20240722_183429

Project	Target validity	Compound's POM	5 day tox	2w tox, CV / Human prediction	GLP tox	Compound improves the disease!	Compound is solid (tox etc)	Compound can enter clinic!	Brain PK/PD	Initial mouse POC tox	Detailed TM	FTE / years
	Target is right (confirm the validity of the target)		Compound's POM, Concept validation, 20200 Ceri: ROA and dose are not important. Eg. ICV or 100mg/kg is OK for PE
NLRP3		Plasma PK/PD
PRKN-PD
TM		High level				Compound improves the disease!	The compound is solid (tox etc)	The compound can enter clinic!	Brain PK/PD (bzATP)	initial tox assessment of the mouse POC and brain BioD (early understanding of dose limits.)	Detailed TM
CKD		Enzyme, Tub-Ac, Solubility, MATA	5 day tox,	2w tox, CV, Human prediction, Nlrp3: dog tox	GLP tox					Liver MS, In vitro PL, Herg, MTT, Pgpi, PK_BBB Acute In vivo (yac128), 2w tox (mouse), CYP, Non-rodent PK, Chronic In vivo, 4w tox @AMES, DDI,	Telemetry, Metabolite, Non-rodent tox, API Synthesis
CKD										2 y	2y
CKD	FTE	1.9								4.3	6.3	1.5 y
CKD		3 ok								6 ok	9 ok

The context is that CDE is too close to the clinic, and doesn’t allow high level discussion (and too far after PE), the idea was to have PDE (a) ~1y before IND to allow time for changes (2) before CS to influence CS

Target ID	incubator	Target entry	Assay dev	Hit finding	TV	PS	Hit-to-lead	LGE	LG	PE	Commit to Medicine Discovery	CN	CS	Commit to clinical asset	Early Dev Entry	Commit to Medicine development	IND
		Target entry	To Explore target validity			To Explore asset feasibility
	A-syn protein degrader (small molecule) (Ruhi)
				aSyn propagation suppressor (phenotypic screening) (=SMOL) (Sebastian TML?)
									SNCA BTV (Brain Transport Vehicle: ASO/HDO + transferrin receptor (TfR) ligand): Maeda Ryota (SNCA HDO의 후예)
									SNCA-ASO (WAVE)

This table needs yet to incorporate 20210224 Research playbook

	PE	CN	PDE	CS
PK/PD, HED				Defined PK/PD relationship and HED & exposure prediction
Criteria	Go/No Go criteria for IND submission		Go/No Go criteria for CDE	·
BM	detailed timeline for TE & PD biomarker development, Translational plan, including pharmacology, safety, digital and efficacy options and rationale for predicting human dosing.	Updated timeline for biomarker development (TE, PD, DR, PS)	Translation biomarker plan	· Updated translation /biomarker/ early clinical plan towards ePoC with patient segmentation strategy NSTM: IVC
M-eg	CCR8-ADC		(fig5, MB49 mouse) Different concentration → T cell depletion → tumor volume	·
clinical plan			Epoc option, Early clinical development plan Early clinical/biomarker plan should focus on discharge of program risks and value creation	ePOC plan and quantitative criteria
safety				Secured safety margin in 2w tox in 2 species
patient			Preliminary high level Patient Diversity strategy/plan
Timeline			Timeline to PDE	Timeline to CDE

[ll molecule 20210224 Research playbook]

	Portfolio Entry (PE)	Candidate Selection (CS)
Definition	Strategy towards CS is clarified Target indication identified	· Clinical candidate is identified with sound confidence in indication, mechanism, translation, safety, execution, and asset itself. Takeda is ready to file IND and invest for clinical studies.
Points to consider	The concept is clear and based on ground evidence. The go/no-go decision criteria is clear along with the key milestones. Anticipated issues/risks/bottlenecks towards CS are identified. There is a roadmap to collect enough information to create target product profile (TPP).	Commitments at PE is met or not Candidate Profile declared at PE is achieved or not Issues/highlighted risks/bottlenecks identified at PE are resolved or not Commitments towards next milestone is clarified Issues/risks/bottlenecks towards next milestone is identified
Evidence in mechanism & pharmacology	Rationale for exploring MOA is clarified in vitro/in vivo pharmacological validation is established with a tool molecule	Review of the data (on the program and candidate molecule) that validates the hypothesis that the target can be drugged in an appropriate model / test system, including downstream effects / markers / models Assessment of genetic and genomic evidence supporting the target
Update on the evolving translation / biomarker / early clinical plan, including timeline of

Uncertain Spans

location	transcription	uncertainty
Top stage-gate table column headers	Several columns (Target validity, Compound POM, 5 day tox, 2w tox CV, GLP tox …)	Header row is partially cut at the top edge of the page; column boundaries inferred from cell alignment of subsequent rows.
Top stage-gate table CKD years row “1.5y” / “2y”	1.5 y / 2 y	Year markers “1.5y” / “2y” are small and may overlap cell boundaries; transcribed as seen.
Stage-gate header row “PS” cell alignment	PS column placement	”PS” header sits between TV and LGE columns; column placement inferred.
”ll molecule 20210224 Research playbook” leading “ll"	"ll molecule” / “[Small molecule”	Image edge crops the leading text; could read as “[Small molecule 20210224 Research playbook]”; transcribed as visible.
Top yellow ROA dose note “20200 Ceri”	20200 Ceri	Year prefix appears as “20200” rather than “2020”; transcribed as seen.
20210224 Research playbook PDE column “fig5, MB49 mouse”	fig5, MB49	Reference label “fig5, MB49 mouse” is small; transcribed as visible.