Overview
Name: Lenalidomide
Synonyms: Revlimid
Chemical Name: 3-(4-Amino-1-3-dihydro-1-oxo-2H-isoindol-2yl)-2,6-piperidinedione
Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline), Inflammation (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Celgene Corporation
Approved for: Multiple myeloma, lymphoma, myelodysplastic syndromes
Background
Lenalidomide is an anti-cancer drug with pleiotropic anti-inflammatory, anti-angiogenic, and immune stimulatory activities. Sold under the brand name Revlimid, lenalidomide has been used since 2006 to treat multiple myeloma, lymphoma, and myelodysplastic syndromes. The capsules are taken by mouth. In cancer patients, the main side effects are abnormal blood counts and blood clots. Lenalidomide is structurally similar to thalidomide, and as such is considered a teratogen with the potential to cause birth defects and fetal death.
Lenalidomide is being pursued as an alternative to thalidomide, whose development for AD was stopped because of dose-limiting toxicity in elderly patients (Decourt et al., 2017). Both drugs have anti-inflammatory activity, lowering the expression of TNFα, IL-6 and IL-8, and increasing expression of anti-inflammatory cytokines, e.g., IL-10. Both are also claimed to reduce amyloidogenesis by inhibiting BACE1 expression. In cancer patients, both drugs have the potential to induce cognitive impairment, according to published case reports (Argente-Escrig et al., 2018; Morgan et al., 2003; Rollin-Sillaire et al., 2013).
No preclinical data has been published for lenalidomide in AD models. In other models, the drug reportedly blocked α-synuclein toxicity by reducing inflammation (Valera et al., 2017; Valera et al., 2015) and extended survival in ALS mice (Neymotin et al., 2009; Kiaei et al., 2006).
Findings
In July 2020, a Phase 2 trial at Cleveland Clinic Lou Ruvo Brain Health Center in Las Vegas began testing lenalidomide in 30 people with mild cognitive impairment. The MCLENA-1 study is enrolling participants with a clinical diagnosis of amnestic MCI plus low hippocampal volume, or a positive amyloid PET scan, or an ApoE4 allele. Enrollees will receive 10 mg lenalidomide or placebo daily for one year, followed by a six-month washout. The primary outcome is cognition, including ADAS-Cog, ADCS-ADL, CDR-SB, and MMSE scores. Other outcomes are safety, measures of brain amyloid, structural MRI, and blood levels of inflammatory markers. The protocol is published (Decourt et al., 2020). The treatment phase is expected to be completed in September 2023.
For details on this trial, see clinicaltrials.gov.
Last Updated: 23 Apr 2021
Further Reading
No Available Further Reading
Overview
Name: Dipraglurant
Synonyms: ADX48621
Chemical Name: 6-Fluoro-2-[4-(2-pyridinyl)-3-butyn-1-yl]imidazo[1,2-a]pyridine
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Parkinson's Disease
U.S. FDA Status: Parkinson's Disease (Discontinued)
Company: Addex Therapeutics
Background
This is a negative allosteric modulator of the mGluR5 metabotropic glutamate receptor, taken by mouth. It is being developed for the treatment of levodopa-induced dyskinesia (LID) associated with Parkinson’s disease. Dyskinesias are uncontrollable, sometimes disabling, muscle contractions brought on by therapeutic doses of levodopa. Dipraglurant reduces the abnormal glutamate signaling that contributes to dyskinesia. The only drug approved to treat LID is amantadine, which also blocks glutamate signaling.
In preclinical work, dipraglurant rendered LID less severe in a macaque model of PD, without reducing levodopa’s efficacy (Bezard et al., 2014). Dipraglurant also reduced involuntary muscle contractions in a mouse model of dystonia, by restoring brain synaptic plasticity (Sciamanna et al., 2014; Martella et al., 2021). The drug improved symptoms in rodent models mimicking non-motor symptoms of anxiety, depression, and obsessive behaviors (Epping-Jordan et al., 2023).
MGluR5 antagonists are of interest in Alzheimer’s, as well, because the receptor is involved in neuron and astrocyte responses to Aβ (Renner et al., 2010; Um et al., 2013; Shrivastava et al., 2013). In mouse models of AD, mGluR5 inhibitors protect memory and reduce amyloid deposition (Hamilton et al., 2016). MGluR5 has also been reported to mediate α-synuclein-induced cognitive impairments in an α-synuclein transgenic mouse model of PD (Ferreira et al., 2017).
In the 2000s, at least three companies besides Addex were developing mGluR5 negative allosteric modulators for indications including Fragile X syndrome, anxiety, major depression, and LID. The programs were stopped for lack of efficacy, dose-limiting side effects, or liver toxicity.
Findings
Addex completed a Phase 2a trial for Parkinson’s Disease LID in 2012. Conducted in the U.S. and Europe, it enrolled 76 people with moderate to severe LID, who received dipraglurant for 28 days, taken at the same time as levodopa. The dose was titrated from 50 mg once daily to 100 mg three times daily over 21 days, and fixed at 100 mg for the last seven days. The primary endpoint was safety. Clinical endpoints included severity of dyskinesia rated on the modified Abnormal Involuntary Movement Scale on days one, 14, and 28, plus the Unified Parkinson Disease Rating Scale, Clinical Global Impression of Change (CGIC), and patient diaries.
The trial met its primary endpoints of safety and tolerability. The treatment group had more severe adverse events than the placebo group; two participants discontinued due to adverse events at 100 mg. Most common were dizziness, nausea, fatigue, and worsening dyskinesia between doses. On clinical endpoints, the treated group saw a 30 percent improvement of dyskinesia compared to placebo. The difference was statistically significant on days one and 14, but not 28. No differences were observed on UPRDS or patient-reported outcomes. The CGIC was improved in 71.2 percent of the treated group compared to 49.9 percent in placebo. Results are published (Tison et al., 2016).
In 2015, the company conducted a Phase 1 PET study to measure mGluR5 receptor occupancy kinetics in 12 healthy adults. According to an April 2016 press release, dipraglurant receptor binding was dose-proportional, with 27 percent occupancy after a 100 mg dose, 44.4 percent after 200 mg, and 53.5 percent after 300 mg. A range of 50 to 70 percent occupancy is claimed to give an optimal anti-dyskinetic effect.
In January 2016, dipraglurant received orphan drug designation from the U.S. FDA for the treatment of LID (press release).
In August 2021, Addex began a three-month Phase 2b/3 trial in PD patients with LID. The 140 participants were to take 150 mg per day for one week, then 300 mg daily for the rest of the study, or placebo. The study included a 12-month open-label extension. The primary endpoint was change in the Unified Dyskinesia Rating scale, a measure developed specifically to assess LID. Secondary endpoints were ON and OFF time based on patient diaries. Completion was slated for August 2023. In June 2022, the company stopped the trial, citing slow recruitment due to the COVID-19 pandemic (company release).
The company also conducted a Phase 2 feasibility study in 15 people with blepharospasm, a form of dystonia that affects the eyelid muscles and can cause vision problems. In a May 2022 press release, Addex said the study was inconclusive.
For details on dipraglurant trials, see clinicaltrials.gov.
Last Updated: 18 Oct 2023
Further Reading
No Available Further Reading
Overview
Name: CNM-Au8
Synonyms: Gold nanocrystals
Therapy Type: Other
Target Type: Metals, Other (timeline)
Condition(s): Parkinson's Disease, Amyotrophic Lateral Sclerosis
U.S. FDA Status: Parkinson's Disease (Phase 2), Amyotrophic Lateral Sclerosis (Phase 2/3)
Company: Clene Nanomedicine, Inc.
Background
CNM-Au8 is a preparation of pure elemental gold nanoparticles in a drinkable bicarbonate solution. The faceted crystals have a median diameter of 13 nm, slightly smaller than a ribosome. Their surfaces catalyze oxidation-reduction reactions, including the conversion of NADH to NAD+ (Huang et al., 2005). NAD+ is an essential cofactor for ATP generation and a cell metabolic sensor. The rationale for the therapeutic use of gold nanocrystals is that they may help ameliorate cellular-energy deficits and oxidative stress characteristic of multiple neurogenerative diseases.
Other gold nanoparticles have been reported to have reactive oxygen-scavenging, anti-oxidant, and anti-inflammatory activity, including in cell models of Aβ toxicity (e.g., Du et al., 2013; Li et al., 2017; Chiang et al., 2021).
In a preclinical study, CNM-Au8 increased NAD+ and ATP concentrations in cultured neurons and glia, and promoted remyelination and recovery of motor function in two mouse models of multiple sclerosis (Robinson et al., 2020).
Findings
In 2015-2016, Clene ran a placebo-controlled Phase 1 study of single and multiple doses of CNM-Au8. It enrolled 86 healthy volunteers, who received 15, 30, 60, or 90 mg single doses, or the same daily doses for 21 days. In its communications, the company reported that drug-related adverse events were neural/gastrointestinal and mild, with none leading to study discontinuation.
In July 2019, the U.S. FDA granted CNM-Au8 Orphan Drug Designation for ALS.
In December 2019, a Phase 2 trial called RESCUE-ALS began enrolling 45 ALS patients in two centers in Australia. Participants had to be within two years of symptom onset, or one year of diagnosis. They took 30 mg drug or a placebo once daily for 36 weeks. The primary endpoint was change from baseline to 36 weeks in an electrophysiological measure of motor neuron function, a biomarker that predicts ALS disease progression. Other endpoints included clinical measures of function, disease progression, and health care utilization. Participants who completed the trial could enter a 48-week open-label extension. For trial details, see Vucic et al., 2021. In November 2021, the company announced that the trial had missed its primary endpoint, but still claimed significant benefits on measures of progression and quality of life (press release). The drug was safe. In July 2022, Clene announced data from the open-label extension, claiming a 70 percent reduced risk of death in the patients who initially received CNM-Au8 compared to those who started on placebo (press release). Results were published after peer review (Vucic et al., 2023).
In July 2020, a Phase 2/3 multicenter study began evaluating CNM-Au8 as part of Massachusetts General Hospital’s Healy ALS Trial Platform. This trial tests four experimental treatments in parallel under a single protocol at 54 locations in the U.S. In the CNM-Au8 arm of the trial, 161 ALS patients were randomized to 30 or 60 mg daily or matching placebo in a 3:1 ratio. The primary outcome was change in severity after 24 weeks, as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R). Secondary outcomes included respiratory function, muscle strength, and survival. The treatment phase finished in April 2022. Outside of this trial, an immediate access protocol is making the drug available to up to 30 patients at MGH.
In December 2019, two open-label pilot trials began to study CNS metabolic effects of CNM-Au8 in people with Parkinson’s disease and with relapsing-remitting multiple sclerosis. Conducted at the University of Texas Southwestern Medical Center, the studies each aimed to enroll 30 patients into a three-month course of 7.5 to 60 mg daily. The primary outcome was the brain’s NAD+/NADH redox ratio as measured by magnetic resonance spectroscopy imaging. The Parkinson’s study ended in June 2021 with 13 patients. A similar trial in 24 people with ALS was planned to start in April 2021, but was withdrawn before starting enrollment.
In March 2022, Clene registered an expanded access study for 15 ALS patients at three U.S. centers, but this was cancelled in June, before any patients were enrolled.
On October 3, 2022, Clene announced CNM-Au8 had failed to change the primary endpoint of functional decline at 24 weeks in the Healy ALS trial. Secondary endpoints of function, survival, and breathing capacity were also negative. The company claimed a potential survival signal at the 30 mg dose, where three patients on placebo died, compared to one on CNM-AU8 (press release). Additional survival data from a 52-week open-label extension is expected in mid-2023.
A placebo-controlled Phase 2 trial in people with MS showed improvements in vision and global neurological function (Nov 2022 press release). No clinical trial results with CNM-Au8 are published in peer-reviewed journals.
For details on CNM-Au8 trials, see clinicaltrials.gov.
Last Updated: 06 Feb 2023
Further Reading
No Available Further Reading
Overview
Name: kMCT-ONS
Synonyms: medium chain triglyceride-based ketogenic oral nutritional supplement, kMCT
Therapy Type: Supplement, Dietary (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Not Regulated)
Company: Nestlé Health Science
Background
kMCT-ONS is a nutritional drink that raises blood ketone concentrations. The brain uses ketones as an energy source when glucose is limited, and inducing mild ketosis has emerged as a strategy to overcome the decline in glucose uptake that occurs in people with Alzheimer’s disease. In multiple small pilot studies, ketogenic diets such as the Atkins regimen, or ketogenic supplements, improve brain energy status and cognitive function in people with MCI and AD (reviewed in Cunnane et al., 2020).
The active components of kMCT-ONS are medium-chain triglycerides of caprylic acid and capric acid. Metabolism of these fats in the liver produces the ketones acetoacetate and β-hydroxybutyrate, which freely enter the brain. kMCT-ONS is produced by emulsifying a commercially available 60:40 mixture of the two fats derived from palm oil into lactose-free skim milk. kMCT’s composition is similar to the medicinal food Ketasyn or the experimental ketogenic drink Tricaprylin, both of which contain caprylic acid triglyceride as their main active ingredient.
kMCT has been shown to increase plasma ketone levels and brain ketone uptake in healthy adults and in people with AD (Croteau et al., 2018). Brain uptake of ketones does not appear to be diminished in people with AD compared to healthy people (Castellano et al., 2015). A meta-analysis of trials testing medium-chain triglycerides for cognitive symptoms in older adults found a substantial increase in brain ketones and metabolic rates, but only occasional or domain-specific cognitive improvements (Meer and Fischer 2024). The authors noted heterogenous and poor study design, and conflicts of interest that weakened the evidence. A meta-analysis of trials in people with subjective cognitive decline, mild cognitive impairment, or AD likewise reported mixed outcomes for cognition (Castro et al., 2023). A third meta-analysis claimed some evidence for improvement in general cognition in people with AD, but only those lacking the ApoE4 allele (Sun et al., 2023). A pharmacokinetic study revealed high variability between people in blood ketone levels after an MCT dose, with major effects of meals and body fat (Juby et al., 2021).
In preclinical studies and one pilot clinical trial, inducing ketosis was reported to reduce amyloid load, ameliorate Aβ toxicity, and improve AD biomarkers (Kashiwaya et al., 2013; Zilberter et al., 2012; Neth et al., 2020).
A commercially available caprylic acid triglyceride supplement derived from coconut oil was claimed to stabilize or improve cognitive scores in most participants in a crossover study of 20 people with mild to moderate AD (Juby et al., 2022). Longer treatment of up to 11 months was reportedly associated with better scores on the MMSE and a Cogstate computerized battery in this study.
Findings
In June 2015, investigators at the University of Sherbrooke, Quebec, began the BENEFIC trial to test effects on brain metabolism of a six-month course of kMCT in 52 people with mild cognitive impairment. The active treatment was a twice-daily shake containing 15 g MCT, or a calorie-equivalent placebo of non-ketogenic high oleic sunflower oil. The primary outcome of the trial was brain glucose and ketone uptake, measured by FDG-PET and 11C-acetoacetate-PET, and tolerability. Secondary outcomes included performance on a neurocognitive battery, changes in global brain energy supply, and the relationship between ketone uptake and cognitive outcomes. According to published results, 19 and 20 people completed the treatment and placebo arms, respectively. Most participants reported gastrointestinal side effects, and one-quarter dropped out because of them. The kMCT group had a doubling of plasma ketones and brain ketone uptake compared to placebo; brain glucose uptake did not differ. The study was not powered to detect treatment effects on cognition, but improvements from baseline in the treated group were noted in several domains (Fortier et al., 2019). An increase ketone uptake into white-matter fascicles, and an associated increase in processing speed, was also reported (Roy et al., 2021).
Based on these results, a larger six-month trial enrolled 122 participants with MCI who were randomized to the same kMCT treatment or placebo. The primary outcome was scores on the neurocognitive battery. In this study, the dropout rate was 32 percent, mainly due to GI side effects. In all, 39 and 44 people completed the active and placebo treatments, respectively. Compared to the placebo group, the treated group improved on tests of memory, executive function, and language; their scores correlated with plasma ketone levels. A metabolic substudy found plasma ketones were elevated for one to two hours post-dosing, and this response was unchanged from the beginning to the end of the study. Results are published (Fortier et al., 2021).
In September 2018, University of British Columbia investigators began enrolling 40 people with a diagnosis of mild to moderate AD for an ascending-dose, safety, and pharmacokinetic study of the kMCT drink. Participants are to receive 10 to 50 g MCT or placebo per day for 10 days. Primary outcomes are serious adverse events and plasma ketone concentrations. Other outcomes include FDG-PET, cerebral blood flow, MR spectroscopy to assess brain chemistry, and daily physical activity.
In May 2024, Nestlé began a pivotal study of a new supplement that combines kMCT-ONS with B vitamins in aging adults with mild cognitive impairment. The rationale for adding B vitamins comes from studies suggesting they can help old adults maintain cognitive function (e.g., Li et al., 2021). The study plans to enroll 380 adults over age 60 with a diagnosis of MCI which is compatible with AD or vascular dementia. Treatment will entail one year of supplementation with 15 g kMCT plus a mix of B3, B6, B9/folic acid, and B12, or a matching placebo. There is an optional six month open-label extension. The primary outcome is change in the Preclinical Alzheimer’s Cognitive Composite score; secondary outcomes include individual components of the PACC, the Montreal Cognitive Assessment (MoCA) score, and the percent of participants who show faster than expected memory decline on the PACC, Wechsler memory scale, or MMSE, as well as adverse events. The trial is running to the end of 2027 in approximately 30 sites in Italy, Spain, France, Germany, Switzerland, the U.K., and the U.S.
For details on these trials, see clinicaltrials.gov.
Last Updated: 19 Jul 2024
Further Reading
No Available Further Reading
Overview
Name: LY3884963
Synonyms: PR006
Therapy Type: DNA/RNA-based
Target Type: Other (timeline)
Condition(s): Frontotemporal Dementia
U.S. FDA Status: Frontotemporal Dementia (Phase 1/2)
Company: Eli Lilly & Co., Prevail Therapeutics
Background
PR006 is a gene-replacement therapy that uses adeno-associated virus 9 (AAV9) to deliver a functional copy of the progranulin gene GRN to the brain. Progranulin mutations are a frequent cause of familial frontotemporal dementia. Mutations result in 30 to 50 percent reductions in cerebrospinal fluid progranulin levels compared to the normal range. The loss of progranulin interferes with proper lysosomal function, leading to build-up of toxic proteins, neuroinflammation, and neurodegeneration (e.g., Sep 2017 news).
GRN is also implicated in Alzheimer’s disease. Variants that reduce progranulin levels increase risk of AD, and progranulin reduction exacerbates AD pathology in animal models (reviewed in Elia et al., 2020).
PR006 is delivered as a one-time injection into the cerebrospinal fluid in the cisterna magna at the base of the brain. At conferences, company scientists reported that PR006 increased progranulin release and improved lysosomal function of neurons derived from FTD-GRN patients, that PR006 restored brain GRN expression and progranulin secretion into the CSF in progranulin knockout mice, and that PR006 appeared safe and resulted in broad progranulin expression in the brain and periphery in nonhuman primates (see Nov 2019 news). This preclinical data have since been published (Sevigny et al., 2024), as was evidence that PR006 normalized lysosomal markers and reduced CNS inflammatory markers in the knockout mice.
Separately, one study reported T cell infiltration, as well as ependymal and hippocampal toxicity, following supra-physiological expression of progranulin from an AAV9-GRN delivered to GRN knockout mice. Some of this toxicity was also seen with progranulin overexpression in wild-type (Amado et al., 2019).
A second study comparing several AAV-GRN constructs in progranulin knockout mice and nonhuman primates reported no such toxicity (Hinderer et al., 2020).
A more recent study evaluated different PGRN-expressing AAV1/9 viruses in TMEM106b/GRN double knockout mice (Feng et al., 2023).
Findings
In July 2020, Prevail began a Phase 1/2 trial of PR006 in 23 people with FTD due to a progranulin mutation. Participants had to be living independently and have symptoms. The study is evaluating a low dose of 2.1 × 1013 viral genomes, and a medium dose of 4.2 × 1013, administered as a single intra-cisternal injection, concomitantly with an immunosuppressive regimen of steroids, sirolimus and rituximab. A third cohort will test the commercially produced drug product at either the low or mid dose. There is no placebo group. The primary endpoints are number of adverse events over a period of five years, plus immunogenicity of the virus and progranulin, and progranulin levels in blood and CSF. Secondary outcomes are one-year changes in measures of clinical decline, as well as neurofilament light chain concentrations in CSF and blood. Called PROCLAIM, the trial is recruiting at eight sites in Australia, Belgium, France, Spain, the U.K., and the U.S., and expected to run through 2029.
Interim results are published on patients on the low or mid dose who reached six months follow-up, and on low-dose patients who reached one year. Adverse events occurred in all 13 patients. Increased white blood cells in CSF, an indication of neuroinflammation, was seen in half. The increase was transient and caused no symptoms in all but one patient, who experienced a hearing impairment that later recovered. Twelve serious adverse events were noted, including multiple instances of blood clots. Deep vein thrombosis in two patients was possibly related to the immunosuppressive therapy in people with multiple risk factors for DVT. There was one death. Most patients had generated AAV9 antibodies; none developed progranulin antibodies. In all participants, CSF progranulin concentration rose, between 2.1- and 6.9-fold. Most attained normal or supernormal CSF progranulin levels at six or 12 months. There was a transient increase in neurofilament light chain in plasma and CSF; it was attributed to inflammation in dorsal root ganglia cells induced by transgene expression. Urine BMP, a candidate phospholipid marker of lysosome function, increased toward normal with treatment. Measures of clinical progression were similar to historical controls (Sevigny et al., 2024).
PR006 has orphan drug designation for FTD from U.S. and European regulators, and fast-track designation for FTD-GRN in the U.S.
In January 2021, Prevail was acquired by Eli Lilly & Company (press release, press release) and PR006 was renamed LY3884963.
For details on PR006/LY3884963 trials, see clinicaltrials.gov.
Last Updated: 20 May 2024
Further Reading
No Available Further Reading
Overview
Name: PRI-002
Synonyms: Contraloid, contraloid acetate, RD2
Chemical Name: all D-ptlhthnrrrrr
Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: Priavoid GmbH
Background
This 12-residue, enantiomeric peptide is designed to interfere with oligomerization of Aβ42 by binding to, and stabilizing, Aβ42 monomers. PRI-002 comprises D-amino acids, the optical isomers of natural L forms. D-peptides are favored for protein drugs, because they can be taken by mouth, resist protease degradation in the stomach and metabolic degradation, and are less immunogenic than natural peptides. They cross the blood-brain barrier.
PRI-002 was identified by the Willbold lab in Düsseldorf, using mirror image phage display to select all-D peptides that bind Aβ42 (Wiesehan et al, 2003). The original hits were optimized for their ability to slow fibril formation and destabilize toxic oligomers (Aug 2009 conference news; Brener et al., 2015; Zhang et al., 2019). PRI-002 (also called RD2) was capable of disaggregating Aβ oligomers extracted from brain tissue of people who had Alzheimer’s disease (May 2022 news).
The lab has published preclinical studies on PRI-002. In mice, the peptide, when given orally, reaches nearly the same concentrations in brain as in blood (Leithold et al, 2016). The peptide appeared effective in three mouse models of Alzheimer’s. In APPSL mice, it improved performance in the Morris water maze after six weeks of treatment (Kutzsche et al., 2017). It similarly enhanced cognition in young or old APP/PS1 mice (van Groen et al., 2017; Schemmert et al., 2018). In the TBA2.1 mouse model of pyroglutamate-Aβ-induced motor neuron neurodegeneration, mice who ate PRI-002 jelly for 12 weeks showed partial improvement of their motor deficit (Schemmert et al., 2019).
At the 2020 CTAD conference, Willbold presented data on aging beagles, a model of spontaneous AD. Dogs that were older than 10, and cognitively impaired, were fed 3 or 30 mg/kg PRI-002 or placebo daily for three months. Treated dogs reportedly improved their accuracy on a test of short-term memory compared to placebo, and the memory benefit of the higher dose was retained during a two-month post-treatment washout. In the subsequent publication of this work, the investigators also reported a decrease in CSF tau oligomers after treatment at the higher dose (Kutzsche et al., 2023). Aβ oligomers were unchanged.
An 18F-labeled analog of PRI-002 was investigated as a potential PET probe for soluble Aβ oligomers, but it failed to discriminate between wild-type and APP/PS1 mice with amyloidosis (Willuweit et al., 2023).
Findings
In 2017, Willbold and others founded Priavoid GmbH, which in 2018 and 2019 conducted a Phase 1 single-ascending-dose study and a second, multiple-ascending-dose study to evaluate the safety of PRI-002 in 64 healthy men in Germany. According to published results, single doses up to 320 mg and multiple doses of 320 mg for up to four weeks produced no drug-related adverse events (Kutzsche et al., 2020). The drug showed favorable pharmacokinetics, and accumulated with repeated administration, reaching steady state after one to two weeks of dosing.
In December 2020, Priavoid began a Phase 1 trial in 20 people with mild cognitive impairment due to Alzheimer’s disease. Participants received a single 300 mg dose daily for 28 days, or matching placebo. Outcomes were safety, including adverse events, laboratory values, and electrocardiograms. The study also measured pharmacokinetics, changes in CSF, plasma and fecal biomarkers of tau, Aβ, and neurofilament light chain, and exploratory cognitive measures. Conducted in Berlin, the trial ended in January 2022. According to a poster presentation at the 2022 AAIC, the drug was safe, with no serious adverse events noted in the trial. No change was seen in CSF biomarkers, but treated patients performed better than those on placebo on an exploratory endpoint related to memory, the CERAD word list. According to additional data presented at the 2023 CTAD conference, the improvement in CERAD was significant one month after treatment ended (news). It was observed in all participants who got drug, and half who got placebo.
At CTAD, the company reported that a Phase 2 trial is planned to begin in early 2024. In the study, at least 270 participants with MCI or mild AD will be randomized to daily doses of 300 mg or 600 mg PRI-002, or placebo, for one to two years. The primary efficacy endpoint is change in CDR-SB. Funded by SPRIN-D, the German Federal Agency of Disruptive Innovation, the study is planned to run at 40 sites in seven European countries. It does not yet appear in a trial registry.
For details on PRI-002 trials, see clinicaltrials.gov.
Last Updated: 22 Nov 2023
Further Reading
No Available Further Reading
Overview
Name: E2814
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Tau (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2/3)
Company: Eisai Co., Ltd.
Background
This humanized, monoclonal IgG1 antibody recognizes an HVPGG epitope in the microtubule-binding domain near the mid-domain of tau. This region is a predominant component of tau tangles and is involved in seeding and spreading pathological tau aggregates. The antibody is intended to bind extracellular tau, prevent cell-to-cell propagation of pathogenic species, and mediate clearance by microglia. Some data indicate that mid-region antibodies more potently interfere with the propagation of pathogenic, aggregated tau than do N-terminally targeted anti-tau antibodies, which have shown no efficacy in clinical trials (Apr 2018 conference news).
The production and characterization of this antibody were described in detail in a peer-reviewed publication (Roberts et al., 2020). Originally discovered in the lab of Rohan de Silva at University College London, E2814 recognized pathological tau structures in postmortem brain, including neurofibrillary tangles from AD and progressive supranuclear palsy and Pick bodies from Pick’s disease. The antibody also recognized normal tau. E2814 inhibited tau aggregation in vitro and in cell-based aggregation assays. It modestly reduced the propagation of aggregated tau in mice injected with K18 P301L tau fibrils, a model of tau transmission.
Findings
In December 2019, Eisai began a Phase 1 trial testing the safety and tolerability of a single intravenous infusion in healthy adults. Secondary outcomes included serum and CSF pharmacokinetics and immunogenicity. An exploratory outcome assessed target engagement by antibody binding to tau protein fragments in the CSF. The trial was completed in August 2020, and results were presented at the November 2020 CTAD conference. The study compared 3, 10, or 30 mg/kg antibody versus placebo in 24 volunteers of both sexes, including Japanese and non-Japanese, who were followed up for four months. Treatment resulted in no significant drug-related clinical changes or dose-limiting events. The most frequent side effects related to drug were headache, nausea, and vomiting. One participant in the highest-dose group had elevated C-reactive protein two to three days after dosing, which produced no symptoms and returned to baseline. Serum and CSF pharmacokinetics were dose-proportional, and comparable to other antibodies. Two participants developed anti-E2814 antibodies by four months. An LC/MS procedure was used to quantify antibody-bound and free-tau fragments containing the microtubule-binding region (Horie et al., 2019; Dec 2020 news). The results showed a dose-related increase in antibody-tau association, which persisted for at least a month. At the 30 mg/kg dose, 60 percent of tau mid-domain fragments were complexed with antibody.
In 2021, the company added a multiple-ascending-dose phase to the study. Enrollment was boosted to 40, with two different dose cohorts receiving three infusions over four months. In 2022, Eisai added two single-dose and two multidose cohorts, increasing enrollment to 72. Endpoints are safety, pharmacokinetics, and induction of anti-E2814 antibodies. The trial was completed in March 2023.
In March 2021, E2814 was chosen to be evaluated in the DIAN-TU prevention trial in people with pathogenic APP and presenilin mutations (Mar 2021 news). In June 2021, a Phase 1/2 trial began to assess safety and target engagement in people with dominantly inherited Alzheimer’s disease. Eight participants with mild to moderate dementia were to receive antibody infusions for 12 weeks, with target engagement to be measured by change from baseline in CSF free, bound, and total tau microtubule-binding region fragments. A second phase will continue treatment for 96 weeks, against endpoints of adverse events, changes in laboratory values, vital signs, and electrocardiogram findings. An add-on cohort of five patients will receive treatment for one year. This trial also assesses pharmacokinetics, anti-E2814 antibodies, and change from baseline in CSF total tau and p-tau, and tau PET.
Eisai presented first trial data at the July 2023 Alzheimer’s Association International Conference (conference news). The drug was safe and well-tolerated up to the highest dose of 4,500 mg in both healthy and AD cohorts. Target engagement was verified by dose-dependent binding of E2814 to tau microtubule binding region epitopes in CSF. The MTBR-tau-243 fragment, an emerging CSF biomarker for tau tangles, declined between 30 and 70 percent after antibody treatment in the AD patients. More data on the eight DIAN-TU participants was presented at the 2024 CTAD conference (Nov 2024 news). They received E2814 for up to two years, although five dropped out before the study ended. Compared to matched historical controls, CSF pTau217 was estimated to be halved after two years. Three participants had PET scans, and showed a trend toward reduction in tau, although this may have been explained by atrophy.
The DIAN-TU study design was amended in November 2021 to allow use of the anti-amyloid antibody lecanemab, in response to the FDA approval of Aduhelm (Nov 2021 news). According to the trial registry, the Phase 2/3 study will enroll 168 participants with normal cognition, mild cognitive impairment, or mild dementia. People with mild cognitive impairment or dementia will receive open-label intravenous lecanemab for 24 weeks, and then be randomized to intravenous E2814 or placebo plus lecanemab for the remainder of the four-year trial. Participants with normal cognition will start on E2814 or placebo for one year, and then add open-label lecanemab. The trial’s primary endpoint is tau spread during E2814 treatment, measured by tau PET in the symptomatic cohort. Secondary outcomes in this group include change in a cognitive composite, amyloid PET, and CSF neurofilament light chain. In the asymptomatic population, change in CSF ptau217/total tau ratio is the outcome. Eisai reported the first patient enrollment in January 2022 (press release). The study, at 39 locations around the world, is fully enrolled with 197 participants, and will run through 2028.
In September 2024, a Phase 2 dose finding study began testing E2814 given concurrently with the anti-amyloid antibody lecanemab. Ninety participants with mild cognitive impairment due to Alzheimer’s will receive one of four doses of E2814 or placebo monthly by infusion, plus weekly subcutaneous lecanemab for 18 months. The primary outcome is change in CSF MTBR-tau-243 at six months. Other outcomes include tau PET, plasma and CSF pTau217, E2814 serum antibody concentration, and safety. The trial is running at 34 locations in the U.S. and Japan until August 2027.
For trial details, see clinicaltrials.gov.
Last Updated: 08 Jan 2025
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Species: Mouse
Genes: App
Modification: App: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: B6(Cg)-Apptm1.1Dnli/J
Summary
Phenotype Characterization
When visualized, these models will distributed over a 18 month
timeline
demarcated at the following intervals: 1mo, 3mo, 6mo,
9mo, 12mo, 15mo, 18mo+.
Plaques
Amyloid plaques seen in AppSAA homozygous mice from 4 months of age and heterozygous mice at 16 months of age.
Tangles
AT8-positive dystrophic neurites, but no neurofibrillary tangles, detected in AppSAA homozygous mice at 8 months of age.
Gliosis
Plaque-associated microgliosis observed by 4 months of age.
Last Updated: 16 Dec 2020
Further Reading
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