Table 1.
Preclinical evidence in mouse models and clinical trials in patients with neurodegenerative disease
| Intervention | Mechanism | Preclinical evidence | Clinical Trial | |||||
|---|---|---|---|---|---|---|---|---|
| Mouse models | Treatment duration | Main findings | Design | Sample size | Treatment duration | Main findings or progress | ||
| Alzheimer’s disease (AD) | ||||||||
| AL002 | Agonist antibody that activates TREM2 signaling to promote microglial clearance of Aβ | 5×FAD mice expressing either the common variant or the R47H variant of TREM2 | Initiated weekly i.p. injections of AL002c or a control IgG at 5 mo of age, and continued until 8 mo of age | Tempered microglial inflammatory response, increased microglial phagocytosis of Aβ, and improved behavior172 | Multicenter, randomized, double-blind, placebo-controlled | 265 early AD | 48–96 weeks |
Phase 2 status: recruiting starte d at 22 Jan 2021 and estimated end at Jan. 2024 (NCT04592874) |
| Cromolyn + ibuprofen | Modulate microglia to promote clearance of Aβ | APPSwedish-expressing Tg2576 mice | Initiated i.p 3 times per week at 5 mo of age, and continued for 3 mo | Cromolyn, alone, or in combination with ibuprofen, increased microglial recruitment to, and phagocytosis of Aβ531 | Multicenter, randomized, double-blinded, placebo-controlled | 620 early AD | 72 weeks |
Phase 3 status: completed n o results posted. (NCT02547818) |
| Nilotinib BE | Tyrosine kinase inhibitor | C57BL6 mice | A 7-day course of daily i.p.injections with nilotinib before i.p.injection with LPS | Modulated neuroinflammatory responses of microglia and astrocyte and improved cognitive function.532 | Multicenter, randomized, double blind, placebo-controlled | 1275 Early AD | 72 weeks. |
Phase 3 Status: not yet recruiting estimated started at 1 Feb 2022 and estimated end at 31 Dec 2025 (NCT05143528) |
| TB006 | Monoclonal antibody targeting galectin 3, stimulate TREM2-DAP12 signaling to regulate microglia activation | Two AD transgenic mice (APPSwe, 5×FAD) and Aβ injection induced mice | Two-week treatment with mTB001, a surrogate of TB006 | Reduced aggregation of Aβ/Tau proteins and neuroinflammation, and significant improvement of cognitive performance (https://www.truebinding.com/) | Multicenter open-label long-term extension study | 180 de novo AD |
113 weeks (101 weeks of dosing and a 12-week safety follow-up period) |
Phase 2 Status: Active, not recruiting Started at 14 Sep 2022 and estimated end at Oct. 2024 (NCT05476783) A Phase 1/2 study concluded that TB006 imporved cognitive function and reduced Aβ load. (NCT05074498, n = 140) |
| Senicapoc | Ca2+-activated potassium channel KCa3.1 inhibitor | 5×FAD mice | Initiated treatment at 6 mo of age, and continued for 3 mo | Reduced microglia-mediated neuroinflammation, decreased Aβ load, and enhanced hippocampal neuronal plasticity.533 | Randomized double-blind, placebo-controlled | 55 MCI and mild AD | 52 weeks |
Phase 2 status: recruiting st arted at 18 Mar 2022, and estimated end at Jun 2025 (NCT04804241) |
| Spironolactone | Inhibit microglial release of proinflammatory cytokines | Sprague-Dawley rats with Aβ injected in the dorsal hippocampus for four consecutive days | I.p. injection spironolactone or vehicle for 14 days. | Significantly lowered Iba1 protein levels534 | Randomize, double-blind, placebo-controlled | 30 MCI and early AD | 12 mo |
Phase 4 status: recruiting start ed at 6 Sep 2022 and estimated end at Sep 2023 (NCT04522739) |
| Metformin | Modulation of microglia phenotype | C57BL6/J mice | Initiated at 18 mo and treatment for 10 weeks | Promoted microglia conversion into an anti-inflammation phenotype, improved cognitive function535 | Randomized, double blinded, placebo controlled | 370 MCI | 24 mo |
Phase 2/3 status: recruiting started at 22 Mar 2021, and estimated end at 30 Apr 2026 (NCT04098666) |
| CORT108297 | A selective glucocorticoid receptors antagonist; changed the phenotype of microglia from an activated to a quiescent form.536 | Sprague-Dawley rats | 1 week after icv injection of Aβ, two times i.p. injections per day for 1 week | Reduced microglia-mediated neuroinflammation and improved cognitive function.537 | Randomized, double-blind, crossover assignment | 52 MCI due to AD | 2 weeks |
Phase 2 status: recruiting started at 28 Jun 2021 and estimated end at 1 Jan 2024 (NCT04601038) |
| Lenalidomide | A thalidomide derivative inhibiting microglia activation and the production of pro-inflammatory cytokines | An animal model of PD (mThy1-α-syn transgenic mice) | Initiated at 9 mo and treatment for 5 weeks | Reduced microglial activation and behavioral deficits538 | Randomized, double-blind, placebo controlled | 30 MCI due to AD | Daily orally treatment for 12 mo followed by 6 mo washout |
Phase 2 status: recruiting started at 22 Jul 2020 and estimated end at Sep 2024 (NCT04032626) |
| Parkinson’s disease (PD) | ||||||||
| MCC950/Inzomelid | NLRP3 inhibitor, significantly inhibited microglial inflammasome activation | 6-OHDA model of PD + PFF model of PD | At 21 days after 6-OHDA lesioning α-synuclein PFF-injected mice at 30 days223 | Abolished α-synuclein-mediated NLRP3 activation and ASC release in microglia223 | Single-center, double blind, randomized, cross-over | 80 healthy adult participants | Up to 16 days |
Phase 1 completed re sults pending. (NCT04015076). |
|
AZD3241 (MPO inhibitor) |
Enzyme myeloperoxidase inhibition (myeloperoxidase is a reactive oxygen generating enzyme and is expressed by microglia.) | MPTP model | [AstraZeneca data on file] | Suppression of microglia activity and neuroprotective effect on dopamine cell survival [AstraZeneca data on file]491 | Multicentre, double-blind, randomized, placebo-controlled, parallel-group | 51 PD | 12 weeks | Phase 2 (NCT01603069); |
| – | – | – | – | Multi center, double-blind, randomized, placebo-controlled, parallel-group | 24 PD | 8 weeks | Phase 2, Microglial activation measured by PET imaging. (NCT01527695) | |
| GLP-1 receptor agonists, NLY01 | GLP-1R activation | α-synuclein (hA53T) transgenic mouse model | Started at six mo of age (for five mon) | Prevent microglial-mediated conversion of astrocytes to an A1 neurotoxic phenotype113 | Multicenter, randomized, double-blind, placebo-controlled | 255 early untreated PD | 36 weeks | Phase 2 (NCT04154072) |
| GLP-1 receptor agonists, Exenatide | – | – | – | – | Multicentre, double-blind, randomized, placebo-controlled | 200 mild to moderate PD | 96 weeeks |
Phase 3 Started at Jau 20, 2020 and estimated end at Jun 30, 2024 (NCT04232969) |
| Multiple system atrophy (MSA) | ||||||||
| Minocycline |
Belongs to tetracyclines. Cross BBB. Inhibits microglial activation and neuroinflammation |
PLP-α-syn mouse |
Treatment for 2 mo starting at 2 mo of age before motor symptom onset |
Suppressed microglia activation, prevented neuronal loss276 | Multicenter, randomized, double-blind, placebo-controlled | 63 probable MSA-P | 12 mo |
Phase 3 status: completed reduc tion of microglia activation assessed by PET, but symptom severity unchanged by clinical assessment500 (NCT00146809) |
| Verdiperstat (MPO inhibitor) | MPO is a key enzyme involved in the production of ROS in microglia and is a mediator of inflammatory processes | PLP-α-syn mouse +3NP model | Treatment for 28 days starting at early stage (6 mo of age) | Suppressed microglia activation, reduced a-syn accumulation, rescued neuronal loss and improved motor deficits495 | Multicenter, randomized, double-blind, placebo- controlled | 59 probable or possible MSA | 12 weeks of verdiperstat (AZD3241) |
Phase 2 status: completed improvemen t on clinical scores and reduced neuroinflammation measured by PET imaging (NCT02388295) |
| – | PLP-α-syn mouse +3NP model | Treatment for 20 days starting at advanced stage (8-9 mo of age) | Reduced microglia activation and a-syn accumulation, but motor impairments and neuronal loss were unchanged496 | Multicenter, randomized, double-blind, placebo-controlled | 336 probable or possible MSA | 48 weeks of verdiperstat (BHV-3241) |
Phase 3 status: active, not recruiting UMSARS score is used to assess the clinical efficacy (NCT03952806) |
|
| Fluoxetine | SSRI, enhances microglia phagocytosis, reduces microglia inflammation | MBP-α-syn mouse |
Treatment for 28 days starting at motor symptom onset (6 mo of age) |
Ameliorated motor deficits, decreased neurodegenerative pathology, increased GDNF and BDNF502 | Multicenter, randomized, double-blind, placebo-controlled | 87 MSA | 6 mo |
Phase 2 status: completed n o change in rate of progression503 (NCT01146548) |
| Progressive Supranuclear Palsy (PSP) | ||||||||
| AZP2006 | Increased levels of progranulin, inhibited microglial activation and proinflammatory cytokine production, and decreased tau phosphorylation | SAMP8 (Senescence Accelerated Mouse Prone-8) mouse model | Administrated at 2 mo, 4 mo, and 6 mo of age, respectively | Inhibits microglial activation and related neuroinflammation, prevent reversed cognitive defects.539 | Multicenter, randomized, double-blind, placebo-controlled | 36 PSP | 84 days. |
Phase 2 status: active, not recruiting star ted at 22 Jun 2020 and estimated end at 16 Jul 2022 (NCT04008355) |
| Fasudil |
Rho kinase inhibitor, inhibited microglial activation and promoted their transformation to an anti-inflammatory phenotype540 |
APP/PS1 Tg mice | Initiated daily i.p. injections of Fasudil at 8 mo of age, and treatment for 2 mo | Inhibits the activation of microglial and astrocytes, and improved the cognitive deficits541 | Open label, single arm assignment | 15 PSP and CBD | 48 weeks |
Phase 2 status: active, not recruiting sta rted at 22 Jan 2021 and estimated end at 30 Nov 2023 (NCT04734379) |
| Amyotrophic lateral sclerosis (ALS) | ||||||||
| Fasudil |
Rho kinase inhibitor, inhibited microglial activation and promoted their transformation to an anti-inflammatory phenotype540 |
SOD1G93Amice | Administrated in drinking water from 5 weeks to dead | Reduced motor neuron loss, slowed disease progression, and increased survival time542 | Multicenter, randomized, double-blind, parallel controlled | 120 ALS | 20 days |
Phase 2 status: active, not recruiting st arted at 20 Feb 2019 and estimated end date at Jul 2023 |
| Ibudilast | Phosphodiesterase inhibitor, suppresses proinflammatory microglial activation543 | – | – | – | Multicenter, randomized, double-blind, placebo-controlled study followed by an open-label extension phase | 230 ALS | Double-blind phase (12 mo) + Open-label extension phase (six mo) |
Phase 2/3 status: recruiting st arted at 28 May 2020, and estimated end at Dec 2024 (NCT04057898) |
| Masitinib |
Tyrosine kinase inhibitor, reduces microglial activation |
SOD1G93A rats | Initiated 7 days after paralysis onset | Decreased microgliosis, and motor neuron pathology in the degenerating spinal cord, prolonged post-paralysis survival by 40 %544 | Multicenter, randomized, double-blind, placebo-controlled | 495 ALS | Add-on therapy to riluzole for 48 weeks |
Phase 3 status: recruiting st arted at 2 Feb 2021 and estimated end at Dec 2023 (NCT03127267) Phase 2/3 n = 394 ALS, Results show that masitinib add-on therapy to riluzole for 48 weeks at 4.5 mg/kg/d can benefit patients with ALS.545 |
| RNS60 | Suppresses microglial NF‐κB546 | SOD1G93A mice | I.p. every other day starting at the disease onset |
Activated phagocytic microglia and increased anti-inflammatory molecules, slowed the disease progression547 |
Multicenter, randomized, double-blind, placebo-controlled | 147 ALS |
Add-on therapy to riluzole for 24 weeks administered by intravenous infusion once/week and inhaled via nebulization every morning |
Phase 2 status: not yet recruiting estim ated start at Nov 2022 and end at Jun 2024 (NCT02988297) Phase 2 The mean rate of decline in respiratory function, the eating and drinking domain ability was slower in the RNS60 arm.548 (NCT03456882) |
| Minocycline | Suppresses proinflammatory microglial activation | SOD1G37R mice | Initiated at the age of 7 or 9 mo and continued treatment until the the mice reached end-stage disease | Inhibited microglial activation, delayed the onset of motor neuron degeneration, declined muscle strength, and increased the longevity of mice549 | Multicenter, randomized, double-blind, placebo-controlled | 412 ALS | 9 mo |
Phase 3 status: completed min ocycline has a harmful effect on patients with ALS550 (NCT00047723) |
| SAR443820 | Receptor-interacting protein kinase inhibitor, inhibit inflammatory microglia | SOD1G93Amice | Initiated at 2.5 mo of age for 4 weeks | Inhibited inflammatory microglia.551 | Randomized, double-blind, placebo-controlled | 261 ALS | 24-week RCT followed by open label up to week 106 |
Phase 2 status: recruiting s tarted at 13 Apr 2022, and estimated at 12 Aug 2025 (NCT05237284) |
| 3K3A-APC | Prevents microglial activation, inhibits NLRP3 inflammasome552 | ALS mouse model | – |
Slowed disease progression and extended survival |
Non-Randomized, open label | 16 ALS | 45 days |
Phase 2 status: completed no re sults posted (NCT05039268) |
| Withania somnifera extract | Blocks NF-kB transcription and inhibit microglial activation553 | SOD1G93A mice | Fed in saline beginning at 50 days of age and continued till the mice were capable to ingest | Reduced glial activation, increased longevity, improved motor performance, and increased number of motor neurons in lumbar spinal cord.554 | Randomize, double-blind, placebo-controlled | 75 ALS | 8 weeks |
Phase 2 status: recruiting sta rted at 19 Oct 2021, and estimated end at Sep 2022 (NCT05031351) |
| Verdiperstat | See Verdiperstat in MSA section | – | – | – | Multicenter, randomized, double blind, placebo-controlled | 167 ALS | 24 weeks |
Phase 2/3 status: active, not recruiting star ted at 28 Jul 2020, and estimated end at Apr 2023 (NCT04436510) |
| Frontotemporal Dementia (FTD) | ||||||||
| Metformin | Modulation of microglia, proinflammatory cytokines, and autophagy, decreases expression of toxic proteins produced from the C9orf72 repeat expansion | C57BL6/J mice | Initiated at 18 mo and treatment for 10 weeks | Promoted microglia into an anti-inflammation phenotype, improved cognitive function535 | Open label, single group assignment | 58 C9-ALS/FTD | 24 weeks |
Phase 2 status: recruiting st arted at 10 Jan 2020, and estimated end at 6 Apr 2023 (NCT04220021) |
| Huntington’s Disease (HD) | ||||||||
| VX15 (pepinemab) | A Humanized IgG4 anti-SEMA4D antibody; Inhibits microglial activation and neuroinflammati-on | YAC128 transgenic HD mouse model | Initiated at 6 weeks of age, and until they reached 12 months of age. | Reduced brain atrophy, improved cognition, and reduced anxiety-like behavior528 | Randomized, double-blind, placebo-controlled | 301 late prodromal and early manifest HD | 18 mo |
Phase 2 status: completed no results posted (NCT02481674) |
| IONIS-HTTRx also known as ISIS 443139 and RG6042 | Non-selective ASO binding to HTT RNA and activating RNase H-mediated degradation | Transgenic BACHD mice containing a full-length human mutant HTT gene | Two weeks’ continuous intraventricular infusion | Reduce the production of toxic mRNA and RAN proteins, reducing microglia activation555 | Randomized, double-blind, placebo-controlled | 46 early HD | Every 4 weeks for four doses | The therapy was deemed safe, with no significant side effects. (NCT02519036). |
| – | – | – | – | An Open-Label Extension Study | 46 early HD | Every 28 days intrathecally for 14 months. | Phase 2 (NCT03342053) | |
| WVE-120101 | ASO targeting the most often occurring SNPs in HD | – | – | – | Multicenter, randomized, double-blind, placebo-controlled | 61 early HD who carry a targeted SNP rs362307 (SNP1) | 210 days | Phase 1b/2a (NCT03225833) |
| – | – | – | – | Multicenter, open-label extension Study | 27 HD who carry a SNP1 | Maximum of 45 weeks of treatment | No significant change in mHTT protein in HD (NCT04617847) | |
| WVE-120102 | – | – | – | – | Multicenter, randomized, double-blind, placebo-controlled | 88 early HD who carry a targeted SNP rs362331(SNP2) | 210 days |
Phase 1b/2a (NCT03225846). |
| – | – | – | – | Multicenter, open-label extension study | 36 HD who carry a SNP2 | Maximum of 12 monthly doses | No significant change in mHTT protein in HD patients (NCT04617860) | |
mo month, i.p. intraperitoneal, icv intracerebroventricular, TREM2 Triggering receptor expressed on myeloid cells 2, MPO Myeloperoxidase, ROS reactive oxygen species, SSRI Selective serotonin reuptake inhibitor, MBP myelic basic protein, PLP proteolipid protein, AD Alzheimer’s disease; PD Parkinson’s disease, MSA Multiple system atrophy; PSP Progressive Supranuclear Palsy, CBD Corticobasal Degeneration, FTD Frontotemporal Dementia, HD Huntington’s Disease, C9-ALS/FTD ALS and FTD patients with expansions of a hexanucleotide repeat (GGGGCC) in the C9orf72 gene, ASO antisense oligonucleotide