Pipeline of GD & GBA-PD

Jaya	NLRP3 CN, PDE Cytokine (Olink), TSPO, QUANTERIX, Proteina, Cambridge, NBB Will you attend GCB meeting?
Katy IL18	CAN we use OLINK 48 cytokine assay? - quantitative, LLOQ 0.95 pg/mL, can it detect rat IL-18? What is LLOQ of the new AVIVA rat IL-18 kit?

Working_Document_PDE_Narrative_NLRP3_v1.docx

NLRP3 inhibition is expected to have a benefit for the majority of PD patients.
the mean percent change from baseline (relative to the placebo arm in a placebo-controlled design)

Scenario	Approach / Biomarker	Notes
Best	NLRP3 PET
Intermediate		Projected human dose and associated plasma PK will be leveraged to calculate the corresponding therapeutic index.
worst	No clinical bm, MTD approach	DR curve, transient IC90, IC50, CSF drug concentration TH -> UPDRS Greffard 2006 Ex-vivo? PBMC? Brain 에서의 exposure (IC90) 1b: fixed dose panel design, consecutive panels of 6-8 patients each receive doses that range from 50% below to 50% or more above the MTD in HVs, to assess the tolerance profile and determine MTD in patient o optimize dose selection for p2 efficacy study, -> p2 dose ranging study, the top dose will be selected based on the MTD, a middle dose, low dose, ..., titration of a fixed panel in order to determine any differences in tolerability between fixed and titrated doses, as titration may redefine the Amtd. PK-pd measurement incorporated. Dopamine metabolite. Pk-pd: central and peripheral simultaneously.

Hi Yulia, Appoliges

GCB PET: Binding (? Binding to what? 우린 붙는 거 없는데? So what is the goal of the study) study: brain homogenate of hTfR KI mouse (Tbos?) 가 access 있는지 확인 요), Human brain,

Ship: Anti TfR1 sdAb by itself. GCB protein by itself, the whole Fusion Protein 이것들을 animal 에 dosing 후 죽인 후 brain homogenate 를 본다는 건가? Or postmortem brain homogenate sample 에 투입후 in vitro study 한다는 건가?
Lysosomotropic PET: Study: pH dependent uptake . ARG pH 4.5 vs 7.4 (note: this study was previously done with other tracer). TR06795793

Sample? PM can't remember WT? Disease model?

Preclinical pharmacological modulation in rodent efficacy model (CBE+A53T aSyn mouse) -> HV (phase 0) (brain uptake, test retested ability and dosimetry) -> GBA-PD patients

Gap, -aSyn assays: oligomer (CDMS, SOBA, RT-quic), p-aSyn (SMCxpro), UPDRS correlation
aSyn Imaging, -> DA TMP, precise window 안에서, clinical domain (PPMI, abstract), aSyn species (monomer, oligo, pSyn)

Owner	20230621	20230815	20231023 / 20231120 / 20231204	20240214 / 20240226
Laura	ePOC Biomarker Quantitative Relationship, Nodthera, PBMC	Proteina: press release, cost RSLT trip?: Oct 2024 Who PO owner? Inflammasome Therapeutics Summit: 3 days, $3,296	Oligomer assay: BSI, RT-Quic, FY23 Goal, Epoc: DATSCAN, VMAT2, indiv data, (tofersen example) 20230926: PQR Oct 10th, Imaging strategy, KAIST travel 20231010: AMP-PD, GCB, TFR: Lysosomal imaging 20231023: Aci termination, NLRP3 meeting note: aSyn frag. functional NLRP3 assays Asyn fragment: Joe Palandra (CBID)NLRP3 AD: Zemin vs Jnaky? Lysosomal PET 20231120: -Nlrp3 BM strategy meeting. -GCB BTV: indications. Comp Bio -PDE: Role? 202312: -Atuka study CSF/plasma data 20231212: PDE: 20231013 Devyani -TSPO plan -GPNMB NLRP3: PDE, Ceri (TSPO plan) Digital: issue, EEG,	Oligomer assay: BSI, RT-Quic, FY23 Goal, ECD-GI2: DDU->GI2-TAU, GI2-Inflammazome summit 20231204: -RT Quic? -p-aSyn? -vmat2? -GCB BTV: strategy -GPNMB? 20240214: Jaya, Sarah 20240226: NLRP3, Thursday, Feb 29, 2024 5:00 PM-5, jAY. Weight loss, sarah, orexin, ceri, collabo with orexin team. Pde: July. Project Argo, Ambagon. 20240408: GCB: CBE-Cyno
	20240311 -Atuka NHP study: imaging already available, so CSF & brain data? -mayor2, BM rat study (budget) -digital: Sep	20240325 -Nlrp3 AD brain samples NBB: Zemin finish? -BSI,	20240408 GCB: CBE-Cyno
		MJF woshop Send back performance review

Owner	20230915	202209	Other cells
Zemin	Nlrp3 AD, ALS, SZ, BSI: BDD vs BSI C3aR 20231208 -NDU STRAtegy document -NDU clin Q meeting presentation -EEG -digital	Epoc? Digital in Ad	Cambridge: Wet lab NLRP1 AD postmortem samples?

Owner	20230925	202310	20231120
Marianthi	Consultancy: guideline, fee, frequency	But please confirm with Arthur and the project team if the plan is really just to use TSPO in the clinic for TE/PD, NLRP3 PQR minute, aSyn frag. Lyso PET, Digital,	Caspase-1 PET? ~~Zemin~~, Janaky PDE timeline: no TSPO, Delay: TSPO: WB 202401 -> IHC 202404 CSF BM (IL-18, Casp1 activity, NFL, total Casp1) result: 202402
	CN backups: No efficacy study?	TR06798980 aav aSyn rat brain data-wb, histology, CSF purse?

Owner	Notes	20240212	20240412
Jaya	Development requirement (eg. no PE BM, no Dev)	-TSPO feasibility: my method. -scenario: no BM, MTD, -my requests to clinical section in narrative, -MAB too,	Mayor1, NLRP3:TSPO,Cytokine, DDC, GCB: min package, TH,

20240129

Result: Lysosomotropic planning with PM, remove/() on GlcCer,GlcSph, rigidity (EMG?)

		F/U	Placebo group	Drug group	a	Beta	tail	Ss per arm
Two group proportion comparison	https://www.stat.ubc.ca/~rollin/stats/ssize/b2.html	3yr	20% (Oftedal 2023) low GBA activity tertile	Drug effect / Proportion with PDD	95%	80%	2	469
				↓30% / 13.2%	95%	70%	2	369
				↓40% / 12%	95%	80%	2	329

Uncertain Spans

location	transcription	uncertainty
GCB PET note	`hTfR KI mouse (Tbos?)`	Parenthetical token after `mouse` is small and partly cut by highlight/edge.
Marianthi row	`CSF purse?`	Final word is visually readable as `purse?`, but the domain term may be another similar word.
Gabi row	`remove/() on GlcCer,GlcSph`	The parenthetical/slash immediately after `remove` is not fully legible.