PE items
Schedule
Team will finish the 1st draft of narrative on 5th Nov. After review by Holger and Sandy, the narrative will be shared to Ceri and Laura on 7th Nov.
- Use the following link to edit the narrative.
Working document_PRC_Narrative_NLRP3_Sep22.docx
- The upcoming pivotal meeting toword PE: AQB1 on 11/12 Nov, TMQB on 16/17 Nov, NSRB on 1/2 Dec, PRC1 on 16 Dec.
- Pre-read deadline for NSRB (1st Dec) is 7-days before - It’s 24th Nov (sorry I said date in Japan…)
- Official submission for PRC1 (16th Dec) is 6-buisiness days before - It’s 8th Dec
- The final submission of narrative to PRC office would be 8th Dec.
| Early PD | Early diagnosed p DOFFERS AN APPROPRIATE AND THE LEAST COMPLICATED OPLATION TO STUDY IN TRYING TO ASSESS THE EFFECT OF AN INTERVENTION ON THE UNDERLYING DISEASE PROCESS. |
|---|---|
| At lamine neurons, after 4 years from diagonosis there is limited staining for dopamine terminals in the dorsal triatum, thus treatment instituted after this time may be less effective, | |
| Asyn spreading too much, | |
| Entire or subpopulation | Characterization, Postmoretem, |
| BM | TE: PET |
| Pharmacodynamic: BM characterization, correlation between markers, correlation with severity, correlatin between matrix | |
| Assay: NLRP3, ASC, NDE? | |
| DR: DATscan, aSyn |
PET
Chemistry PET
| In vitro Bmax 용 | In vivo 용 | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Desired profile |
Potent activity (Ki <5 nM), High Fu brain (> 5%), High specific activity (>67.6 Ci/mmol) |
-Good PK (brain uptake and elimination profile: Ki and Fub, -MDR1(A>B*/ER) : - (<6) | ||||||||||||
| 20210805 (RSLT) |
-TR126이 Kd는 16-17nM (20220707_CNS01365_report_new validatio.pdf), -in binding assay, Bmax of NLRP3 (-containing Biomass ie insect cells overexpressing Nlrp3) (from [3H]-TR06616126 concentration-dependent test) (120min reaction) is calculated 65 pmol/mg protein, which is~ 3.2 nM |
Marianthi: Let's first optimize the 6-OHDA model → TR06673219 and then we can discuss for the rest of the screening 추가) To Confirm a specific binding
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| 20220325 |
After measurement of Ki values (@@, previous slide) at TSD, the compound will be decided. For preparation of [3H] compound, it takes 1-2 months for precursor synthesis and additional 1-2 months for tritiation. | |||||||||||||
| 2022 | For tritiation of TR493, four related compounds, precursor, standard, and OMe-/NMe-compounds will be shipped to Novandi this week. ✓ | |||||||||||||
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The tritiated TR493 will be delivered in Aug. The most of tritiated compound will be used in TBOS. TSD will check the necessity of 3H-TR493. ✓ As TR493 has Me group, high radioactivity more than 67.6 mCi can be expected. There is a difficulty to synthesize a target compound; bymethylation, the nitrogen of thepiperidine was not methylated and other partwasmethylated. It is not clear where the methylation occurred compared to the reference compounds. The timing of the end of the synthesis has not yet been determined. Improvement of experimental conditions might beneeded. | ||||||||||||||
| 20221012 | [TR06780135] IC50 1.1 nM (h), Fu brain 1% (r) RI binding assay 중 (to determine Kd?) | |||||||||||||
| 20230111 | [³H]Compounds for in vitro Bmax measurement (Takeda chemistry slide; preserved as body_r03 evidence with structures of MCC-950, TR06616126, TR06706493, and "Potent, but Low Fub" TR06780135) | |||||||||||||
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Yamatake) Anyway, our first step is ARG study of patient using TR493. And then, we have to discus in vivo study depends the result of ARG study. Candidates for in vivo PET study 20230212 (Takeda chemistry slide; preserved as body_r03/body_r04 evidence with structures and TSD/TSHO data for TR06647850, TR06683015, TR0676285?, TR06683014 + 6-OHDA / LPS model file references) | ||||||||||||||
Sharefold for PET
https://mytakeda.sharepoint.com/sites/InterACT-RAD-Pipeline/NLRP3%20Inhibitor/Shared%20Documents/Forms/AllItems.aspx?RootFolder=%2Fsites%2FInterACT%2DRAD%2DPipeline%2FNLRP3%20Inhibitor%2FShared%20Documents%2F08%5FPET%2FMeeting&FolderCTID=0x012000793CD60BC65C13458F56FF0F6488CB5E&View=%7B9232?B%2D46BC%2DA4EE%2D055039848432%7D 이게 정답!
Progress
| Date | Notes |
|---|---|
| 20210701 |
the radiolabeling of a candidate is ongoing and the synthesis will be completed in Aug. The cost of Bmax evaluation in CRO (Invicro et al) is estimating |
| 20210830 | - brain homogenate binding will be generated in a few months by TCAL [Bmax] |
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• Phase 1 (1.5 months from receipt of radioligand) : to determine the optimization of assay condition using 6-OHDA rat brain with NLRP3 expression confirmed by antibody. • Phase 2 (Dec 2021 as best case) : to generate Bmax with [3H]ligand using rat 6-OHDA brain and mouse NLRP3 KO brain (negative control) this might be done TNTechnos. | |
| 20210923 Marianthi |
Will measure Bmax (before PE, at INVICRO LONDON, Ashley guide), Makoto Fushimi is leading |
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12/2021 (PE): Measure rodent NLRP3 Bmax 1-6/2022: Measure NHP/human NLRP3 Bmax (should be discussed at the NLRP3 PET meeting on Oct 26) 10/2021 – 3/2023 (CS): Optimize PET ligand By CS: Discover PET probe candidate for NHP and/or human imaging study | |
| 20211006(?) |
Tomimatsu: 1. Hit the compound dose for in vivo triage with single rat PK (iv) (to aim near LLOQ) 2. Preparation of rat 6-OHDA model a. Intraparenchymal administration of 6-OHDA (Is the striatum the easiest to do?) b. Wait for a certain period of time and select an appropriate individual using the rotation behavior in the apomorphine challenge as an index (If you are accustomed to it, you can omit this step) 3. Dosing to the 6-OHDA model a. LLOQ-targeted dose and self-saturated high-dose. Also, is it a group that follows the time transition in each? b. With the 6-OHDA model, I feel that the existence of specific signals can be estimated to some extent by comparing the injection side and the non-injection side. 4. Sample preparation (homogenate, plasma preparation / dispensing) 5. PK measurement 아래처럼 하자, -12/2021 (PE): rodent NLRP3 Bmax 202201-202207: NHP/Human Bmax 202201-CS: Triaging compounds CS-XX: NHP imaging study |
| 20221209 PRC RUMENT |
). Current Actions include: • Measuring NLRP3 Bmax in 6-OHDA rats using [3H]TR06616126 • Discovering a PET probe: A Lead series has been identified • Planning in vivo LCMS uptake study using TR06673219 and TR06647850 in 6-OHDA rats 2nd Bmax phase 1 STUDY: ARG, [³H]PBR28 for TSPO binding, in 6OHDA Rat striatum? → confirms lesioning success in inducing neuroinflammation, The low specific binding window 60 specific binding) observed using 3 H]Candidate 1 in the first optimisation, coupled with the increased neuroinflammatory signal seen with 3 H]PBR 28 may suggest that the ligand may not lend itself as a tool compound for NLRP 3 |
| NLRP3 PET |
MAKI 와 정리,
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Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
| 20210805 row | -TR126이 Kd는 16-17nM | The numeral after TR126 is ambiguous; could read TR126이 (Korean particle) or TR1260. |
| 20221012 row | IC50 1.1 nM (h), Fu brain 1% (r) | ”1.1” reading is consistent but the decimal could be a comma. |
| 20211006 row | 1. Hit the compound dose | The verb Hit could also read Fix/Set at this resolution. |
| 20221209 row | 2<sup>nd</sup> Bmax phase 1 STUDY: ARG | The roman-style superscript is faint; could read 2nd Bmax Phase1. |
| Sharefold link | View=%7B9232?B%2D46BC%2DA4EE%2D055039848432%7D | The %7B9232 segment contains an illegible character marked ?; the URL likely contains a GUID with a hyphen at that position. |