기타 MOA들 (continued)
| Target | Treatment | type / MOA | Trial / source | phase | patients / dose | Result / Design | Reference | ||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Not Inosine trials but source data on urate | PRECEPT Schwarzschild, 2008 #663) |
demonstrated non-futility of inosine treatment for slowing disability
| |||||||||||||||||||||||||||||||||||||||||||||||||||||
| DATATOP (Ascherio, 2009 #664) 2009 asch |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Nilotinib | 원래 c-abl phosphorylates parkin → ↓parkin activity | JAMA Neurology Study Georgetown Univ NCT02954978 Phase 2 NILO-PD Study Parkinson Study Group, Tanya Simuni, NCT03205488 | P1 | OL 군당 25명(pcb, 150mg, 300ng) |
(Pagan, 2020 #709) ↑CSF HVA, DOPAC (12 m), = ↑plasma DOPAC (12 M), = CSF TOTAL AsYN (12M), ↓The ratio of CSF oligomeric/total α-syn, (이외 Tau도 봄) Shaltiel-Karyo et al. 2013 (reference column) | ||||||||||||||||||||||||||||||||||||||||||||||||||
| mannitol | ↓α-syn fibrils aggregation ( | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| NZP437 (New Zealand Pharmaceuticals) next-generation bile acid | MOA |
| |||||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fibroblast (sPD |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| patient derived DA iNeurones |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| AD/PD 2021) compound A: INDUCEd DA neurons from fibroblasts Spd: |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| MPTP mice |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| NHP? |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| CLINICAL PLAN |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Meeting 20210611 |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Confidential data package | Pw: Jedi123. (case sensitive, . is part of the pw) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| UDCA | NZP437 | |
|---|---|---|
| MOA | lipid transporter of PA | |
| Cardiolipin | Do not Restore cardiolipin level | Restore cardiolipin level |
| Caspase 33 level in iNeuron | Mild ↓ | NZP437 normalizes caspase 3 to that of age matched controls. |
| ATP assay | 10x more active in the ATP assay (?) |
| Target | Treatment | type / MOA | phase | patients / Design | Result / outcomes | Reference |
|---|---|---|---|---|---|---|
| RNAi | cxix) {Yang, 2021 #1319) 2nd: cause acute neurotoxicity in HNP | |||||
| cxx) | ||||||
| exo-ASO4 (Exosome-mediated delivery of ASO4 ) | In vitro | (Yang, 2021 #1319) primary neuronal culture, exo-ASO4 → HIGH cellular update, ↓aSyn mRNA & aggregation (both p- and unp- aSyn) induced by aSyn PFF | ||||
| In vivo | (Yang, 2021 #1319) A53T MICE, exo-ASO4 (ICV) → ↓aSyn mRNA & aggregation (both p- and unp- aSyn) aggregation, ↓DA ndgn Cf) ASO is a single-stranded gapmer that can mediate sequence-specific cleavage of different types of RNA, including mRNA and non-coding RNA, targeted by the endogenous RNase H1. ASO molecules can hardly pass through the cell membrane by itself and are likely to be degraded quickly by the proteases. Currently, multiple carriers, such as lipofectamine, liposomes, or lipid-based nanoparticles, are being used to deliver ASOs into the neurons | |||||
| KM-819 (FAScinate) | a potent inhibitor of FAF1 | , a key regulatory protein in cell death pathways, apoptosis, and necrosis, and leads to neuronal cell protection in pre-clinical studies. A higher level of FAF1 is found in PD patients and could contribute to the early cell death. | ||||
| CVN424 | GPR6 inverse agonist, small molecule, |
- GPR6 is an orphan GPCR that has enriched expression in the striatopallidal, indirect pathway, MSN neurons of the striatum - a target present in striatal neurons that express dopamine receptor D2. The company claims that CVN424 does not affect D1-dependent pathways, and that this selective targeting will help avoid LID associated with D1 activation. CVN424 is being developed as an add-on to L-DOpa | P2 P1 preclinical |
2019, a Phase 2, randomized, place-controlled study began enrolling 66 people with Parkinson's who experience motor fluctuations on a stable dose of levodopa. To be eligible, patients must average more than 2 hours per day of "off time," i.e., periods when symptoms reappear between levodopa doses. Participants will be randomized to high or low dose drug or placebo, taken as an oral suspension once daily for one month. The primary outcomes are adverse events and safety measures; secondary outcomes include an unspecified efficacy measure, and pharmacokinetics. This trial takes place at 16 sites across the U.S., and is expected to end in 2020. [Results] Beyond meeting safety objectives, the drug achieved a significant and meaningful, dose-dependent reduction of "OFF time 2019, Cerevance completed a Phase 1 single- and multiple-dose safety study in healthy adults. Sixty-six volunteers received single CVN424 doses from 1 to 225 mg, or seven daily doses of 25, 75, and 150 mg or matching placebo. According to an April 2019 company press release, the drug caused no serious adverse events or changes in common safety measures including vital signs, cardiac function, and laboratory analyses. | (Brice, 2021 #1897) | |
| MRx0005 and MRx0029 (4D pharma') | orally delivered single strains of bacteria that are naturally found in the healthy human gut. | P1 | multi-center, randomized, double-blind, placebo-controlled study Rx0005 and MRx0029 are two unique single strain Live Biotheraputic candidates, which have been shown pre-clinically to have positive impacts on multiple key aspects of Parkinson's disease pathology, including gut barrier integrity, neuroinflammation, oxidative stress and neuroprotection. In animal models of Parkinsonian syndrome, 4D pharma demonstrated that MRx0005 and MRx0029, respectively protected against the loss of dopamine metabolites and dopamine-producing neurons in the brain. | |||
| nicotinamide riboside (NR), Haukeland UH and Bergenwas, | nicotinamide adenine dinucleotide (NAD) replenishment therapy | P1 NADPARK | (Brakedal, 2022 #2012} DB, total 30 with early PD received 1,000 mg NR, NAD-precursor, or placebo for 30 days.--> led to a significant, but variable, increase in cerebral NAD levels—measured by 31phosphorous MRS—and related metabolites in the cerebrospinal fluid. NR recipients showing increased brain NAD levels exhibited altered cerebral metabolism, measured by 18fluoro-deoxyglucose positron emission tomography, and this was associated with mild clinical improvement. NR augmented the NADmetabolome and induced transcriptional upregulation of processes related to mitochondrial, lysosomal, and proteasomal function in blood cells and/or skeletal muscle. Furthermore, NR decreased the levels of inflammatory cytokines in serum and Csf | |||
| NE3107 (BY BIOVIE) | Insulin resistance | P3 P2 Preclinical |
•[plan이겠지] NM202 Phase 3: Potential pivotal design to evaluate NE3107 promotoric activity in 200 patients starting L dopa or, depending on Phase 2 results, 200 patients that have received L dopa therapy for more than 3 years — Primary endpoint: MDS UPDRS parts 1 4 Phase 2 began Q1 2022 with possible topline data readout expected Q2 2022 • NM201 Phase 2: Assess NE3107 promotoric activity while adhering to FDA requirement for a drug drug interaction study involving L dopa • 40 patients with defined L dopa "off state", 1:1 active:placebo, 20 mg BID for 28 days — Safety assessments: Standard measures of patient health, L dopa PK and DDI — Efficacy assessments: MDS UPDRS* parts 1 4, Hauser ON/OFF Diary, Non Motor Symptom Scale NE3107 Impact in Parkinson's Mice Models |
Below table from (Biglan, 2017 #1563)
Uncertain Spans
- “Aging등” (NZP437 MOA bullet xcvi) — second character reads as the Korean particle “등”; transcribed as printed.
- “mannitol” row’s mechanism cell ends with an unclosed parenthesis “↓α-syn fibrils aggregation (” — preserved as printed.
- “Fibroblast (sPD” — left-column label is missing the closing parenthesis in the source; preserved as printed.
- “CVN424 … LID associated with D1 activation” — source prints “LiD” (mixed case); transcribed as “LID”.
- “NE3107 (BY BIOVIE)” Preclinical row — sentence starting with “NE3107 Impact in Parkinson’s Mice Models” ends mid-thought; the continuation falls outside this page.