretase modulator that affected Aβ- and other amyloid-related outcomes. Subsequent preclinical studies proposed other mechanisms of action, such as restoring neurogenesis, reorganizing the astrocytic cytoskeleton, reducing tau, rescuing synaptic plasticity, or acting on microglia to counteract inflammation (see Nov 2012 conference story; Sivilia et al., 2013).
Findings
Phase 1 clinical trials consisted of three studies in 144 healthy young men to establish pharmacology and initial safety data. CH 5074 was reported to be safe and tolerable in these subjects; one notable side effect was mild diarrhea.
In 2011, a first multicenter Phase 2 trial compared doses of 200, 400, and 600 mg/day, primarily to determine the maximum tolerated dose at 12 weeks. Participants were 96 patients with amnestic or nonamnestic mild cognitive impairment (MCI); no amyloid or tau biomarkers were used for inclusion. CH 5074 pharmacology was similar to Phase 1; some patients withdrew due to diarrhea. An anti-inflammatory benefit measured as reduction in CSF CD40 and TNF-α concentration, as well as a trend toward improved executive function, were reported for carriers of the ApoE4 risk allele but not noncarriers (see Ross et al., 2013).
This trial went into a 24-week extension study to determine longer-term tolerability, and 51 participants then enrolled into a second extension. Clinicaltrials.gov reports this second extension will continue to 48 weeks, a CereSpir™ media release claims 90 weeks. CereSpir™ was founded to complete the clinical development of CHF 5074 and market it.
A second, two-year Phase 2 trial was to have started in 2012 to compare two undisclosed doses of CH 5074 and placebo for their effect on brain volume and other outcomes in a population of people with amnestic MCI who were genetically enriched for AD risk by being ApoE4 carriers. This trial was withdrawn from clinicaltrials.gov prior to enrollment, reportedly to be placed on hold to await the outcome of licensing negotiations (see Nov 2012 news story, Aug 2013 conference story).
Clinical Trial Timeline
- Phase 2
- Study completed / Planned end date
- Planned end date unavailable
- Study aborted
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| Chiesi Pharmaceuticals Inc. |
NCT01421056 |
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| Chiesi Pharmaceuticals Inc. |
NCT01602393 |
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Last Updated: 13 Nov 2013
Further Reading
No Available Further Reading
Overview
Name: Epigallocatechin Gallate (EGCG)
Synonyms: Sunphenon EGCg
Therapy Type: Supplement, Dietary (timeline)
Target Type: Amyloid-Related (timeline), Inflammation (timeline), Other (timeline)
Condition(s): Alzheimer's Disease, Down's Syndrome, Multiple System Atrophy
U.S. FDA Status: Alzheimer's Disease (Phase 2/3), Down's Syndrome (Phase 2), Multiple System Atrophy (Phase 3)
Company: Taiyo International
Background
EGCG is a polyphenolic flavonoid extracted from green tea leaves and widely considered to be the key bioactive ingredient of green tea. It has been reported to have beneficial effects ranging from antitumor and anti-inflammatory to neuroprotective. EGCG has been reported to affect multiple biological pathways, such as gene expression, growth-factor-mediated signaling, mitogen-activated-protein kinase-dependent pathways, antioxidant pathways, and ubiquitin/proteasome degradation. Specifically in neurodegeneration research, EGCG has been proposed to inhibit the formation of toxic oligomers by steering misfolded Aβ, α-synuclein, and mutant huntingtin away from folding pathways that lead to amyloidogenic β-sheet structures, either by binding the protein directly or possibly by acting on a protein chaperone (May 2008 news). EGCG has also been proposed to increase α-secretase cleavage of the amyloid precursor protein, and to improve the cognitive, synaptic, inflammatory, and metabolic phenotypes of multiple different strains of APP/PS1 transgenic mouse model (Obregon et al., 2006; Bao et al., 2020; Ettcheto et al., 2020).
EGCG's effects are consistently reported in vitro. In vivo, however, EGCG is unstable. Its bioavailability in target tissues has been questioned, and efforts to develop synthetic analogs with stronger pharmacological drug properties are underway (Mereles and Hunstein, 2011; Landis-Piwowar et al., 2013).
Findings
More than 60 trials on various EGCG extracts and formulations have been conducted or are ongoing, the majority on various types of cancer.
In Alzheimer's disease, one Phase 2/3 study conducted at Charite University in Berlin compared 18 months of treatment with EGCG to placebo in one group of patients who also took donepezil and another group who did not. The trial enrolled 21 early stage patients and measured change on the ADAS-cog battery as the primary outcome. The trial started in October 2009 and was completed in February 2015. No results have been published.
In 2012, a Phase 2 trial began at the Parc de Salut Mar Hospital in Barcelona. It assessed the effect of 12 months of treatment with EGCG on various cognitive outcomes and plasma Aβ biomarkers in 84 people with Down's syndrome, age 14 to 29, to assess whether EGCG slows the development of AD-like symptoms and biomarkers in Down's. Secondary outcomes include further cognitive and brain imaging tests, among others. Participants who received ECGC and cognitive training did significantly better on tests of memory, executive function, and attention than those who did cognitive training only. Amyloid biomarkers were not reported due to technical problems with measurement (de la Torre et al., 2012; de la Torre et al., 2016).
In January 2014, a Phase 3 trial ramped up at Ludwig Maximilians Universität and Technische Universität, both in Munich, to evaluate EGCG in multiple-system atrophy. MSA is a rapidly progressing Parkinsonian disease that responds poorly to dopaminergic therapy and for which there is no effective therapy. In this trial, 92 patients with clinically possible or probable MSA took high-dose EGCG (1.2 g per day, equivalent to 50 cups of green tea) for one year and were compared with patients on placebo on the Unified MSA Rating Scale (UMSARS-ME) and other clinical and neuroimaging outcomes (Levin et al., 2016). According to results presented at the April 2020 AAT-AD/PD conference, the treatment had no effect on the primary readout, and led to liver damage in some participants.
In October 2019, investigators in Barcelona, Spain, began a trial to test the ability of a one-year multimodal intervention including ECGC to prevent cognitive decline in ApoE4 carriers with subjective cognitive impairment. The study will enroll 200 participants in four arms, who will receive ECGC or placebo along with a program of social activities, cognitive training, and personalized diet and exercise, or ECGC or placebo with lifestyle recommendations only. The maximum ECGC dose will be 520 mg per day. The primary outcome is a Preclinical Alzheimer’s Cognitive Composite-like battery. Secondary outcomes are brain connectivity measured by functional MRI; exploratory endpoints include changes in microbiota, plasma, saliva and urine metabolomics, additional cognitive markers, and AD-related biomarkers of Aβ and tau. Treatment is scheduled to run through December 2020.
EGCG has also been evaluated in multiple sclerosis, Huntington's disease, and Fragile X, as well as in many non-neurological conditions. For all clinical trials of EGCG, see clinicaltrials.gov.
Last Updated: 30 Apr 2020
Further Reading
No Available Further Reading
Overview
Name: Avagacestat
Synonyms: BMS-708163
Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: Bristol-Myers Squibb
Background
This arylsulfonamide γ-secretase inhibitor was reported to selectively block processing of the enzyme's APP substrate, relatively sparing Notch processing. Notch is a transmembrane receptor whose signaling is important for cell-fate decisions in the intestine and in lymphocyte maturation. In preclinical models, Notch acts as a tumor suppressor in the skin. Notch inhibition is thought to have caused side effects that forced the termination of the previous clinical compound semagacestat; consequently, subsequent drug-development programs have aimed to achieve a greater separation between APP and Notch inhibition.
This drug has been reported to have 137-fold selectivity for APP over Notch in cell culture, and to robustly reduce CSF Aβ levels without causing Notch-related toxicity in rats and dogs. Other research has challenged the selectivity of this compound (Albright et al., 2013; Crump et al., 2012). Preclinical toxicology studies reported effects on fertility, fetal development, and other side effects in rats and dogs, that are consistent with inhibition of Notch processing (Sivaraman and Sanderson, 2023; Simutis et al., 2018).
Findings
About a dozen Phase 1 trials evaluated avagacestat's safety and pharmacology in healthy volunteers and people with Alzheimer's disease. In particular, drug interaction studies were conducted with cholinesterase inhibitors, blood thinners, and a range of other drugs commonly used in aging populations, including skin anti-infectives.
In 2009, two Phase 2 trials were started, of which one was completed, and the other was terminated. The first trial was a multinational, six-month, dose-ranging study comparing 25, 50, 100, and 125 mg/day to placebo in 209 people with mild to moderate Alzheimer's disease. The two lower doses led to similar discontinuation rates as placebo, the two higher doses to more discontinuations than placebo. Most patients dropped out due to gastrointestinal and dermatological side effects such as diarrhea, nausea, vomiting, rash, and itching skin; nonmelanoma skin cancers were also seen. The trial generated dose-dependent pharmacodynamic effects on CSF biomarkers in some patients, but at the two higher doses cognition trended toward a worsening compared with placebo (see Coric et al., 2012). This trial was further notable for raising awareness that amyloid-related imaging abnormalities (ARIA) can occur not only with immunotherapy but also with γ-secretase inhibition (see Jul 2011 news).
In this study, patients started out on 125 mg/day of study drug but were switched to 50 mg/day when high-dose intolerability in the dose-ranging study became apparent. Participants were assessed for brain imaging and fluid biomarkers, as well as cognition. An interim analysis conducted when the trial had enrolled 263 participants showed similar results as the prior trial in mild to moderate AD. In the prodromal population, too, avagacestat increased the rate of nonmelanoma skin cancers such as squamous- and basal-cell carcinoma. Diarrhea, nausea, vomiting, and rash were more common in the treatment group. These side effects were attributed to the study drug. On efficacy, patients on avagacestat progressed to dementia at similar rates as patients on placebo. CSF analysis showed a small reduction in amyloid with treatment; volumetric MRI results showed slightly more atrophy with treatment, i.e., modest evidence of target engagement. Results were published after peer review (Coric et al., 2015).
In November 2012, Bristol-Myers Squibb terminated this trial and announced its decision to end further development of avagacestat (see company news release). Experts in the field consider the benefit of this study to be that it validated a new trial design for prodomal AD (see Dec 2012 news story) and that Phase 2 signals were read correctly, avoiding a costly Phase 3 failure.
Clinical Trial Timeline
- Phase 2
- Study completed / Planned end date
- Planned end date unavailable
- Study aborted
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| Bristol-Myers Squibb |
NCT00890890 |
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Last Updated: 10 May 2023
Further Reading
No Available Further Reading
Overview
Name: Bexarotene
Synonyms: Targretin®
Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline), Unknown
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Ligand Pharmaceuticals, Inc., ReXceptor Inc.
Approved for: Cutaneous T-cell Lymphoma in US
Background
This retinoid drug is approved by the FDA and EMA to treat T cell lymphoma of the skin. It is an agonist of a nuclear transcription factor called retinoid X receptor, which forms heterodimers with peroxisome proliferator-activated receptor γ (PPARγ) or liver X receptors (LXRs) to aid in the formation of ApoE lipoprotein particles. In 2012, bexarotene was reported to rapidly increase brain ApoE concentration, reduce interstitial fluid Aβ levels and amyloid deposition, and reverse cognitive deficits in APP/PS1 mouse models (Feb 2012 news). Subsequent studies, using the same or different rodent models and outcome measures, replicated only portions of the original findings (May 2013 news; Laclair et al., 2013; O'Hare et al., 2016). Other preclinical studies have implicated bexarotene in ApoE lipidation, reported ApoE isoform-specific effects, or postulated that bexarotene dampens network hyperexcitability (May 2014 news; Sep 2014 news; Bomben et al., 2014).
Findings
In 2014, a Phase 2 biomarker proof-of-concept study at the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas evaluated the effect of a one-month blinded course of 300 mg bexarotene per day, followed by another month of open-label treatment. The primary outcome was brain amyloid load in 20 patients with probable Alzheimer's disease. Results published in January 2016 indicated no reduction in overall or regional amyloid burden in the group as a whole. A prespecified subgroup analysis by ApoE genotype found no amyloid reduction in ApoE4 carriers, but in ApoE4 noncarriers it did find regional amyloid reductions. These correlated with elevated serum Aβ42. Bexarotene-treated patients had significantly elevated blood lipid levels, a risk factor for stroke and heart attack (Cummings et al., 2016).
Also in 2014, a Phase 1 proof-of-mechanism pilot study conducted by ReXceptor Inc. and C2N in Orlando, Florida, began. It measures generation and clearance of newly generated CSF Aβ and ApoE in response to a five-day course of 450 mg bexarotene per day. This study enrolled 12 young healthy adults who are homozygote ApoE3 carriers. It found that bexarotene poorly entered the central nervous system. The plasma to CSF ratio was 85:1, with bexarotene below the limit of quantitation in most CSF samples. CSF ApoE increased by one-quarter, but Aβ peptides did not change (Ghosal et al., 2016).
For all bexarotene Alzheimer trials, see clinicaltrials.gov.
Last Updated: 16 Aug 2019
Further Reading
No Available Further Reading
Overview
Name: Continuous Positive Airway Pressure
Synonyms: CPAP
Therapy Type: Procedural Intervention
Target Type: Unknown
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 3)
Approved for: Sleep Apnea in US
Background
Continuous Positive Airway Pressure (CPAP) is an approved treatment using a machine and nasal mask to deliver continuous air flow and help keep the airways open during sleep. Sleep-disordered breathing and obstructive sleep apnea cause sleep fragmentation and nighttime hypoxia. People with Alzheimer’s have high rates of insomnia and other sleep disorders (e.g., Cooke et al., 2006). Beyond making them sleepy during the day, these sleep disorders are thought to worsen their cognitive impairment. Sleep-disordered breathing has been linked to cerebrospinal fluid and brain-imaging biomarker changes that predict Alzheimer's dementia, raising the question of whether hypoxia-inducing sleep disorders are a contributor to or a consequence of AD pathogenesis (Osorio et al., 2014; Osorio et al., 2014; Daulatzai 2013). In general, human and animal model research is implicating sleep more broadly in the pathogenesis of Alzheimer's disease (e.g., May 2014 conference story; Aug 2012 conference story).
CPAP is standard treatment for sleep-disordered breathing and sleep apnea. The rationale of testing CPAP at various stages of Alzheimer’s disease is twofold: to test whether continuous brain oxygenation during sleep delays the deterioration of memory and other existing symptoms of Alzheimer’s and related dementias, and to see whether improving brain oxygenation during sleep might even have a mechanistic effect on the underlying neurodegeneration.
Findings
In the early 2000s, a controlled, randomized trial at the University of California, San Diego, tested a three- and a six-week course of CPAP in 52 people with mild to moderate Alzheimer’s and obstructive sleep apnea. The primary outcomes were sleep quality and daytime sleepiness as reported by patient and caregiver, and cognitive function. Published results from this trial indicated improvements in certain aspects of cognition, but were underpowered to make definitive statements. This study contacted participants a year later and compared five patients who continued to use CPAP to five others who did not. The report on this follow-up indicated a larger cognitive improvement for continued CPAP users but clearly noted insufficient power and other limitations (Chong et al., 2006; Ancoli-Israel, 2008; Cooke et al., 2009; Richards 2009). These papers sparked interest in further clinical exploration of CPAP to address sleep quality as a potentially treatable factor in cognitive impairment in AD.
In 2010, a single-center trial in Saint-Etienne, France, started evaluating a four-month course of CPAP in 100 people with mild to moderate Alzheimer's. This trial measures the effect of nightly CPAP on cognition using Behavioral Assessment of Dysexecutive Syndrome (BADS) zoo map scores; its secondary measures are rate of sleep apnea, neuropsychological tests, and a quality-of-life questionnaire. The study is set to be completed in spring 2015.
In 2012, a trial at three sites evaluated a six-month course of CPAP in 110 people with mild cognitive impairment. Primary outcome measures include several memory-test and other cognitive assessments. Secondary outcome measures include eight additional cognitive, clinical, and functional measures widely used in Alzheimer's trials, as well as three neuroimaging measures. This trial was to conclude in 2014 but results have not been announced.
In July 2013, a small, open-label prevention trial started up at New York University. It will enroll an estimated 45 cognitively normal people aged 50 and older who have sleep-disordered breathing. Some will be offered a six-month course of CPAP; those who decline CPAP or do not comply with the CPAP regimen will be considered controls. The trial's primary outcome measures are CSF tau and Aβ42 levels, as well as two MRI measures, hippocampal volume, and cerebral vasoreactivity to CO2 challenge. The trial has an interventional component that measures these outcomes, as well as some memory functions, again after six months of CPAP treatment, and an observational component that revisits these measures at a two-year longitudinal followup. This trial is set to run until July 2017.
For all clinical trials of CPAP in Alzheimer's, see clinicaltrials.gov.
Last Updated: 25 Sep 2023
Further Reading
No Available Further Reading
Overview
Name: Dexpramipexole
Synonyms: R-pramipexole, RPPX, KNS-760704 , BIIB 050
Chemical Name: (R)-2-Amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline), Other (timeline)
Condition(s): Alzheimer's Disease, Amyotrophic Lateral Sclerosis
U.S. FDA Status: Alzheimer's Disease (Phase 2), Amyotrophic Lateral Sclerosis (Discontinued)
Company: Biogen, Knopp Biosciences LLC, Virginia Commonwealth University
Background
Dexpramipexole is an (R)-(+) optical enantiomer of pramipexole, a marketed dopamine agonist by Boehringer Ingelheim that is used in many countries around the world for the treatment of Parkinson's disease and restless leg syndrome. R-pramipexole has a lower affinity for dopamine receptors than pramipexole, and thus it can be administered and studied at a wider dose range. The compound originated at Virginia Commonwealth University. Besides modulating dopamine receptors, it has been variously described to act as an antioxidant, apoptosis inhibitor, and free radical scavenger. R-pramipexole is thought to protect neurons through effects on microglia and to improve free radical-induced cognitive impairment following general anesthesia in rats (e.g. Abramova et al., 2002; Ferrari-Torinelli et al., 2010; Alavian et al., 2012; Boscolo et al., 2012). Preclinical studies reported dexpramipexole to be orally bioavailable and to reach high central nervous system concentrations relative to plasma, raising interest in this compound for the treatment of several different neurodegenerative diseases (Bozik et al., 2011).
Findings
Biogen Idec conducted four Phase 1 studies to assess safety, tolerability, pharmacokinetics, food effects, metabolism and drug-drug interactions of single and multiple doses of dexpramipexole in healthy volunteers in the United States and Japan. Single doses of 50, 150, or 300 mg, and multiple doses of 50, 100, or 150 mg twice daily over several days were found to be safe and well tolerated. Dexpramipexole was rapidly absorbed and eliminated in urine without generating toxic metabolites (e.g. NCT01449578, NCT01424176, NCT01597310, NCT01536249, NCT01424163, see also Bozik et al., 2011).
In 2009, the U.S. Food and Drug Administration granted fast-track designation to dexpramipexole for amyotrophic lateral sclerosis (ALS). Knopp Neurosciences conducted a Phase 2 trial of dexpramipexole in 102 ALS patients (see Rudnicki et al., 2010). Biogen Idec subsequently evaluated the compound in a multinational Phase 3 program for this indication; however, in January 2013 top-line results of the pivotal Phase 3 trial EMPOWER showed that it had missed the co-primary endpoint of function and survival, as well as key secondary endpoints and analyses in patient subpopulations. The trial had administered 150 mg of dexpramipexole twice daily for up to 18 months in 943 patients with ALS. Subsequently, Biogen Idec ended development of dexpramipexole (Cudcowicz et al., 2013).
In July 2011, an investigator-initiated Phase 2 trial at the University of Kansas began evaluating R-pramipexole in 20 patients with Alzheimer's disease. Sponsored by Virginia Commonwealth University and the Alzheimer’s Drug Discovery Foundation, this safety and efficacy trial aims to assess oxidative injury to cells in the blood and spinal fluid by measuring levels of isoprostane, a biomarker for oxidative stress, and by measuring brain glucose metabolism with FDG-PET before and after treatment. The trial admisters ascending doses of 100 to 300 mg/day for a total six months of treatment. The trial, NCT01388478, is set to run until 2014.
Clinical Trial Timeline
- Phase 2
- Study completed / Planned end date
- Planned end date unavailable
- Study aborted
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| Virginia Commonwealth University |
NCT01388478 |
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Last Updated: 12 Feb 2016
Further Reading
No Available Further Reading
Overview
Name: PF-05212377
Synonyms: PF-5212377, WYE-103760, SAM-760
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: Pfizer
Background
SAM-760 is an orally available antagonist of the serotonin 6 receptor (5-HT6). By modulating serotonin levels in the brain, 5-HT6 antagonists are thought to lead to secondary increases in the levels of the neurotransmitters acetylcholine and glutamate, benefitting learning and memory. Wyeth originally developed PF-5212377 as WYE-103760, also known as SAM-760, before becoming a subsidiary of Pfizer in 2009.
Findings
Between 2009 and 2014, Wyeth and then Pfizer conducted four Phase 1 trials of PF-05212377 in about 230 healthy volunteers. One trial, conducted in France, evaluated the effect of a single dose of PF-5212377 on scopolamine-induced cognitive impairments for its ability to improve performance in the Groton Maze Learning Task. Also in France, a multiple-ascending-dose study assessed safety, tolerability, and pharmacokinetics of once-daily dosing for 14 days, and a similar study evaluated ascending single doses of PF-5212377. A U.S. trial using positron emission tomography (PET) correlated plasma drug levels and 5-HT6 receptor binding in the brain following a single dose.
In November 2012, Pfizer initiated a Phase 2 study to assess the efficacy of a 30 mg capsule of PF 5212377, taken once daily, in mild to moderate Alzheimer's patients with neuropsychiatric symptoms who are on a stable dose of donepezil (NCT01712074). Change on the ADAS-cog 13 was the primary outcome measure, change on the NPI the secondary outcome. This trial was intended to enroll 342 patients from the United States, but stopped after 186. In October 2015, Pfizer terminated this study because a futility analysis indicated lack of efficacy; results were published in 2016 at AAIC (Fullerton et al., 2016).
In November 2013, Pfizer started a Phase 1 study in four healthy volunteers to determine 5-HT6 receptor occupancy levels achieved with single oral doses of 70 mg of PF-5212377 and less. News coverage of the trial's termination included claims of receptor occupancy needed to achieve efficacy (see Feb 2016 FierceBiotech story).
Clinical Trial Timeline
- Phase 2
- Study completed / Planned end date
- Planned end date unavailable
- Study aborted
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NCT01712074 |
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Last Updated: 02 Feb 2018
Further Reading
No Available Further Reading
Overview
Name: Carvedilol
Synonyms: Coreg, Artist , Aucardic, Dilatrend, Kredex
Chemical Name: 1-(Carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanol
Therapy Type: Small Molecule (timeline)
Target Type: Unknown
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 4)
Company: Procter & Gamble
Approved for: Hypertension, heart failure, angina pectoris
Background
Carvedilol phosphate is a non-selective α/β-adrenergic receptor antagonist and vasodilator. This drug has been available in the United States and many other countries since the mid-1990s. It is widely prescribed to treat high blood pressure and other cardiovascular problems, and is available as an extended-release capsule. Its side effects include slowness of movement, dizziness, fatigue, headache, and nausea.
The rationale for evaluating it in Alzheimer's disease grew out of several lines of research suggesting that neurovascular dysfunction contributes to age-related dementia, that antihypertensive treatment in incident Alzheimer's may slow further cognitive decline, and that carvedilol improves synaptic transmission and amyloid-related and cogntive outcomes in mouse models of Alzheimer's disease (Dunn and Nelson, 2014; Rosenberg et al., 2008; Wang et al., 2011). Meta-analysis of the epidemiological literature has shown hypertension in mid-life—but not in late life—to increase risk for dementia (see AlzRisk).
Findings
Carvedilol is being evaluated in an investigator-initiated study at the Alzheimer's Disease Research Center of Johns Hopkins University Medical Center. This six-month, 50-patient trial aims to determine whether daily treatment with 25 mg carvedilol—the half-maximum dose used in clinical practice—improves memory in Alzheimer's disease compared to placebo. The study enrolls people with mild AD, and measures episodic memory with the Hopkins Verbal Learning Test, as well as cerebrospinal fluid levels of Aβ oligomers. The trial is set to run through 2016. For details see clinicaltrials.gov.
Last Updated: 08 Sep 2023
Further Reading
No Available Further Reading
Overview
Name: LY2886721
Synonyms: BACE inhibitor
Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease, Mild Cognitive Impairment
U.S. FDA Status: Alzheimer's Disease (Discontinued), Mild Cognitive Impairment (Discontinued)
Company: Eli Lilly & Co.
Background
LY2886721 was the first BACE inhibitor to reach Phase 2 clinical research. Prior compounds by Lilly and many other pharmaceutical companies had lacked sufficient brain penetrance, exposure, or other key pharmacological characteristics. Inhibiting the β-secretase enzyme responsible for APP processing with a small molecule drug has been a goal in Alzheimer's drug development since the identification of BACE1 in 1999. The rationale is that this approach blocks the amyloid cascade at its inception, regardless of which species of the Aβ peptide is most toxic to the brain.
At research conferences, Lilly scientists reported that LY2886721 was selective for BACE, i.e., it did not inhibit other aspartyl proteases such as cathepsin D, pepsin, and renin, and reduced Aβ in a dose-dependent manner in HEK293Swe cells and in primary neurons from PDAPP transgenic mice. In mice, the compound’s half-life was short, but a 3–30 mg/kg dose lowered brain Aβ by 20–65 percent relative to vehicle-treated groups; the effect lasted up to nine hours after dosing. In beagles, the compound’s half-life was longer and a 0.5 mg/kg dose halved CSF Aβ in nine hours; plasma Aβ levels were reduced for 24 hours (see Jul 2012 conference story). No peer-reviewed research articles on this compound have been published thus far.
Findings
Lilly completed six Phase 1 studies of LY2886721’s safety, tolerability, and pharmacology in a total of 150 healthy volunteers and people with Alzheimer’s disease at doses of 1–70 mg. Single and multiple ascending oral dosing was accompanied by repeat CSF sampling in the hours and days thereafter. This was done to assess CSF penetration and target engagement by way of measuring levels of the drug, BACE1 substrate, and BACE1 cleavage products. The compound lowered CSF Aβ40, Aβ42, and sAPPβ concentrations while increasing sAPPα, consistent with expectations for BACE1 inhibition. Fourteen days of daily dosing reduced BACE1 activity by 50–75 percent, and CSF Aβ42 by 72 percent. No safety concerns were apparent in dosing up to six weeks (see Jul 2012 news story).
In March 2012, Lilly started an international Phase 2 study to compare the tolerability, efficacy, and pharmacodynamics of 15mg and 35mg doses of LY2886721 in 128 patients with MCI due to Alzheimer's disease (AD) or with mild AD and biomarker evidence of brain amyloid deposition. Patient selection was based on revised diagnostic criteria. The trial was to measure CSF Aβ40 and 42 levels at weeks 12 and 26. In June 2013, however, the company ended dosing in this trial after routine monitoring flagged four cases of abnormal liver biochemistry values. Patients continued to be monitored, but clinical development of LY2886721 was halted (see Lilly press release). Its toxicity was generally considered to be an off-target effect of the compound unrelated to BACE inhibition (see Jun 2013 news story).
This compound had been chosen based on Phase 1 and preclinical data to be evaluated in the first Dominantly Inherited Alzheimer's Network (DIAN) therapeutic trial (see Oct 2012 news story).For Lilly, this was the second BACE inhibitor to fail early in the clinic. A previous compound, LY2811376, had been discontinued in late Phase 1 when simultaneous rat toxicology studies showed damage to the pigment epithelium of the eye (see Jul 2013 conference story).
Last Updated: 11 Nov 2014
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Overview
Name: NeuroAD
Synonyms: Repetitive Transcranial Magnetic Stimulation , rTMS-Cog
Therapy Type: Procedural Intervention
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Rejected)
Company: Neuronix Ltd
Background
NeuroADTM rTMS is a non-invasive neuromodulation system. It combines brief trains of 10 Hz electric pulses to brain regions affected in AD, i.e., frontal, temporal, and parietal regions, alternating with sessions of computerized cognitive training designed to engage those same regions. Pulses are delivered by a figure-eight-shaped magnetic coil placed outside the head, near the scalp. Six brain regions are stimulated separately. A course of treatment consists of two or more weeks of daily sessions.
High frequency TMS (10 Hz or greater) increases cortical excitability, induces LTP-like changes in synaptic strength, and increases brain-derived neurotrophic factor levels. The end effects vary based on the frequency and intensity of the pulses, and the brain areas targeted.
NeuroAD is one of several rTMS protocols that have been evaluated for Alzheimer’s disease. Multiple meta-analyses indicate that, overall, this form of neuromodulation can improve cognitive function in people with mild to moderate AD, although trials have not shown a consistent benefit from concurrent cognitive training (e.g., see Menardi et al., 2022; Wang et al., 2020 ; Lin et al., 2019). One study suggests that rTMS is less effective in ApoE4 carriers than noncarriers (Wei and Chen, 2021).
rTMS targeted to the left dorsolateral prefrontal cortex is approved for the treatment of refractory depression worldwide. In Europe, rTMS is approved for treatment of Alzheimer’s, Parkinson’s, and other conditions. rTMS is considered safe, with minor side effects including headache, scalp discomfort at the stimulation site, tingling, spasms or twitching of facial muscles, toothache, neck pain, and lightheadedness.
Findings
Early studies on the NeuroAD device claimed improvements in ADAS-Cog scores after six weeks of daily 10 Hz TMS stimulation of the right and left dorsolateral prefrontal cortex, the left frontal and left posterior temporal lobe, and the right and left parietal somatosensory association cortex, plus computerized cognitive training, but lacked a sham comparison group (e.g., see Bentwich et al., 2011). Additional open-label studies subsequently reported improvements in cognition and long-term positive effects on apathy, with high treatment completion rates and no safety issues (Rabey and Dobronevsky, 2016; Nguyen et al., 2017; Suarez Moreno et al., 2022).
Two placebo-controlled trials compared the active treatment with sham rTMS and sham cognitive training. The first, run in Israel from January 2010 to September 2011, involved 15 patients with early to moderate AD. The placebo consisted of a mock stimulation procedure using an inactive coil, and viewing a nature movie instead of cognitive training. Treatment was in one-hour sessions five days a week for six weeks, followed by three months of biweekly maintenance sessions. The study reported improvement in the primary outcome of ADAS-Cog by 3.76 points after six weeks compared to 0.47 on placebo; and a 3.52-point improvement after 4.5 months compared to a worsening in the placebo group (Rabey et al., 2012). The second trial, in 2013, used the same treatment and control paradigm in 28 patients in Korea; it likewise reported an improvement in the ADAS-Cog after six weeks in the treated compared to sham control group (Lee et al., 2016).
A study run from 2010 to 2015 incorporated an additional control group to test the effect of cognitive training alone. Thirty-four participants were divided into three groups: One received six weeks of 10 Hz stimulation and cognitive training, while the others received sham stimulation paired with real or sham cognitive training, against a primary outcome of ADAS-Cog one month after treatment. In this study, the stimulation/training group improved their ADAS-Cog scores compared to sham/sham, while the patients who got cognitive training alone did not (Brem et al., 2020).
In 2012, NeuroAD™ was approved in Europe to treat AD, and was distributed in Europe, Australia, and Israel.
Between October 2013 and January 2016, Neuronix conducted a pivotal trial for U.S. FDA approval. It enrolled 131 people with mild to moderate AD at 10 sites in the U.S. and Israel, comparing six weeks of NeuroAD to the sham treatment. The study failed to show any difference in the primary outcome of change in ADAS-Cog from baseline to week 7. In a posthoc analysis of only people with milder AD, those whose baseline ADAS-Cog score was below 30 had a significant improvement of 2.11 points with treatment, compared to 0.32 points in the sham group (see Apr 2017 conference news; Sabbagh et al., 2020).
A study planned to start in November 2014 enrolling 40 patients and comparing the same two groups was terminated after just one was enrolled, citing an administrative decision.
An application for marketing approval was rejected by the U.S. FDA in June 2018. The company filed an appeal and the FDA denied it again in March 2019, citing a lack of demonstrated benefit in clinical trials (Mar 2019 news). Neuronix closed in late 2019.
For details of these trials, see clinicaltrials.gov
Last Updated: 02 Mar 2023
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