Overview
Name: Leucettinib-21
Synonyms: (R,Z)-5-(benzo[d]thiazol-6-ylmethylene)-2-((1-methoxy-4-methylpentan-2-yl)amino)-3,5-dihydro-4H-imidazol-4-one
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease, Down's Syndrome
U.S. FDA Status: Alzheimer's Disease (Phase 1), Down's Syndrome (Phase 1)
Company: Perha Pharmaceuticals
Background
Leucettinib-21 is a small-molecule inhibitor of the dual-specific, tyrosine phosphorylation-regulated kinase DYRK1A (Lindberg and Meijer 2021). Abnormally active DYRK1A has been implicated in memory and learning problems in Alzheimer’s disease and Down's syndrome. Taken in tablet form, this drug is claimed to cross the blood-brain barrier.
Dyrk1 has been found to regulate alternative splicing of tau exon 10 (Qian et al., 2011; Yin et al., 2012). For a review of tau isoforms in Alzheimer’s and related diseases, see Buchholz and Zempel, 2024).
In AD, proteases cleave full-length DYRK1A into a more stable and active kinase. Many substrates have been identified, including tau at residue 212 (Kimura et al., 2007), but also APP, presenilin, and other synaptic and cytoskeletal proteins. Excess DYRK1A activity has been shown to dysregulate tau splicing to favor the 3R isoform (Yin et al., 2017).
In Down's syndrome, DYRK1A is overexpressed due to the presence of the gene in the trisomy region of chromosome 21.
Pharmacological or genetic inhibition of DYRK1A has been reported to reduce pathology or improve cognition in AD and DS rodent models (e.g. Velazquez et al., 2019; Branca et al.., 2017; see Meijer et al., 2024 for comprehensive listing).
Leucettinib-21 was derived by medicinal chemistry optimization of the marine sponge natural product Leucettamine B (Deau et al., 2023; reviewed in Meijer et al., 2024). It inhibits DYRK1 with a 2.4 nM IC50. The compound was reported to correct memory deficits in the Down's syndrome mouse model Ts65Dn (Lindberg et al., 2023).
Findings
In January 2024, Phase 1 began with a four-part study to assess safety after single and multiple doses in healthy men, food effects, as well as safety of single doses in men with Down’s syndrome and Alzheimer’s disease. The placebo-controlled trial involves 120 participants, at one study site near Grenoble, France. Healthy men are to receive 5, 10, 30, 60, or 120 mg doses, 40 mg with or without a high fat meal, or multiple doses of 60 or 120 mg per day for 14 days. Twelve men with Down’s syndrome and 12 with AD are to receive a single, 60 mg dose. Primary outcomes are safety and tolerability and, in the food study, plasma pharmacokinetics. Secondary outcomes include pharmacokinetics, protein phosphorylation, and DYRK1 activity in blood after treatment. Other biomarkers include pTau212 and pTau217. The study was planned to end in August 2024.
First results were presented at the October 2024 CTAD conference. Doses of 10, 30, or 60 mg in healthy men resulted in blood levels exceeding the IC50 for DYRK1A; the drug persisted for 3.5 hours at the highest dose.
For details on Leucettinib-21 trials, see clinicaltrials.gov.
Last Updated: 29 Jan 2025
Further Reading
No Available Further Reading
Overview
Name: BXCL501
Synonyms: Dexmedetomidine sublingual film, IGALMI™
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 3)
Company: BioXcel Therapeutics, Inc.
Approved for: Acute Agitation in Schizophrenia and Bipolar Disorder
Background
BXCL501 is an orally dissolvable film formulation of the α2A adrenergic receptor agonist dexmedetomidine. It is approved to treat acute agitation associated with schizophrenia or bipolar disorder in people under medical supervision. Currently, BXCL501 is being tested to treat agitation in people with Alzheimer’s disease.
Dexmedetomidine given intravenously is commonly used for sedation and anesthesia in surgical and intensive care patients. It is also used by veterinarians to sedate cats, dogs, and horses. BioXcel Therapeutics developed BXCL501 to improve oral bioavailability of the drug. It comes in doses of 120 and 180 micrograms on a rectangular film containing 2 microdeposits of dexmedetomidine hydrochloride. After application, dexmedetomidine is absorbed into the blood stream in five to 20 minutes, where it has a half-life of 2.8 hours.
In 2022, the FDA approved BXCL501 for people with schizophrenia or bipolar disorder, after trials showed significant reduction in agitation 20 to 30 minutes after administration (Citrome et al., 2022; Preskorn et al., 2022). Common side effects include sleepiness, numbness or pricking feelings in the mouth, dry mouth, dizziness, and low blood pressure. Users self-administer the drug in the presence of a health care professional who can monitor vital signs and alertness to prevent falls or fainting. It may interact with, and enhance the effects of, other sedatives and β-blockers.
In animal models of amyloid toxicity, dexmedetomidine has been claimed to be neuroprotective and anti-inflammatory (e.g. Ma et al., 2024; Lian et al., 2024; many earlier papers). Previously, α2 adrenergic agonists were reported to promote non-amyloidogenic processing of the amyloid precursor protein (Nizari et al., 2016). On the other hand, dexmedetomidine was shown to increase tau phosphorylation and promote tau aggregation in human Tau expressing mice (Whittington et al., 2015; Huang et al., 2015). As a sedative, dexmedetomidine has been reported to be associated with less delirium in intubated patients compared to lorazepam or midazolam (Pandharipande et al., 2007; Riker et al., 2009).
Findings
In December 2019, BioXcel began the Phase 1/2 Tranquility trial to test safety and efficacy in people with acute agitation and dementia. The dose-finding study enrolled 100 elderly adults with all forms of dementia, who had a history of agitation that required intervention or impaired their social or daily activities. Three cohorts of 10 patients each received 30, 60, or 90 micrograms sublingual film, or placebo, self-administered at the appearance of agitation under the supervision of a trained staff member. In the adaptive study design, an additional fourth cohort of 46 people took 40 micrograms, or placebo. Primary endpoints were change in the Positive and Negative Syndrome Scale-Excited Component (PEC) Total Score between baseline and two hours after dosing, and adverse events. The PEC score is the same endpoint used in previous trials for FDA approval. Secondary outcomes were additional scales of agitation, the time for medication to dissolve, and negative reactions to the film by patients. The trial finished in May 2021; results are posted on clinicaltrials.gov. The 60 and 40 microgram doses significantly reduced the PEC score. Secondary measures of agitation were likewise improved. Half of patients taking 40 micrograms, and three-quarters taking 60 micrograms, reported adverse events, most commonly sleepiness and hypotension, followed by dry mouth, gastrointestinal issues, urinary tract infection, and dehydration. The film took minutes to dissolve, and investigators noted no negative reactions to it.
Two studies were planned to start in 2022, a Phase 2 trial in patients with all-cause dementia, and a Phase 3 trial in people with agitation due to Alzheimer’s. Both were terminated for business reasons.
In April 2022, a Phase 3 study, called Tranquility II, began in patients with acute agitation and AD. The 12-week study planned to enroll 151 participants from assisted living or residential care facilities. Participants must have a history of acute agitation and require assistance with daily activities. They were randomized to self-administer at least one and no more than 28 doses of 40 or 60 micrograms, or placebo, as episodes of agitation arose. The primary endpoint was change from baseline in PEC score two hours after the first dose. The study was completed in June 2023. On June 29, the company announced positive top-line results (press release). The same day, BioXcel disclosed that the FDA had found protocol violations at one site that enrolled 40 percent of the trial participants (SEC Form 8-K). An independent audit uncovered no indication of misconduct, fraud, or issues with data integrity, the company said (Oct 2023 press release).
According to a poster presented at October 2024 CTAD, the 60-microgram group met the primary endpoint, showing improvement from baseline in PEC compared to placebo. The difference was apparent by one hour and maintained out to the last assessment at four hours. Effects were consistent across secondary endpoints of additional agitation scales. In 12 weeks, 443 episodes of agitation were treated, and the reduction in PEC in subsequent episodes was similar to the first dose. All adverse events up to 24 hours were mild or moderate; they included sleepiness, low blood pressure, and slow heart rate. One fall within 24 hours of medication occurred in the placebo group. Three deaths in the study occurred more than one month after the last dose.
The company is planning a second Phase 3 trial to test the efficacy of 60 microgram dose in 150 AD patients residing in nursing facilities or assisted living memory care units (Apr 2024 press release).
BXCL501 is also being tested for acute stress disorder, alcohol use disorder with comorbid PTSD (Petrakis et al., 2025), opioid use disorder (Jones et al., 2023), and sleep enhancement (Schnider et al., 2024). BioXcel is conducting a trial of at-home treatment in people with schizophrenia or bipolar disorder.
For details on BXCL501 trials, see clinicaltrials.gov
Last Updated: 29 Jan 2025
Further Reading
No Available Further Reading
Overview
Name: Autologous Adipose-derived Stem Cells
Synonyms: RB-ADSC, CEREWiNT®, Astrostem
Therapy Type: Other
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1/2)
Company: Regeneron Pharmaceuticals Inc.
Background
This approach uses mesenchymal stem cells isolated from a patient’s own fat tissue to treat neurodegenerative diseases. The stem cells are supposed to assist in repair of damaged tissue and regeneration of cells. Compared to bone marrow stem cells, adipose stem cells are easier to obtain and are more likely to differentiate into neuron progenitors.
There is a large literature on neuroprotective and regenerative capabilities of adipose-derived mesenchymal stem cells, or exosomes derived from these cells (for review, see Pappola et al., 2024). Intravenous, intranasal, and direct brain injection of adipose-derived stem cells have been investigated in animal models of Alzheimer’s, Parkinson’s, and other diseases. In APP/PS1 AD mice, brain transplantation of stem cells activated microglia, reduced amyloid plaque load, and improved learning and memory (Ma et al., 2013). Intravenously administered stem cells were found to travel to the brain, reduce pathology, and improve learning and memory in the Tg2576 mouse model (Kim et al., 2012).
Findings
In a pilot study, a single intravenous infusion of Nature Cell Company’s Astrostem adipose-derived stem cells caused no adverse effects in spinal cord injury patients (Ra et al., 2011).
From May 2017 to August 2019, the company conducted a Phase 1/2 in 21 Alzheimer’s patients. Participants with mild to moderate AD received 10 intravenous infusions of stem cells or placebo at two-week intervals, against primary outcomes of adverse events and change in the ADAS-Cog after 30 weeks. The study ran at three locations in California and Hawaii. No results have been made public. This company registered a Phase 2 study in 100 AD patients to start in February 2023, but as of January 2025, has not started recruiting. The company is currently running a separate trial in COVID patients.
In 2017-2020, three other companies registered trials of adipose-derived stem cell preparations for Alzheimer’s, but none were conducted.
In initial work on brain delivery, investigators associated with Regeneration Biomedical injected freshly harvested, mixed adipose cell fractions into the cerebral ventricles of patients with AD, ALS, multiple sclerosis, Parkinson’s disease, or neural injury. A total of 31 patients, ranging from 41 to 83 years old, received 113 injections and were followed for up to three years. Twelve of the injections caused one to four days of meningeal irritation, and mild temperature elevation, with two instances requiring hospitalization for symptoms. One patient had his reservoir removed and later replaced for presumed infection. The three AD patients treated had a reduction in CSF phosphoTau after injection. One AD patient, who received 12 injections over three years, showed signs of increased hippocampal volume (Duma et al., 2019).
In August 2023, the company began a Phase 1 open-label safety study of direct brain injection of purified and expanded adipose-derived stem cells in people with AD. Nine patients in three cohorts are planned to receive escalating doses of 2, 5, or 10 million autologous, adipose-derived stem cells via intraventricular injection. Participants must be younger than 80, with moderate to severe dementia, and PET and CSF evidence of AD pathology. Cells collected by liposuction are purified, and grown in culture to enrich for expression of WNT, a marker of self-renewal potential, and neuron lineage markers. The cells are delivered via a catheter into the lateral ventricle. A one-year follow-up includes repeated CSF sampling, cognitive testing, and amyloid-PET and MRI scans. Completion is expected in March 2025.
Results of the first cohort of three patients were presented at the October 2024 CTAD conference. In a poster, the company claimed only minor adverse events during liposuction and installation of the ventricle port, and no adverse events related to the infusion. In all three patients, CSF phosphoTau was lower after 12 weeks. In two patients evaluated, amyloid PET signal was also decreased. Two of the three improved on the MMSE at four or 12 weeks compared to baseline.
In other trials, additional sponsors are testing intravenous infusion of adipose-derived stem cells in Parkinson’s patients, and intrathecal injections in people with ALS.
For details on adipose-derived mesenchymal stem cell trials in dementia, see clinicaltrials.gov.
Last Updated: 29 Jan 2025
Further Reading
No Available Further Reading
Overview
Name: ANPD001
Synonyms: DANPC (dopaminergic neuron precursor cell)
Therapy Type: Other
Target Type: Other Neurotransmitters (timeline)
Condition(s): Parkinson's Disease
U.S. FDA Status: Parkinson's Disease (Phase 1)
Background
ANPD001 is a dopaminergic neuron replacement therapy derived from a patient’s own tissue. Fibroblasts from a skin biopsy are converted into pluripotent stem cells and then differentiated into dopaminergic neuron precursor cells. The cells are surgically infused with MRI guidance into the putamen on both sides of the brain, where they are expected to replace dopaminergic neurons that die in Parkinson’s disease. Because the patient’s own cells make up the graft, no immune suppression is needed.
The procedure for producing pluripotent stem cells and neurons was developed at Scripps Research, San Diego, California (Boland et al., 2017). The technology for generating dopaminergic neurons formed the basis for the founding of Aspen Neurosciences in 2018.
In preclinical work, ANPD001cells derived from two Parkinson’s disease patients were transplanted into rats with chemically induced parkinsonism (Hills et al., 2023). Neuron precursors that were differentiated for 18 days, but not 25 days, could relieve motor symptoms. Both types of grafts survived and expressed dopaminergic cell markers, but only the 18-day cells supported robust neurite outgrowth, and thus integration of the cells into the host brain. Gene expression analysis defined a profile associated with efficacy in the model. As presented at meetings, Aspen Neurosciences developed quality control benchmarks based on RNA expression profiling, to guide the selection of cells for transplantation (e.g., June 2022 press release).
A company-sponsored study used non-human primates to optimize the infusion technique (Emborg et al., 2024). Cynomolgus macaques received low-volume intraputaminal injections of 25 to 50 microliters over 10 to 20 minutes, using two needle tracks per side, under MRI guidance. This technique produced accurate placement of cells, which survived out to the last observation at 30 days. The first four animals implanted experienced minor brain swelling and three had transient reduced vision; modifications to surgery subsequently prevented these complications.
Findings
In April 2022, Aspen Neurosciences announced the start of patient screening for a planned Phase 1 trial (press release). The company initiated this trial-ready cohort to identify possible trial participants and begin cell manufacture.
In October 2023, ANPD001 received fast track designation from the FDA (press release).
In January 2024, Phase 1 began with an open-label safety and tolerability trial, making ANPD001 the first autologous cell therapy to enter human testing for Parkinson’s. Nine participants, who will be at least four years past diagnosis and without cognitive impairment, are to receive bilateral cell infusions targeted to the putamen by MRI guidance. Patients will be followed for five years post-transplantation, to assess adverse events, and effects on Parkinson’s symptoms. Cell survival will be measured by 18F-DOPA PET. After that, telephone follow-up will assess safety and tolerability for an additional 10 years. The study is enrolling by invitation at seven sites in the U.S., and is funded by the California Institute for Regenerative Medicine (press release).
On January 13, 2025, the company announced the completion of dose escalation and the first two cohorts in the trial. They reported no serious adverse events. The trial will proceed to test their commercial formulation (press release).
In an independent effort, researchers at McLean Hospital in Boston reported transplantation of patient-specific dopaminergic neuron progenitor cells in one person with Parkinson’s disease. The cells survived without the need for immunosuppression. Clinical symptoms stabilized or improved 18 to 24 months after implantation (Schweitzer et al., 2020). In August 2024, this group began a single-center Phase 1 safety trial in six patients, funded by the NIH and Oryon Cell Therapies. The study will deliver cells to the putamen on one side of the brain, and assess adverse events for 18 months after surgery.
For details on the ANPD001 trial, see clinicaltrials.gov.
Last Updated: 24 Jan 2025
Further Reading
No Available Further Reading
Overview
Name: AQNEURSA
Synonyms: N-acetyl-L-leucine, NALL, IB1001, levacetylleucine
Therapy Type: Small Molecule (timeline)
Target Type: Inflammation (timeline), Other (timeline)
Condition(s): Niemann-Pick Diseases, Ataxia, Lysosomal Storage Diseases, Nervous System
U.S. FDA Status: Niemann-Pick Diseases (Approved), Ataxia (Phase 3), Lysosomal Storage Diseases, Nervous System (Phase 2)
Company: IntraBio
Approved for: Neurological symptoms of Niemann-Pick Disease Type C
Background
N-acetyl-L-leucine is a modified derivative and prodrug of the naturally occurring essential amino acid leucine. In September 2024, the FDA approved this formulation of the pure L-leucine isomer to treat neurologic symptoms of the lysosomal storage disease Niemann-Pick type C in adults and children. NALL is currently in clinical trials for ataxia telangiectasia.
N-acetylation of L-leucine allows the amino acid to more easily enter cells (Churchill et al., 2021). The racemic mixture N-acetyl-DL-leucine has been used in France since the 1950s for the treatment of acute vertigo and dizziness, despite a lack of randomized clinical trials supporting its effectiveness (Vanderkam et al., 2019). Anecdotal reports and case studies reporting improvements in movement, cognition, and quality of life in patients with Niemann-Pick type C (NPC) or cerebellar ataxias of varying etiologies spurred interest in repurposing this drug (Bremova et al., 2015; Strupp et al., 2013). Other case series reported no benefit in cerebellar ataxia patients (Pelz et al., 2015), or in people with multiple systems atrophy (Scigliuolo et al., 2017).
Additional anecdotes describe improved mobility, cognition, and mood in mentally healthy elderly people, that disappear when the drug is discontinued (Platt and Strupp, 2016; Kolb, 2023). Symptomatic improvements and possible neuroprotection have also been reported in two people with REM sleep disorder, a prodrome of Parkinson’s disease (Oertel et al., 2024; Balint and Bhatia, 2024), and in people with the movement disorder restless leg syndrome (Fields et al., 2021).
The mechanism of NALL in these conditions is unknown. Earlier preclinical work indicated that N-acetyl-DL-leucine was able to normalize activity in vestibular neurons responsible for balance. This gave rise to a theory that similarly normalizing cerebellar neuron activity could improve ataxia symptoms. In a mouse model of NPC, the L-enantiomer NALL, but not the D-version, significantly delayed the onset of gait abnormalities and motor dysfunction, slowed disease progression, reduced microgliosis, and survival (Kaya et al., 2020). In a similar study of a mouse model of a lysosomal storage disease called Sandhoff’s, N-acetyl-dl-leucine improved motor function and slightly increased lifespan (Kaya et al., 2020). In these models, NALL normalized glucose and glutamate metabolism, increased autophagy, increased levels of superoxide dismutase, and improved mitochondrial energy metabolism.
NALL was investigated in other neurodegenerative conditions. In a mouse model of Parkinsonism, it alleviated motor deficits and was associated with neuroprotection and diminished neuroinflammation (Xu et al., 2023). NALL prevented cortical cell death and neuroinflammation, and improved functional recovery, in a mouse model of traumatic brain injury (Hegdekar et al., 2021).
Findings
NALL was approved to treat NPC based on a Phase 3 trial involving 53 children and adults. Twelve weeks of treatment improved total scores on the Scale for the Assessment and Rating of Ataxia (SARA), which includes gait, sitting, stance, and speech symptoms (Bremova-Ertl et al., 2024; and commentary by Tifft, 2024). The most common side effects were abdominal pain, difficulty swallowing, upper respiratory tract infections, and vomiting. The approved dose is 4 g daily for adults, and the drug is formulated as granules to be suspended in water, orange juice, or almond milk. In tests of phagocytic function of peripheral blood macrophages as a biomarker for microglial activity in NPD, NALL treatment was found to decrease this activity in six patients tested (Dinkel et al., 2024).
Prior to the pivotal Phase 3, IntraBio had completed Phase 2 studies for NPC and the related lysosomal storage diseases Tay-Sachs and Sandhoff. In both trials, NALL improved symptoms, functioning, and quality of life for children and adults, and was well-tolerated with no serious side effects (Bremova-Ertl et al., 2022; Martakis et al., 2023).
In 2016-2017, ALCAT tested 5 g daily acetyl-DL-leucine in 80 people with cerebellar ataxia of varying etiologies. This investigator-initiated trial showed no difference between drug and placebo on the SARA (Feil et al., 2021).
In January 2020, IntraBio began a Phase 2 trial for the symptomatic treatment of ataxia telangiectasia (Fields et al., 2021). This rare genetic disorder of DNA repair includes prominent symptoms of ataxia. The trial assesses six weeks of up to 4 grams daily NALL in 39 children and adults, with a primary endpoint of clinician impression of change in severity. Secondary outcomes include ataxia scales, and clinician, parent, or patient clinical global impressions, and quality of life. The trial, at five locations in the U.S., Germany, Spain, and the United Kingdom, is expected to finish in March, 2025. At that time, the company plans to begin a new, pivotal Phase 3 study in 60 children and adults, who will be treated for 12 weeks with 2-4 g daily against a primary outcome of the SARA. That trial is planned to run to the end of 2027.
Previously, an independent trial of children with ataxia telangiectasia found no benefit of 1-4 grams NALL per day on ataxia symptoms, although constipation and nausea improved (Beyraghi-Tousi et al., 2024).
NALL has multiple Orphan Drug Designations for rare inherited lysosomal storage disorders, spinocerebellar ataxia, ataxia telangiectasia, multiple systems atrophy, and others. Investigators in Switzerland and Germany are awaiting approval to conduct clinical trials in PD and AD (Jan 2025 news).
For details on NALL trials, see clinicaltrials.gov.
Last Updated: 23 Jan 2025
Further Reading
No Available Further Reading
Species: Mouse
Genes: Park2
Modification: Park2: Knock-Out
Disease Relevance: Parkinson's Disease
Strain Name: B6.129S4-Prkntm1Shn/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+.
Neuronal Loss
In the substantia nigra, the number of dopaminergic neurons (as detected by TH staining) did not differ between parkin KO and wild-type mice up to 24 months. Dopaminergic projections in the striatum were also normal.
Dopamine Deficiency
Levels of striatal dopamine and metabolites DOPAC and HVA were normal at 6, 12, 18, and 24 months. In another study, striatal extracellular dopamine was increased, as measured by no-net-flux microdialysis, in 8-9-month-old mice. In a third study, evoked striatal dopamine release was reduced in striatal slices of 2-4-month-old mice.
α-synuclein Inclusions
Inclusions of α-synuclein were not observed in any brain region.
Neuroinflammation
Spinal cord staining of GFAP did not differ between non-transgenic and parkin KO mice at 130 days of age.
Mitochondrial Abnormalities
Mitochondrial defects begin at 7 weeks. Proteomic analyses reveal differences in ventral midbrain lysates of proteins involved in mitochondrial function. Respiratory and antioxidant capacity, mitophagy, and mitochondrial DNA are affected. Mitochondrial structure appears intact in the brain, but is affected in heart tissue.
Motor Impairment
On the beam traversal task, KO mice displayed deficits starting at 2-4 months of age. General behavior (beam breaks) on the open-field test did not differ at 6, 12, and 18 months of age. Findings on the Rotarod suggest no differences or that KO mice may have enhanced performance.
Non-Motor Impairment
Novel object recognition was decreased at 4-5 months of age and reduced sociability, increased repetitive behaviors, and deficits in communication were present at 2-3 months of age. Outcomes from the forced swim test, time spent investigating novel odors, latency to find buried food, the Barnes maze test, hot plate test, Morris water maze appear unaffected.
Last Updated: 25 Nov 2024
Further Reading
No Available Further Reading
Overview
Name: LY3954068
Therapy Type: DNA/RNA-based
Target Type: Tau (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: Eli Lilly & Co.
Background
LY3954068 is a small interfering RNA (siRNA) that targets expression of the microtubule-associated binding protein tau. No information is available about the makeup of LY3954068. In general, siRNAs are double-stranded RNA molecules about 20 to 25 nucleotides long, which bind to complementary sequences on mRNA and induce RNA interference, resulting in degradation of target mRNAs. As such, LY3954068 is designed to reduce the levels of tau protein. This strategy assumes that decreasing the abundance of tau will slow the formation of tau aggregates and progression of tau pathology. LY3954068 is being studied for the treatment of neurodegenerative diseases.
No preclinical work is published on LY3954068. More generally, one published study tested the effects of a MAPT siRNA delivered directly to the brains of P301S tau-expressing mice. After a single injection, the siRNA partially spread through the hippocampus and suppressed tau expression, with no signs of neurotoxicity or neuroinflammation (Xu et al., 2014). MAPT siRNA improved recovery after spinal cord injury in rats (Chen et al., 2023). However, another study claimed it impaired the migration of Schwann cells after nerve injury in rats, interfered with cytoskeletal protein expression and distribution, and compromised myelin and lipid debris clearance in these cells (Yi et al., 2019).
An alternative approach to reducing tau expression uses antisense oligonucleotides to block mRNA translation (DeVos et al., 2013; DeVos et al., 2017). Two of these are in early stage clinical trials (BIIB080; NIO752).
Findings
In August 2024, Lilly began a first-in-human study of LY3954068 in 32 people with early symptomatic Alzheimer's Disease. Participants must have a Clinical Dementia Rating of 0.5 or 1, and a TAUVID™ PET scan indicating tau pathology. In the first part of the study, they will receive a single intrathecal injection of siRNA or placebo, and be followed up for six months. The primary outcome is number of participants with adverse events. Secondary endpoints are plasma and CSF pharmacokinetics, and change in CSF tau concentration. An optional multiple-dose arm will test two injections, with additional follow-up. Completion is expected in February 2027.
For details on this trial, see clinicaltrials.gov.
Last Updated: 25 Nov 2024
Further Reading
No Available Further Reading
Overview
Name: RNS60
Synonyms: oxygen nanobubbles
Therapy Type: Other
Target Type: Inflammation (timeline), Other (timeline)
Condition(s): Amyotrophic Lateral Sclerosis
U.S. FDA Status: Amyotrophic Lateral Sclerosis (Phase 2)
Company: Revalesio Corporation
Background
RNS60 is saline containing charged oxygen nanobubbles. It is created by mixing 0.9 percent normal saline with pressurized oxygen using a technique owned by Revalesio. The nanobubbles allow oxygen to be retained in the solution for longer and at higher concentrations compared to conventionally dissolved oxygen. RNS60 is delivered intravenously or by inhalation. It is unclear where or how the oxygen is delivered to cells.
According to preclinical work funded by Revalesio, RNS60 can activate phosphatidylinositol-3-kinase (PI3 kinase) to promote anti-inflammatory, immunomodulatory, and neuroprotective actions (Dec 2014 conference news; Jana et al., 2018). Independent researchers reported increased mitochondrial activity, ATP production, and synaptic activity in cells treated with RNS60 (Choi et al., 2014; Choi et al., 2015), as well as improved neurotransmission and reduced fatigue in isolated muscle preparations (Ivannikov et al., 2017).
Revalesio-funded work claimed neuroprotective effects in a mouse model of Parkinson’s disease of 300 μl daily intraperitoneal injections or delivery by nebulizer (Khasnavis et al., 2014; Mondal et al., 2017). The proposed mechanism was enhancement of regulatory T cell (Treg) activity. Another study reported upregulated mitochondrial biogenesis and increased levels of neuroprotective gene expression in isolated dopaminergic neurons after RNS60 exposure (Chandra et al., 2018; Jana et al., 2023).
In the 5XFAD transgenic mouse model of Alzheimer’s disease, intraperitoneal injection of 300 μl RNS60 every other day for two months reportedly suppressed neuronal apoptosis, attenuated tau phosphorylation, inhibited glial activation, reduced hippocampal Aβ, and improved memory and learning (Modi et al., 2014). RNS60 was also claimed to enhance expression of genes related to synaptic plasticity, and to increase calcium influx in cultured hippocampal neurons (Roy et al., 2014).
Other company-funded or co-authored studies reported beneficial effects of intraperitoneal administration in the SOD1 mutant mouse model of ALS (Vallarola et al., 2018), and models of traumatic brain injury (Rangasamy et al., 2020), heart attack (Zabielska-Kaczorowska et al., 2022), and stroke (Baena-Caldas et al., 2024).
Starting in 2014, Revalesio’s subsidiary Reliant Hydration briefly marketed an oxygenated water for athletic performance and recovery (press release). In 40 healthy adults, drinking the water for 23 days was claimed to reduce exercise-induced muscle damage and inflammation, and improve muscle recovery (Borsa et al., 2013). A Phase 1 trial, run from 2012-2015 at New York University, tested the water against placebo for changes in brain activity measured by magnetoencephalography in healthy adults. No results were made public. The product drew an FDA warning when a National Football League player and company investor claimed the water protected him against concussion (2015 news). See also 2014 Derek Lowe blog. Several RNS60 papers were flagged on PubPeer and have been corrected.
Findings
In 2011-2013, Revalesio ran multiple Phase 1 studies. The first was a safety and tolerability study of intravenous RNS60 in 12 healthy subjects. Each received intravenous infusions of RNS60 or normal saline at three escalating rates for 48 hours. Other trials tested a single 4 ml dose of nebulized RNS60 in 36 healthy adults or mild asthma patients, or nebulized RNS60 in combination with the asthma treatment budesonide. No results have been disclosed for these trials.
In 2012, the FDA approved a single-person compassionate use trial for ALS patient Tony Wood, the inventor of the process to make RNS60. Wood received twice weekly infusions beginning in March 2012 (Dallas Morning News). He died of ALS in August 2015.
In 2015, Revalesio ran a Phase 1 study in 56 healthy adults in the UK, who received 4 ml RNS60 or normal saline by nebulizer twice daily for 22 days. On day 19, participants undertook an exercise protocol to induce muscle damage, followed by measurement of creatine kinase and C reactive protein markers of muscle strain and inflammation. No results have been reported.
From 2015-2017, a Phase 1 pilot trial at Massachusetts General Hospital in Boston tested RNS60 in 16 ALS patients. A 23-week regime of weekly intravenous infusion of 375 ml and daily 4 ml nebulization causes no serious adverse events or withdrawals due to adverse events (Paganoni et al., 2019). Eighty percent of enrollees finished the treatment, with no significant changes in blood IL-17 or Treg function, or in brain inflammation measured by TSPO PET.
In December 2016, Revalesio registered a Phase 2 trial to test nebulized RNS60 in ALS patients. Originally planned to start in October 2018, the study is now slated to run from October 2025 to November 2027. It will enroll 140 participants for six months of daily RNS60 or placebo, against a primary outcome of the ALSFRS-R. Secondary outcomes are deaths or tracheostomies, Treg numbers, lung function, patient-reported outcomes, and adverse events.
In May 2017, a Phase 2 ALS trial began at the Mario Negri Institute in Italy. This academic-sponsored, placebo-controlled biomarker trial enrolled 147 patients at multiple sites in Italy. They received 24 weeks of RNS60 or normal saline, delivered by once-weekly 375 ml infusions and daily 4 ml nebulization. All participants also took riluzole. Primary endpoints were changes in blood biomarkers known to be modified in preclinical studies, i.e., Il-17, Tregs, and protein nitration, as well as ALS markers MCP-1 and PPIA, and the neurodegeneration marker NfL. Secondary endpoints included clinical measures of ALS Functional Rating Scale-Revised, survival, decline in lung function, quality of life, and safety. The trial finished in May 2021, and results are published. There were no treatment-related changes in biomarkers. Decline on the forced vital capacity measure of lung function, and eating and drinking abilities, were slower in the RNS60 group. In a post hoc subgroup analysis, NfL increased over time in bulbar onset placebo patients, but remained stable in those treated with RNS60, although differences with treatment were not statistically significant (Beghi et al., 2023). After 2.8 years median follow-up, the treated group survived a statistically significant six months longer than the placebo group. The survival benefit was greatest in patients with low NfL and MCP-1 levels at the start of the study (Pupillo et al., 2024).
Other Phase 2 trials have been completed for asthma, multiple sclerosis, and stroke. No results have been released. Additional studies planned for asthma, multiple sclerosis, knee pain, and hip pain were withdrawn.
For details on RNS60 trials, see clinicaltrials.gov.
Last Updated: 21 Nov 2024
Further Reading
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Overview
Name: AV-1980R/A
Synonyms: AV-1980R
Therapy Type: Immunotherapy (active) (timeline)
Target Type: Tau (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Background
AV-1980R/A is recombinant protein-based tau vaccine designed to elicit antibodies to pathologic tau. It fuses three copies of a tau2-18 peptide to 12 T-cell activating antigens. This MultiTep vaccine platform includes a synthetic pan-T cell antigen, as well as antigens derived from Tetanus toxin, hepatitis B, and influenza virus. The foreign antigens function to boost antibody responses to the tau peptide by activating memory and helper T cells, while avoiding stimulation of potentially harmful autoreactive T cells. This is important in older people, who tend to mount weaker responses to vaccines. The vaccine is formulated with the adjuvant AdvaxCpG55.2.
This vaccine targets a different tau epitope than did previous, failed N-terminal directed tau antibodies (Nov 2022 conference news). The tau2-18 peptide includes tau’s so-called phosphatase activation domain, which is hidden in normally folded tau, and becomes exposed once tau starts to aggregate (Combs et al., 2016; Combs and Kanaan, 2017).
In preclinical work, AV-1980R/A induced high antibody titers in mice (Davtyan et al., 2016). Antibodies from vaccinated PS19 tau transgenic mice recognized neurofibrillary tangles and plaque-associated dystrophic neurites in AD brain sections, and nondenatured tau from AD brain (Hovakimyan et al., 2019). Vaccination prevented age-related motor and cognitive deficits in the PS19 mice, and significantly reduced insoluble and phosphorylated tau species in brain. In the Tg4510 tau mouse model, immunization induced strong antibody responses, and detectable IgG in brain. These animals had improvement in short-term memory, but not in other behavioral tasks. Antibodies reduced pSer396 tau, but not other phosphorylated species, in brain (Joly-Amado et al., 2020). In nonhuman primates, the vaccine elicited antibodies that recognized pathological tau tangles and tau-positive neurites in sections from AD brain without staining sections from non-AD brain, supporting human trials (Hovakimyan et al., 2022).
A DNA version of AV-1980 produced high titer antibodies, with no evidence of autoreactive T cell responses in THY-Tau22 mice (Davtyan et al., 2017). Vaccination reduced brain total tau and some forms of phosphorylated tau in the mice.
The MultiTEP platform is being used to develop other vaccines for neurodegenerative diseases. The Aβ vaccine AV-1959D is currently in Phase 1. Vaccines to α-synuclein, and a dual Aβ/tau vaccine are also being developed (Kim et al., 2022; Davtyan et al., 2019).
Findings
A Phase 1 study is planned to begin in July 2025. It will enroll 48 participants with preclinical AD who are amyloid-positive and without cognitive impairment. Three cohorts are to receive 20, 60, or 180 μg, or placebo, by intramuscular injection four times over 36 weeks. Primary outcomes are safety, tolerability, and adverse events. Secondary outcomes will assess anti-tau antibodies in blood, T helper response, and possible activation of autoreactive T cells. Exploratory outcomes are changes in AD-related brain and plasma biomarkers including Aβ42, Aβ40, Aβ42/40, p-tau217, p-tau181, p-tau231, t-tau, NfL, GFAP, and tau MK-6240 PET; and immune response profile by immunoglobulin isotypes, cytokines, and other measures.
This trial is not listed in registries yet.
Last Updated: 21 Nov 2024
Further Reading
No Available Further Reading
Species: Mouse
Modification: Multi-transgene
Disease Relevance: Down's Syndrome, Alzheimer's Disease
Strain Name: B6EiC3Sn a/A-Ts(1716)65Dn/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
Although Ts65Dn mice exhibit age-related increase in APP and Aβ levels in the cortex and hippocampus, they do not show plaque pathology. However, an increase in soluble Aβ oligomers and small amyloidal extracellular inclusions in the deep granular cell layer of the cerebellum has been reported.
Tangles
Although Ts65Dn mice exhibit increased tau phosphorylation, they do not develop neurofibrillary tangles.
Neuronal Loss
By 6 months, there is a loss of basal forebrain cholinergic neurons in the medial septal nucleus. From 10-11 months, a decrease in ChAT+ motor neurons are observed. Additional deficits include reduced brain volume, impaired neurogenesis, decreased neuronal density, and abnormal dendritic spine morphology, which are present in earlier stages of development.
Gliosis
Ts65Dn mice show a developmental shift from neuronal to astrocytic lineage, leading to an increased percentage of astroglial cells in the cortex and hippocampus. By 10 to 18 months, an elevated density of CD45+ microglia cells are found in the hippocampus and basal forebrain, with IBA1 upregulation at 12 months and reduced expression of the homeostatic microglial marker P2RY12 at 15 months.
Synaptic Loss
Ts65Dn mice have more inhibitory synapses, and fewer excitatory synapses. Synaptic density is decreased in both the hippocampus and neocortex, accompanied by enlarged pre-synaptic boutons and spines. Changes in the physical distribution of afferent inputs also occur.
Changes in LTP/LTD
Ts65Dn mice demonstrate impaired hippocampal long-term potentiation (LTP) due to excessive GABA-mediated inhibition.
Cognitive Impairment
Ts65Dn mice exhibit reduced attention, and deficits in hippocampal-dependent functions, including contextual fear conditioning, working memory, and long-term spatial memory.
Last Updated: 20 Nov 2024
Further Reading
No Available Further Reading
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