Overview
Name: AIT-101
Synonyms: Apilimod, apilimod dimesylate, STA-5326, LAM-002A
Chemical Name: N-[(E)-(3-methylphenyl)methylideneamino]-6-morpholin-4-yl-2-(2-pyridin-2-ylethoxy)pyrimidin-4-amine
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Amyotrophic Lateral Sclerosis
U.S. FDA Status: Amyotrophic Lateral Sclerosis (Phase 2)
Company: OrphAI Therapeutics
Background
AIT-101 is a proprietary oral formulation of apilimod, an inhibitor of the phosphatidylinositol phosphate kinase PIKfyve. This lipid kinase phosphorylates signaling molecules in early endosomes that control endosomal function and fusion with lysosomes. Inhibitors of PIKfyve promote trafficking and clearance of aggregation-prone proteins via autophagy.
Apilimod was originally developed for autoimmune diseases, because it blocked inflammatory cytokine production evoked by Toll-like receptor activation (Wada et al., 2007). The compound progressed to Phase 2 clinical trials for Crohn’s disease and rheumatoid arthritis, where doses of 50-200 mg daily were safe but lacked efficacy (Sands et al., 2010; Krausz et al., 2012). Side effects were mild to moderate headache, fatigue, dizziness, and nausea. After these studies, apilimod’s target was identified as PIKfyve (Cai et al., 2013). Apilimod inhibits PIKfyve with an IC50 of 14 nM, and shows no activity toward other lipid or protein kinases.
The interest in repurposing apilimod for ALS arose when PIKfyve inhibitors were identified in a drug screen to extend the survival of iPSC-derived motor neurons from C9ORF72 ALS patients (Shi et al., 2018). In these cells, apilimod protected against neurotoxicity, and promoted clearance of toxic C9ORF72-encoded dipeptides by autophagy. In mouse models, apilimod blocked neurodegeneration and lowered levels of dipeptide protein aggregates in hippocampal neurons. It similarly rescued motor deficits in a zebrafish model of dipeptide toxicity (de Calbiac et al., 2024). Apilimod increased the exocytosis of toxic aggregates of the RNA binding protein TDP-43 in C9ORF72 cells and animal models of ALS, and also in cells from sporadic cases, or cases caused by mutations in TDP-43 or FUS. In ALS mouse models, intracranial delivery of apilimod reduced pathology and extended survival (Hung et al., 2023).
Apilimod has also been reported to reduce lysosomal trafficking and seeding of tau and synuclein aggregates (Soares et al., 2021; See et al., 2021).
Findings
In December 2021, AI Therapeutics began a Phase 2 biomarker study evaluating AIT-101’s safety, tolerability, and activity in 14 patients with C9ORF72-associated ALS. The trial compares 12 weeks of 250 mg daily AIT-101 or placebo, divided in two doses of five capsules each, added to standard care. After the placebo-controlled period, participants were to be offered 12-week and 36-week open-label extensions, for a maximum of 60 weeks on drug. Primary outcomes are adverse events and dropouts at 12 weeks, as well as plasma and CSF pharmacokinetics. Other outcomes include changes in plasma and CSF levels of C9 repeat expansion proteins, ALS disease biomarkers, and clinical measures of ALS symptoms.
On April 5, 2023, the company claimed announced positive results of the placebo-controlled study (press release). Participants taking AIT-101 for 12 weeks were claimed to have a 73 percent reduction in C9 poly(GP) proteins, and increased expression of a target engagement biomarker, sGPNMB. The drug was safe, and entered the brain. Results were published after peer review (Babu et al., 2024). Patients who completed the 12-week treatment were offered the drug under a compassionate use extension protocol.
Under the name LAM-002A, AIT-101 completed Phase 2 for SARS-COV2 infection in April 2021, and was also evaluated for lymphoma (Harb et al., 2017; see Phase 2 results on clinicaltrials.gov). Neither indication is listed on the company pipeline.
In 2023, AI Therapeutics changed its name to OrphAI Therapeutics. AIT-101 has orphan drug status in the U.S. and Europe. According to the company website, further development of AIT-101 is on hold pending additional funding.
For details on these trials, see clinicaltrials.gov.
Last Updated: 18 Oct 2024
Further Reading
No Available Further Reading
Species: Mouse
Disease Relevance: Alzheimer's Disease, Frontotemporal Dementia, Nasu-Hakola Disease
Strain Name: B6J-Trem2em4(mKate2)Bwef
Summary
In this mouse, TREM2 and the fluorescent protein mKate2 are co-expressed under the control of the endogenous Trem2 promoter, allowing researchers to indirectly assess expression of TREM2 by measuring mKate2 fluorescence (Feiten et al., 2024).
Last Updated: 17 Oct 2024
Further Reading
No Available Further Reading
Species: Mouse
Modification: Conditional Knock-out
Disease Relevance: Parkinson's Disease
Strain Name: Ndufs2tm1.1Job Slc6a3tm1.1(cre)Bkmn/SurmJ
Modification Details:
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
TH expression decreased at 30 days in the dorsal striatum. By age 60 days, TH expression decreased in substantia nigra dopaminergic neurons. No neurodegeneration was observed in axons, cell bodies, or dendritic arbors of SN dopaminergic neurons at 60 days. By 120 to 150 days, neurodegeneration is present and about 40% of SN dopaminergic neurons are lost.
Dopamine Deficiency
Profound loss of evoked dopamine release in the dorsolateral striatum as early as 30 days. In contrast, somatodendritic dopamine release in the SN did not differ between genotypes at 30 days, but was dramatically reduced by 60 days.
Mitochondrial Abnormalities
By 20 days mitochondria were in an oxidative phosphorylation deficit. Altered mitochondria structure, but not mitochondrial density, was observed at 35 days in dopaminergic neurons of the SN. Metabolic reprogramming to a glycolytic-predominant state of mitochondria was indicated by alterations in expression of genes and functional pharmacologic experiments.
Motor Impairment
Striatal motor learning (adhesive removal test) was impaired starting at 30 days. Rearing in the cylinder testing was impaired at 40 days. Total distance travelled was decreased by 60 days on the open-field test. By 100 days, splayed hindlimbs, abnormal paw placement, and alterations in stride observed.
Non-Motor Impairment
Impaired associative learning (Y-maze test) at 30 days . Impaired sleep functions starting at 6 weeks of age, with significantly altered sleep-wake patterns (total, NREM, and REM sleep), increased sleep fragmentation, and altered EEG activity.
Last Updated: 14 Oct 2024
Further Reading
No Available Further Reading
Species: Mouse
Genes: Gba1
Modification: Gba1: Knock-In
Disease Relevance: Parkinson's Disease
Strain Name: B6.129X1(C)-Gba1tm1.1Eginn/J
Modification Details:
Summary
These Gba1 knock-in (KI) mice carry a leucine to proline mutation (L444P) in exon 10 of the mouse Gba1 (glucosidase [GCase], beta, acid 1) gene, resulting in Gba deficiency (Ginns et al., 2014; The Jackson Laboratory). This mutation is commonly found in humans with Gaucher disease, and people with GBA1 mutations have a higher risk of developing Parkinson’s disease.
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
No loss in dopaminergic cell numbers in the substantia nigra at 14 months of age.
α-synuclein Inclusions
α-synuclein deposition reported in the striatum of 1-year-old mice in one study, but no differences in α-synuclein levels found in brain extracts of 6- and 14-month-old KI mice in another study.
Neuroinflammation
Increased GFAP immunoreactivity observed in the striatum of 1-year-old mice in one study, but no differences in striatal GFAP or Iba-1 immunostaining observed in another study of 14-month-old KI mice.
Mitochondrial Abnormalities
Motor Impairment
No deficits in motor balance, as detected by Rotarod and balance beam tests, observed in 16-month-old L444P KI mice.
Last Updated: 07 Oct 2024
Further Reading
No Available Further Reading
Species: Mouse
Genes: Park2
Mutations: Park2 S65A
Modification: Park2: Knock-In
Disease Relevance: Parkinson's Disease
Strain Name: C57BL/6-Prkntm1.1Muqit/J
Modification Details:
Summary
These knock-in (KI) mice carry a serine to alanine mutation (S65A) in the N-terminal ubiquitin-like domain of the Park2 gene that encodes Parkin, a ubiquitin E3 ligase (McWilliams et al., 2018). Serine 65 is the site at which PINK1 (PTEN-induced kinase 1) phosphorylates Parkin to induce mitophagy. This mutation is relevant to Parkinson’s disease as PARK2 mutations (including at serine 65) are associated with early-onset disease in humans.
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
No deficits in striatal anatomy or volume or in nigrostriatal innervation in 18-month-old homozygous KI mice.
Dopamine Deficiency
No differences in levels of striatal dopamine and 3,4-DOPAC, nor in their ratio, between 18-month-old homozygous KI mice and wild-type mice.
Neuroinflammation
Immunolabeling of astrocytes (GFAP) and microglia (Iba1) did not differ between homozygous Parkin KI mice and wild-type mice.
Mitochondrial Abnormalities
Mitochondrial respiration (respiratory control ratio) was impaired in an age-dependent manner—at 12 months, but not at 3 months—in homozygous KI mice. No deficits in basal mitophagy.
Motor Impairment
Impaired performance on the raised balance beam at 12 and 18 months of age in homozygous KI mice. No deficits in Rotarod performance or gait analysis.
Last Updated: 22 Sep 2024
Further Reading
No Available Further Reading
Overview
Name: Foralumab
Synonyms: TZLS-401, NI-0401, 28F11-AE
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Inflammation (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Tiziana Life Sciences
Background
Foralumab is a human monoclonal IgG antibody to the CD3 T cell antigen receptor. It modulates the immune system to promote immunosuppressive and anti-inflammatory responses, in part by stimulating the production of regulatory T cells. This antibody, originally from Novimmune, was acquired by Tiziana. It is administered as an intranasal spray.
Immune control by regulatory T cells (Tregs) appears to be compromised in people with AD (Faridar et al., 2020). In animal studies, Tregs that were transferred into AD mice entered the brain and stopped Aβ plaque growth (Faridar et al., 2022). Multiple labs have reported beneficial effects of Treg expansion on plaque load and memory deficits in mouse models of AD (Dansokho et al., 2016; Alves et al., 2017; Yuan et al., 2023). The rationale for foralumab is similar to that of low-dose interleukin-2, another immune modulatory therapy being tested in AD.
In preclinical work with the 3XTg mouse model of AD, nasal administration of 1 microgram foralumab three times weekly for five months improved spatial learning and long-term memory, but caused no change in brain Aβ accumulation (Lopes et al., 2023). Treatment increased the frequency of Tregs in the periphery, and promoted infiltration of T cells into the brain, where they associated with microglia. Microglial gene expression changed in favor of a homeostatic phenotype, rather than inflammatory or neurodegenerative profiles. Previously, nasal foralumab had been shown to increase Tregs, and ameliorate autoimmune symptoms in a model of Lupus in mice (Wu eat al., 2008). In a multiple sclerosis mouse model, nasal antibody induced regulatory T cells that dampened brain microglia inflammation (Mayo et al., 2016).
Findings
A Phase 1 study involving 27 healthy volunteers tested foralumab doses of 10, 50, or 250 μg, or placebo, given daily as a nasal spray for five days. According to published results, all doses were well-tolerated, with no serous adverse events reported. No participants developed anti-drug antibodies. RNA sequence analysis of peripheral immune cells found induction of genes related to Tregs, and promotion of anti-inflammatory responses in monocytes. Effects were most prominent at 50 μg, and minimal at 10 or 250 μg. The treatment did not appear to directly expand cells with a classical Treg phenotype (Chitnis et al., 2022).
In a pilot trial in 39 mild COVID-19 patients, the antibody reduced serum markers of inflammation (Il-6 and C-reactive protein), and led to faster lung recovery (Moreira et al., 2021; Moreira et al., 2023). Treatment was tolerated, with no serious adverse events, changes in blood cell counts, or hypersensitivity reactions.
On June 26, 2024, the company announced that AD patients would be treated with nasal foralumab under an FDA-approved expanded access program (press release).
In September 2024, a small, placebo-controlled Phase 2 trial began to test foralumab in 16 people with AD. Treatment is planned to be 50 or 100 microgram three times weekly for two weeks, followed by a one-week break, for four cycles of treatment over three months. Participants must have early Alzheimer’s symptoms and a positive amyloid PET scan. Primary outcomes are safety, microglia function measured by [18F]PBR06 PET, and the ratios of T cell subsets in blood. The study, at Brigham and Women’s Hospital in Boston, is planned to finish in June 2026.
This antibody is also in development for multiple sclerosis, under an FDA fast track designation (July 2024 press release). A Phase 2a trial, slated to finish in late 2024, is assessing safety and brain microglia activation with PET. Additional patients are being treated under an expanded access program.
For details on foralumab trials, see clinicaltrials.gov
Last Updated: 10 Sep 2024
Further Reading
No Available Further Reading
Species: Mouse
Genes: GBA1, Gba1
Modification: GBA1: Transgenic; Gba1: Knock-Out
Disease Relevance: Parkinson's Disease
Strain Name: Gba1tm1.1Clk Tg(CAG-GBA*L483P)8Clk/Mmjax
Modification Details:
Summary
This mouse model carries one copy of a human HGBA L444P transgene, which encodes a mutated acid β-glucosidase (also known as β-glucocerebrosidase or GCase), on a mouse Gba1 null background and is referred to as the HGBA L444P/Gba−/− mouse (Sanders et al., 2013). This hemizygous expression of a mutated human transgene rescues homozygous Gba1 null mice from perinatal lethality.
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
Older HGBA N370S/Gba−/− mice do not show evidence of neuropathology.
α-synuclein Inclusions
Older HGBA L444P /Gba−/− mice do not show evidence of α-synuclein inclusions.
Motor Impairment
No obvious phenotypic features noted.
Last Updated: 28 Aug 2024
Further Reading
No Available Further Reading
Species: Mouse
Genes: GBA1, Gba1
Modification: GBA1: Transgenic; Gba1: Knock-Out
Disease Relevance: Parkinson's Disease
Strain Name: Gba1tm1.1Clk Tg(CAG-GBA*N409S)#Clk/Mmjax
Modification Details:
Summary
This mouse model carries one copy of a human HGBA N370S transgene, which encodes a mutated acid β-glucosidase (also known as β-glucocerebrosidase or GCase), on a mouse Gba1 null background and is referred to as the HGBA N370S/Gba−/− mouse (Sanders et al., 2013). This hemizygous expression of a mutated human transgene rescues homozygous Gba1 null mice from perinatal lethality.
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
Neuronal Loss Older HGBA N370S/Gba−/− mice do not show evidence of neuropathology.
α-synuclein Inclusions
Older HGBA N370S/Gba−/− mice do not show evidence of α-synuclein inclusions.
Motor Impairment
No obvious features noted.
Last Updated: 28 Aug 2024
Further Reading
No Available Further Reading
Overview
Name: VG-3927
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 1)
Company: Vigil Neuroscience, Inc.
Background
VG-3927 is a brain-penetrant, small-molecule agonist of the TREM2 receptor on microglia. TREM2 activation stimulates proliferation and phagocytic function of microglia, which play a central role in Alzheimer's disease pathology. Genetic variation in TREM2 is linked to AD (see TREM2 Mutations), whereby reductions in receptor activity increase risk.
TREM2 agonist antibodies and small molecules are being tested for their ability to spur phagocytosis and clearance of Aβ and treat Alzheimer's disease. VG-3927 is taken by mouth.
Preclinical work has been presented at conferences. At AD/PD 2023, the company reported that its TREM2 agonist compounds bring together TREM2 receptors on the cell surface. In humanized TREM2 mice, and in nonhuman primates, the compounds entered the brain. There, they suppressed the levels of soluble TREM2, an extracellular domain receptor fragment. This suggests the compounds may slow processing and internalization of TREM2 (Apr 2023 conference news). At AD/PD 2024 in Lisbon, the company presented that 5XFAD mice fed VG-3927 for six weeks had about 40 percent less plaque and insoluble Aβ42. Microglia expressed a neuroprotective, disease-associated microglia (DAM)-like gene expression signature (Apr 2024 conference news).
Preclinical results presented at AAIC 2024 showed that VG-3927 preferentially binds to membrane TREM2 over soluble receptor fragments, suggesting that the compound’s activity may not be diminished by soluble TREM2 that accumulates around plaques in AD brain. In mice, the compound increased microglial amyloid phagocytosis comparably to an approved Aβ antibody. VG-3927-induced phagocytosis was not affected by Fc antibody receptor blockage, confirming that its mechanism differs from Aβ antibodies, and that the two could be used together without reducing efficacy.
Findings
In September 2023, VG-3927 became the first small-molecule TREM-2 agonist cleared to enter the clinic. In October 2023, the first volunteer was treated in a Phase 1, placebo-controlled, single- and multiple-ascending-dose safety study being conducted in Miami. The trial plans to enroll 90 healthy volunteers in seven single-dose and four multiple-dose cohorts. Endpoints are to be safety, pharmacokinetics, and CSF levels of drug and soluble TREM2. The FDA allowed the trial to begin under a partial clinical hold that limited the maximum drug exposure (press release). The agency subsequently requested additional preclinical toxicology data before it would lift the limit. The company claims that predicted efficacious doses fall below the exposure limit set by the FDA (press release).
At the July 2024 AAIC, Vigil presented single-dose results, reporting that VG-3927 thus far was safe. Adverse events were mild or moderate and resolved on their own; there were no serious adverse events. Pharmacokinetics were suitable for daily dosing. The drug caused significant reductions in soluble TREM2 at the three highest doses, demonstrating target engagement. In a press release, the company claimed safety and lower CSF soluble TREM2 in two completed multiple-dose cohorts, who received drug daily for two weeks. The company intends to add a cohort of AD patients to explore biomarker responses to VG-3927, and to report complete trial data in early 2025.
For details on VG-3927 trials, see clinicaltrials.gov.
Last Updated: 05 Aug 2024
Further Reading
No Available Further Reading
Overview
Name: ADEL-Y01
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Tau (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: ADEL, Inc., Oscotec Inc.
Background
ADEL-Y01 is a humanized IgG1 monoclonal antibody that binds tau protein modified by acetylation at lysine residue 280. Tau acetylation at lysine residues is associated with protein aggregation and pathology in various tauopathies, including Alzheimer’s disease (e.g. Min et al., 2010; Cohen et al., 2011). K280 lies in a region critical for tau aggregation, and acetyl-K280 has been detected in AD and other human tauopathies (Irwin et al., 2012; Wesseling et al., 2020).
In preclinical work, an acetylated tau fragment spanning K280 was able to seed and accelerate aggregation of tau in vitro and in cells, and was more neurotoxic than the non-acetylated version. Mutational analysis suggested that K280 acetylation accounted for the enhanced toxicity. In the P301L mouse model of tau pathology, immunization with a tau 275-286 peptide, acetylated at K280, decreased the levels of phosphorylated and acetylated tau in brain, and improved cognitive and motor performance. The Y01 monoclonal antibody raised to this peptide interacted with acetylated K280 and surrounding residues in intact tau, inhibited aggregation and propagation of acetylated tau, and promoted tau uptake by microglia. The antibody detected K280-acetylated tau in human AD brain sections and CSF, and in P301L mouse brain lysates. Treatment of P301L mice with the antibody reduced memory impairment, behavioral deficits, and tau pathology (Song et al., 2023). A different group reported comparable effects on tau pathology and behavior after treatment of tauopathy mice with an antibody to acetylated tau K174 (Parra Bravo et al., 2024).
Findings
In February 2024, ADEL and Oscotec began a first-in-human Phase 1 study of ADEL-Y01. Forty healthy participants are to receive single intravenous infusions of antibody at 2.5, 7.5, 20, 50, or 100 mg/kg, or placebo. After that, a multiple-ascending-dose study is planned for 33 participants with MCI or mild AD who are to receive six doses of 7.5, 20, and 50 mg/kg, or placebo, given every two weeks. Primary outcomes include adverse events and clinical safety assessments; secondary outcomes span pharmacokinetics, immunogenicity, CSF exposure, and, in the patients, preliminary clinical measures of the CDR-SB and MMSE. The study will also assess CSF and plasma biomarkers of Aβ, phosphorylated tau and acetylated tau, as well as markers related to neurodegeneration and inflammation. CSF will be assayed for tau aggregates and tau seeding potential. The trial will run by a clinical CRO in Anaheim, California, through May 2026.
For details on ADEL-Y01 trials, see clinicaltrials.gov
Last Updated: 02 Aug 2024
Further Reading
No Available Further Reading
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