| Scenario | Plasma NLRP3 | Brain NLRP3 | Brain Microglia | cell content | Statistical method | |
|---|---|---|---|---|---|---|
| If continuous | continuous 갰지 | 각각 고민해야 겠네 | ||||
| continuous | +/- | 각각 고민해야 겠네 | ||||
| If +/- | Continuous | 이경우, next step 으로 brain microglia imaging 의 cut point 정해야 하네. | 각각 고민해야 겠네 | |||
| +/- | +/- | 이게 결국 우리가 임상에서 하려는 거인데… | 각각 고민해야 겠네 | |||
| SZ | plasma Aβ42 and Aβ40 continuous | Brain Amyloid PET +/- (a threshold of florβpir SUVr = 1.11 to a cortical summary region normalized by the whole cerebellum reference region [11-13].) | AUC | |||
| Next step | Determine the appropriate cut-points for |
Modelling
| sharepoint | NLRP3 Inflammasome > QS M&S > Slides-Hamid (Slides-Hamid) |
NHP
| mouse | NHP | Rat | |
|---|---|---|---|
| Support Biodistribution? | OK for small molecule | ||
| IVC → human dose prediction | |||
| Confidence literature? | |||
| Human disease prediction: pathology magnitutude / DA characterization | |||
| NLRP3 pathway characterization | |||
| Timeline | 1m observation needed | Characterization → 4m observation | |
| Quality: China issue? | OK if non-GLP study |
PDE
Sharefolder: Devyani
- Presentation: more detail than PE presentation,
- Resource gap: ? this should be operational risk,
- Scientific risk > operational risk,
- Timeline: PDE → CE (IE EDE), OPTIONS TO Epoc, how to show Epoc, (IS there a faster one?), epoc → poc,
- Earliest signal to give us confidence, what are the methods, what the sure one, different timing, readout sooner,
- Pros & cons, among options team’s recommendation, PRC would give direction,
- Reason of pde: disconnect between pe vs ede,
- To give feedback before IND,
- Timeline: little bit after CN but definitely before CS,
- Asset discussion x, TPP X, Focus is on early clinical plan, BM clin, CMC,, roa,
- China: is there cmc problem? Number of subject? Include china on registrational trial? Prevalence difference in china?, china publishes every year on rare disease,
- no specific epidemiology study,
- Diversity: high level, are you going to include diversity?
- Digital: devices (ann Heatherington), just binary question (just a question, if you want or not),
- Just say: the same as previous PE narrative,
- 10 pages text, figures in text, recocc, TPP, decision tree, in main text, tpp no text in appendix, appendix has to have
- 20 pages in total, no change from PE, can send her draft, they are messangeers, between senior leadership,
- Cmd or any other section: if issue, highlight, (raise hand),
Meeting with PRC office over PDE-rough notes
January 10 2023
Generally the Pde narrative should (a) be high level only, 10pgae +~10pages of appendix (b) focus on Translational and clinical plan and not other topics
- Can assume PRC members have the PE document for other sections and if no change its possible to just write “no change from PE”
- No asset discussion
- Within clinical and translational plan one focus is risks and mitigations, at a high strategic level
- The second focus is ePOC options and PROs and CONs, encouraging a discussion also on options that are more exploratory and risky (“sometimes the ePOC is almost POc”), the team should have a recommendation but explore additional scenarios
Another area of focus is manufacturing (a) in case it risks the clinical plan (b) ROA considerations might also need to be discussed and
Timeline needs to be detailed only up to CDE, after that (up to ePOC can be based on assumptions)- operational details beyond high level risks are not a focus.
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
There are a few general things introduced to PRC documents- digital plan, china elevation and patient diversity plan. At the level of PDE is more like a Yes/No question-
- when/if china will be in clinical development (should already be introduced at PE)
- is the team planning diversity goals (and then diversity will be part of GPT topics)
- digital tool overview - new topic, might need to consult with Anne what is desired
(no clear guidance how to introduce it, will evolve over time)
First team is going in Feb. 26 (oncology). Second is rare (TAK-028) on March 16. DMPK-MTV will need to update on new desired date.
Philip’s thought? GO, Stat (to address Anne Heatherington), Epoc, AH: criteria for success? TST (Allen Cristi?)
45 minutes for PRC1, the applicable TAU Head, DDU Head, TA Franchise Head, GPL and GPM
- • Head Global Product & Launch Strategy
- • Head Global Clinical Operations
- • Head Global Portfolio Strategy
- • Head R&D Strategy & External Innovation
- • Head Pharmaceutical Sciences
- • Head Global Regulatory Affairs Oncology (for all Therapeutic Areas)
- • Head of Preclinical and Translational Sciences
- • Head Drug Safety & Evaluation
- • Head Quantitative Clinical Pharmacology
- • Internal rotating member
20221215 minute: Meeting with Ceri, PDE timing will be discussed with Ceri-The PDE is rescheduled from 16 Feb to 25 Apr. CS would be delayed to Q1 FY23. Email: ?
20230104 minute: Option 1 - TR098; target PDE and CS are 25th Apr and May email: O
Working document PRC Narrative NLRP3 23Nov2021wRef.docx
11209 QA list in PRC.xlsx
Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
| Brain Microglia row | continuous 갰지 | The trailing Korean two-character marker may be 같지 or 갰지; preserved as visible. |