20240722_183208

	below LLOQ ? what about CSF?
	Takeda rationale or pursing NLRP3: animal data was, so far, only striatum, not SN, Assay difference: WB vs ELISA
	Takeda plan: Brain: check Quanterix Antibody for rat reactivity → PM brain tissue 로 assay? CSF: PM CSF collection (serial, if possible)
20240503	Presentation: Quanterix is open (with MJF permissiion) is open to collaborate and to get and test PD samples and healthy controls to further validate the assay Mingwei: we need 150ul for each sample to measure at duplicate, same for plasma and CSF Ariana: the assay is not yet ready for external human sample testing. We are still in the process of some additional validation steps including dynamic range and test-retest reliability. We have not yet run PD vs HC CSF samples, so there is no de-identification to be done in that regard. Unfortunately, we are no longer pursuing assay development for the other analytes you mentioned.
Qs	LLOQ, what is MJF need? Freeze-thaw, volume required? Slide: 7,8 plasma, LLOQ 4 (buffer, what is in PLASMA?). slide 8 figure : values below LLOQ ? what about CSF?
Consideration	Name, Michele Wolfe Billerica, MA Human: assay available, PD vs HC?: NOT critical dQuanterix, , USAsample available? we need 150ul for each sample to duplicate, same for plasma and CSF Can we likely reduce it? we need 150ul for each sample to measure at duplicate, same for plasma and CSF

CBID (BST):

Tech Transfer to CRO	Audit → wait time	IP though – this will need a careful Legal review. If we co-develop and assay and want to tech-transfer it to a more scalable CRO, we need to have sufficient FTO to do that.
	Validation, trouble shoot,
Sample processing	How to collect Sample
regulatory	Submission
	Stability test
Biology	Reagent - : antibody missing epitope,

total 1 yr.

P1
Exploratory biomarker potentially alongside other candidate biomarkers, as Olink's strength is multiplexing	secondary endpoint-status later on. I don't think we need it to be "fully" quantitative though, as Takeda has a lot of Olink secondary endpoint assays that are quantitative
	I don't think Takeda has any secondary endpoint semi-quantitative Olink assays in play, you were right. I'm following up with him to get the details, but I think if the assay will indeed be for a go/no-go decision then semi-quantitative is too risky; we'll have to have a quantitative assay to start with
.
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Summary of NLRP3 biomarker detection methods in the literature

Protein	Samples	Detection method	Reference
NLRP3	CSF	ELISA (MyBioSource)	Wallisch et al, 2017
	CSF	ELISA (CSB-E15885h, Cusabio)	Peng et al, 2020
	Serum	ELISA (My Biosource)	Chatterjee et al, 2020
	Serum EV	anti-NLRP3 (Cyro-2, AG-20B-0014, AdipoGen)	Baroja-Mazo et al, 2014
ASC	CSF	Ella Simple Plex system (Protein Simple)	Kerr et al, PLoS 2018
	CSF	anti-ASC (Bethyl Laboratories)	Adamczak et al, 2012
	Brain-EV	Ella Simple Plex system (Protein Simple)	Kerr et al, Front Mol Neurosci 2018
	Serum	Ella Simple Plex system (Protein Simple)	Keane et al, 2018
	Serum EV	anti-ASC (AL177, AG-25B-0006, AdipoGen)	Baroja-Mazo et al, 2014
Caspase-1	CSF	anti-Caspase-1 (Epitomics)	Adamczak et al, 2012
Caspase-1	Serum	Ella Simple Plex system (Protein Simple)	Keane et al, Front Mol Neurosci 2018
IL-1b	CSF	ELISA (Bender MedSystems)	Peng et al, 2020
	Brain-EV	Ella Simple Plex system (Protein Simple)	Kerr et al, Front Mol Neurosci 2018
	Serum	Ella Simple Plex system (Protein Simple)	Keane et al, 2018
	Serum	ELISA (Thermo Fisher Scientific)	Chatterjee et al, 2020
	Cells	ELISA (#DLBSO, R&D systems)	in-house data
IL-18	CSF	Ella Simple Plex system (Protein Simple)	Kerr et al, PLoS 2018
	CSF	ELISA (R&D systems)	Niezgoda et al 2001
	Brain-EV	Ella Simple Plex system (Protein Simple)	Kerr et al, Front Mol Neurosci 2018
	Serum	Ella Simple Plex system (Protein Simple)	Keane et al, 2018
	Cells	ELISA (#DLBSO, R&D systems)	in-house data

Epitope information

[whole slidedeck]

Budget & FTE

NLRP3 FTE&Budget_20211119.xlsx

Ceri

	100% NLRP3 inhibition + BM of cell death → decision making (why 100% is easy?) NOT DEATH, BUT DAMAGE bm: NFL?
narrative	Report x, story (fiction) O
	Responder subpopulation. → EX VIVO SCREENING
	Tie to DR BM change
	Bm change in pph, (link to CNS)
	CAPS → PD (how to bridge?)
	aSyn dependent vs independent contribution to death.

Chemistry

20112

Current frontrunner is TR06692993 , de-priotized IP issue,

Minitox for TR993 is not necessary because that of TR443, the same chemotype to TR993, is ongoing. The rat DRF study in 3 or 7 days will be planned to find the doses for 2W tox. After checking the accumulation of the compounds after single and multiple dosing, the period will be determined.

The TR2993 low dose rat PK (IV/PO) study is planned to be released end of Jan.
TR2993 ascending dose rat PK will be scheduled for Feb.
To support future Atuka studies, multi-day mouse PK for TR2993 will be run at TCAL in Feb. Study will check for tissue accumulation. Plasma, brain, and liver concentrations will be compared between Day 1 and Day 5.
Both dog and monkey hepatocyte stability are being run at TCAL for TR2993.
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The extended CL evaluation in human hepatocyte will be planned for TR2993 due to low CL. Data from this human hepatocyte CL study will be utilized for human PK prediction.

Runner up:

Tsho (Satoshi Mikami)'s runner up : (series 5)
TR06693098

Another: TR06696869 (EUTOMER, SERIES 6)

TSD Chemistry Goals

Profile Existing Phenolic Candidates

Series 3 Lead - TR06692993
Series 3 DHP subtype
Series 3x

Uncertain Spans

location	transcription	uncertainty
Quanterix discussion row	”Quanterix is open (with MJF permissiion)“	Original spelling preserved (single “i” missing in “permission” looks intentional in the source).
Summary of NLRP3 biomarker slide	Reference column “Wallisch et al, 2017” and similar	Inserted slide is small; Reference labels are kept verbatim from the photo but periods/commas may differ slightly.
TSD Chemistry Goals slide footer area	sub-headings under “Profile Existing Phenolic Candidates”	Only “Series 3 Lead - TR06692993”, “Series 3 DHP subtype”, “Series 3x” are legible; further sub-bullets cut off at the bottom of the photo.
Ceri narrative table top row	”100% NLRP3 inhibition + BM of cell death → decision making”	The leading “100%” appears highlighted; reading is preserved as-seen.

JS PD KB

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