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
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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
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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
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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
Further Reading
No Available Further Reading
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
Further Reading
No Available Further Reading
Overview
Name: Atomoxetine
Synonyms: ATX, Strattera
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 2), Parkinson's Disease (Phase 1)
Status in Select Countries: Approved in North America, European Union, and may other countries for treatment of Attention Deficit Hyperactivity Disorder (ADHD)
Company: Eli Lilly & Co.
Approved for: ADHD in US
Background
Atomoxetine is a norepinephrine uptake inhibitor. It blocks a norepinephrine transporter and boosts noradrenaline levels in the brain. It is one of the few non-stimulant drugs used to treat attention deficit hyperactivity disorder in children, and is prescribed widely around the world. Norepinephrine is mainly produced by neurons of the locus coeruleus, a midbrain region that shows neuropathology and degeneration early in both AD and Parkinson’s disease (e.g., Jacobs et al., 2021). This and other lines of research implicate loss of noradrenaline in Alzheimer's disease (see, e.g., Dec 2010 conference news), hence atomoxetine's value as an add-on medication was investigated.
In preclinical work using the 5XFAD mice, increasing brain noradrenaline using atomoxetine and the noradrenaline precursor L-DOPS suppressed glial activation and Aβ deposition, and improved performance in the Morris water maze (Kalinin et al., 2011).
Findings
Between 2003 and 2006, Eli Lilly conducted a six-month Phase 2/3 repurposing trial at eight sites in the United States to evaluate the effectiveness of 25-80 mg/day of atomoxetine in 92 patients with mild to moderate Alzheimer's disease who were on stable doses of standard acetyl cholinesterase inhibitor therapy. Cognition as measured by the ADAS-Cog was the primary outcome of this trial. Atomoxetine in these patients was reported to be generally safe, though with an increase in heart rate; however, it did not benefit cognition in these patients (Mohs et al., 2009).
From 2012 to 2018, a Phase 2, 12-month biomarker study at Emory University assessed atomoxetine in people with mild cognitive impairment. It enrolled 39 people who had to have CSF Aβ and tau levels indicative of AD, to receive placebo or flexible doses of atomoxetine starting at 10 mg per day and increasing weekly to 100 mg or a maximum tolerated dose. In a crossover design, participants took drug or placebo for six months each, followed by an optional two-year open-label extension. Blood and CSF biomarkers were assessed at baseline, six, and 12 months. The primary outcome was change in neuroinflammation measured by CSF IL1 and thymus-expressed chemokine concentrations. Other primaries were adverse events and drop-out rate. Results are published (Levey et al., 2021). Atomoxetine treatment led to increased plasma and CSF norepinephrine concentrations, demonstrating target engagement. IL-1α and thymus-expressed chemokine were undetectable in most samples. CSF tau and p-tau181 were reduced by 5-6 percent compared to placebo, Aβ42 was unchanged. FDG-PET and functional MRI measures found increased glucose uptake and inter-network connectivity in the hippocampus and temporal lobe circuits with treatment. The differences persisted for six months after treatment. The regimen was safe and tolerable, with all but two participants reaching the 100 mg dose. Common adverse events were gastrointestinal symptoms, dry mouth, and dizziness. Other side effects were consistent with atomoxetine’s established profile and included increased heart rate, weight loss, and a trend for higher blood pressure. A proteomics analysis noted normalization of CSF biomarkers related to synaptic function, brain metabolism, and inflammation. As expected, there were no significant effects on cognition and clinical outcomes.
Atomoxetine is also being tested as a cognitive enhancer in people with Parkinson’s disease. It gave mixed results in several small trials (see analysis in Ghosh et al., 2020). One study indicated that Parkinson’s patients with low locus coeruleus volumes respond to atomoxetine (O’Callaghan et al., 2021).
For details on atomoxetine trials, see clinicaltrials.gov.
Last Updated: 24 Jan 2022
Further Reading
No Available Further Reading
Overview
Name: HMTM
Synonyms: LMTM, LMTX, LMT-X, TRx0237, Tau aggregation inhibitor (TAI), Methylene Blue
Chemical Name: Hydromethylthionine mesylate, Leuco-methylthioninium bis(hydromethanesulfonate)
Therapy Type: Small Molecule (timeline)
Target Type: Tau (timeline)
Condition(s): Alzheimer's Disease, Frontotemporal Dementia
U.S. FDA Status: Alzheimer's Disease (Phase 3), Frontotemporal Dementia (Phase 3)
Company: TauRx Therapeutics Ltd
Approved for: Methylene Blue predates FDA. Used for treatment of malaria and methemoglobinemia.
Background
TRx0237 (LMTX™) is a second-generation tau protein aggregation inhibitor for the treatment of Alzheimer's disease (AD) and frontotemporal dementia. It is a replacement formulation for Rember®, the first company's first proprietary formulation of methylthioninium chloride (MTC). Both TRx0237 and Rember are derivatives of Methylene Blue, an old drug that predates the FDA and is being widely used in Africa for the treatment for malaria, as well as for methemoglobinemia and other conditions. TRx0237 and Rember share the same mode of action, but TRx0237 has been designed as a stabilized, reduced form of MTC to improve the drug's absorption, bioavailability, and tolerability.
The rationale behind this approach is that these compounds prevent tau aggregation or dissolve existing aggregates to interfere with downstream pathological consequences of aberrant tau in tauopathies including Alzheimer's and other neurodegenerative diseases. Tau pathology is widely considered to be downstream of Aβ pathology and is more closely linked to cognitive deficits in Alzheimer's disease. Mutations in the tau gene cause frontotemporal dementia, not Alzheimer's disease, but tau is considered a central drug target for all tauopathies, including Alzheimer's.
Prior to the first publicized Phase 2 trial on Rember TM in 2008, one peer-reviewed paper to support this rationale had been published, which reported that Methylene Blue interfered with the tau-tau binding necessary for aggregation (Wischik et al., 1996). In 2015, the same lab published on LMTX®, claiming a Ki of 0.12 micromolar for inhibition of intracellular tau aggregation, and a similar potency for disrupting tau aggregates isolated from AD brain (Harrington et al., 2015).
Numerous independent academic investigations of the commercially available parent compound, Methylene Blue, have reported potentially beneficial effects on a growing list of cellular and system-level endpoints, including tau fibrillization in vitro (Crowe et al., 2013), autophagy (e.g. Congdon et al., 2012), neuroprotection via mitochondrial antioxidant properties (e.g. Wen et al., 2011), as well as on Aβ clearance and proteasome function in transgenic AD mouse models (Medina et al., 2011), and spatial learning and brain metabolism in rats (Deiana et al., 2009; Riha et al., 2011). One mechanistic study found that Methylene Blue oxidizes cysteine sulfhydryl groups on tau in a way that keeps tau in the monomeric state (Feb 2013 news). Subsequently, TRx0237’s developers reported that the inhibition of tau aggregation is cysteine-independent (Al-Hilaly et al., 2018).
In preclinical work, LMTX was reported to improve learning and reduced brain tau load in two strains of tau transgenic mice (Melis et al., 2015). The compound increased cholinergic signaling, mitochondrial function, and expression of synaptic proteins and neuroprotection in mice (Kondak et al., 2023; Schwab et al., 2024; Zadrozny et al., 2024). These effects, but not tau aggregation, were blocked by chronic pretreatment with an acetylcholinesterase inhibitor or memantine (Riedel et al., 2020; Kondak et al., 2022; Santos et al., 2022). Proteomic analysis of tau mice suggested LMTX acts via tau-dependent and -independent actions (Schwab et al., 2021). These studies all originate from one lab. An independent group reported that neither Methylene Blue not LMTM protected cells in a high throughput screen for tau-mediated toxicity (Lim et al. 2023).
Some studies reported a generalized anti-aggregation effect for Methylene Blue against aggregation-prone proteins, such as prion protein and TDP-43 (e.g. Cavaliere et al., 2013; Arai et al., 2010). Other papers report no inhibition of tau- and polyglutamine-mediated neurotoxicity in vivo (see van Bebber et al., 2010). In mice overexpressing human α-synuclein, LMTM treatment reduced α-synuclein inclusions in the brain, and normalized movement and anxiety-related behaviors (Schwab et al., 2017). It did not alter glutamate release or related behaviors in these mice (Schwab et al., 2022).
According to a case report, an asymptomatic carrier of the P301S MAPT mutation remained cognitively stable and cerebral atrophy progressed more slowly than expected after 5 years on LMTM treatment during the expected time of onset of frontotemporal dementia symptoms (Bentham et al., 2021).
Findings
No information on Phase 1 trials of TRx0237 is available. A four-week Phase 2 safety study of 250 mg/day of TRx0237 in patients with mild to moderate Alzheimer's disease began in September 2012 but was terminated in April 2013, reportedly for administrative reasons.
In November 2012, TauRx started a Phase 3 study comparing 200 mg/day of LMTM to placebo in a planned 800 patients with a diagnosis of either all-cause dementia or Alzheimer's disease mild enough to score above an MMSE of 20. The trial ran at more than 90 sites in North America and Europe. As primary outcomes, it used standard cognitive (ADAS-Cog 11) and clinical (ADCS-CGIC) batteries, as well as temporal lobe brain metabolism as measured by FDG-PET and safety parameters. Results were presented—and disputed—at the 2016 CTAD meeting. Participants on LMTM declined on cognition (ADAS-Cog) and functional scales (ADCS ADL) as rapidly as did patients on placebo, which contained a low dose of active compound for coloring purposes (Dec 2016 conference news; Wilcock et al., 2018).
Another Phase 3 trial compared 150 and 250 mg/day of TRx0237 with placebo in 891 patients with mild to moderate Alzheimer's disease with an MMSE of 14 or higher. Started in 2013, this trial involved more than 80 sites in North America, Australia, Europe, and Asia. It used clinical (ADCS-CGIC), cognitive (ADAS-Cog 11), and safety measures as primary outcomes. Negative results from this trial were presented at the 2016 AAIC conference in Toronto and later published after peer review (Jul 2016 conference news; Gauthier et al., 2016).
A third Phase 3 trial evaluated TRx0237 in the behavioral variant of frontotemporal dementia, the most common form of this disease. Begun in August 2013, this trial targeted enrollment of 180 people with probable bvFTD who have frontotemporal atrophy confirmed by MRI and whose MMSE is above 20. The trial compared 200 mg/day to placebo for the drug's ability to show clinical benefit on activities of daily living as measured by the modified ADCS-CGIC Alzheimer's scale and the revised Addenbrooke's Cognitive Examination (ACE-R), a widely used psychometric tool in FTD clinical research. This trial was to be conducted at 45 sites in North America, Europe, Australia, and Singapore. At the 2016 ICFTD conference in Munich, this trial was reported to have missed its co-primary endpoints (Sep 2016 conference news; company press release). Results were published after peer review (Shiells et al., 2020).
These three Phase 3 trials used “active placebo” tablets that include 4 mg of TRx0237 as a urinary and fecal colorant to help maintain blinding; hence the "placebo" group received a total of 8 mg/day of TRx0237. TRx0237's predecessor compound, Rember TM, colors urine and feces, and the blinding of its Phase 2 trial has been questioned (see Oct 2012 news for details and Q&A with TRx0237's founding scientist, Claude Wischik). However, post-hoc pharmacokinetic analyses of the Phase 3 trials led the investigators to claim that even 8 mg daily TRx0237 was sufficient to induce changes in brain structure and function (e.g., see Schelter et al., 2019).
In January 2018, TauRx started a Phase 2/3 monotherapy trial aiming to enroll 180 people with all-cause dementia and Alzheimer's disease, at 55 sites in North America, Belgium, Poland, and the U.K. The trial compares a six-month course of 4 mg of LMTM—renamed to HMTM—twice daily. This is the daily dose of HMTM previously admixed to "active placebo'' in the prior Phase 3 trials. LMTM is compared to 4 mg Methylene Blue twice weekly. Acetylcholinesterase inhibitors or memantine are not allowed. Primary outcomes include 18F-FDG-PET imaging and safety; secondary outcomes include structural MRI, as well as measures of cognition and activities of daily living.
In September 2018, TauRx changed the trial protocol to add a third treatment arm of 8 mg HMTM twice daily. The trial increased enrollment to 375, and extended dosing to nine months. Eligibility criteria were changed to accept only people with mild cognitive impairment due to AD, a Global Clinical Dementia Rating of 0.5, and a positive amyloid PET scan. Primary outcomes were also changed, to include a composite measure of cognition and function comprising selected items from the ADAS-Cog and ADCS-ADL scales. The trial was enlarged to 147 sites in North America and Europe.
Recruitment ended in October 2019. In late 2019, the first of three listed primary outcomes was changed from 18F FDG PET to ADAS-Cog 11; the composite measure was changed to the ADSC-ADL23. The inclusion criteria were relaxed to once again include people with more advanced disease, from an earlier MMSE range of 20-27 to 16-27, from a CDR of 0.5 to now include CDR 0.5 to 2, and from excluding all epilepsy to including people with a single episode. Enrollment changed from 375 to 450, study duration changed from nine to 12 months, with a one-year open-label extension. This final protocol was published (Wischik et al., 2022).
According to a trade news report, the company announced top-line results in an October 2022 press release; however, this information is no longer available on the company web site.
According to a company presentation at the December 2022 CTAD conference, the trial failed on both primary endpoints (Medscape). In July 2023, the company showed some biomarker results at the AAIC in Amsterdam. Plasma neurofilament light was shown to have increased in the Methylene Blue control group, but not in the treated group. NfL levels reportedly correlated with trends in plasma p-tau181. At the March 2024 AD/PD conference, the company presented post hoc subgroup analyses of the MCI group, claiming that progression from a CDR of 0.5 to 1 was halved by treatment, that the ADAS-Cog11 declined less in MCI participants who had taken 16 mg per day for two years compared to those who took placebo the first year, and that, when compared to historical controls, the MCI group had declined less on the ADAS-Cog11 and preserved more brain volume over 24 months (Mar 2024 conference news).
TauRx will apply for marketing authorization for HMTM in the U.K. and is in discussions with the European Medicines Agency and Chinese regulators.
For all clinical trials with TRx0237, see clinicaltrials.gov.
Clinical Trial Timeline
- Phase 2
- Phase 2/3
- Phase 3
- Study completed / Planned end date
- Planned end date unavailable
- Study aborted
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| TauRx Therapeutics Ltd |
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NCT01689246 |
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| TauRx Therapeutics Ltd |
NCT01626378 |
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NCT03446001 |
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Last Updated: 10 May 2024
Further Reading
No Available Further Reading
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