HDAC6 PET Protocol End, Budget/Responsibilities, And Start Of Project Team Function Table
HDAC6 [18F]EKZ-001 Clinical PET Protocol (continuation)
| 참고: activator는 target occupancy level 과 downstream efficacy 간에 linear relationship 이 없는 경향. | ||
| Success criteria |
Js: 유주 from 2017 Smith (PSP)
|
Protocol, cutoff, T-RT, kinetics, interindividual variability
above: 2014 Honer
Evaluation of ligand candidates in human
- Tracer meets design requirements in preclinical studies
- GMP audit to assess compliance of positron emission tomography (PET) centre with applicable cGMP requirements
- Synthesis of precursor material
- Pharmacology and toxicology studies as per ICH M3 (R2)
- Dosimetry study in rodents
- Clinical protocol developed
- Preparation of abbreviated CMC section for application to health authority
- Validation of radiochemistry at PET centre
- CTA application for EU or eIND or IND application for USA
- Ethics committee or Institutional Review Board application
- Radiation safety committee approval (if required e.g. ARSAC application for the UK)
- All approvals granted
- Clinical studies begin in healthy volunteers
- Acquisition of baseline data to evaluate brain entry and distribution (each subject has one scan)°
- Blocking studies (if possible) to evaluate in vivo selectivity and assess possible reference regions (each subject has two scans: (i) baseline and (ii) blocked – i.e. after medication)
- Collection of test-retest data
- Collection of whole-body human dosimetry data
- Further studies in healthy volunteers and patients (e.g. examination of variability in binding with age, sex, disease severity, etc.)
- Cf: biodistribution study
- Labels test drug, (not target)
- Informs on concentration-time course of the drug in the interested tissue
- calculation of the tissue ‘free’ concentration from the total tissue concentration is typically not feasible from PET data alone, but can be done by combining
- Accurate estimation of the fraction of the non-displaceable compartment which is attributable to ‘free’ drug is performed by combining the PET estimates of the total blood : tissue partition coefficient with in vitro equilibrium dialysis assays that account for any non-specific binding in the tissue [2].
Budget/Responsibilities
| Activity name | Funding division | Mil$ (=OKY) | Parkin GT | ||||
|---|---|---|---|---|---|---|---|
| General | NLRP3 | General | NLRP3 📊 NLRP3 FTE&Budget_2021 1119.xlsx | ||||
| PET Tractability Assessment | -Compound with desired physical characteristics (e.g. Ki, Log P etc.) will selected. QTS Imaging will have responsibility and lead these efforts | 3H-labelling compounds for Bmax assessment | DDU, ANCEL (PET), 후이카이 | 0.018 | 0.018 mil$ | 다음 셋 다 일치시켰음. C:\Users\XOK4225\OneDrive - Takeda\PRKN GT\Budget: BOB, CRO tracking | |
| Where feasible this compound will be tritiated and in vitro assessment of target expression across species along with regional distribution performed to inform PET tracer viability. | Bmax assessment=in vitro binding assay for PET ligands | NSTM (이건 translational이니까 확실) | Chemistry (Holger' budget) | 0.005 | (Invicro) ~86K for the use of 2 radioligands And 0.09 mil$ | Bmax자체는 안 넣고 (Ashley 가 하니까), | |
| Optimization of physical properties and non-imaging triaging of potential candidates | , the Med Chem will undertake rational PET tracer design: Access to searchable structural database with compounds physical characteristics listed Identify lead series - Optimize and characterize compounds | Optimization of physical properties (=ligand optimization) | DDU, ANCEL (PET) -But if this involves signifinant money, eg potency testing using CRO, then NSTM should cover | 0 | 다음 셋 다 일치시켰음. C:\Users\XOK4225\OneDrive - Takeda\PRKN GT\Budget: BOB, CRO tracking | ||
| [non-imaging triaging] -. DMPK will have responsibility and support non-imaging triaging -Binding assay, in silico and LC-MS screening | Rodent blocking study =In vivo LCMS uptake | NSTM (makoto: DMPK should cover brain PK work in normal animals) =in vivo LCMS uptake CRO tracking에 ($283,663) → 20220625 cancelled로 변경 (DMPK 가 NSTM돈 안 쓰니까) | C:\Users\XOK4225\OneDrive - Takeda\NLRP3 inhibitor\Budget 엔 x. Bob (E-013, CAMH/Invicro)와 CRO tracking에 있던것들을 ($283,663) → 20220625 cancelled로 변경 (DMPK 가 NSTM돈 안 쓰니까) | 0 | 6OHDA 등 Model 사용해야 하니 돈 들 듯. | 안 넣은듯 | |
| In vivo Preclinical PET Imaging | -PET SC will rank potential PET tracer candidates that have been successfully triaged in order of tractability -For each individual target, PET Steering Committee assess the best location to conduct the preclinical PET imaging work -PET sc identify the preclinical scope of work requirements with QTS Imaging responsible for organizing and implementing these efforts -Results generated reviewed within PET Steering Committee to inform next steps in preclinical PET tracer qualification | Rodent PET study (sometimes not necessary, but IP6K did this because selective binding in non-imaging study was unclear) | NSTM/(Maky said QTS) | C:\Users\XOK4225\OneDrive - Takeda\NLRP3 inhibitor\Budget: 존재하나 fy23 budget으로 존재 Bob (E-013, CAMH/Invicro)와 CRO tracking에: $226,931 | 0.15 | 0.2 | 0.165 |
| NHP PET study | NSTM/(Maky said QTS) | 0.250 | 0.3 | 0.3 | |||
| 5.275 Clinical PET tracer translation | -QTS Imagin-will assess the clinical tractability of any PET tracer candidate -QTS Imaging will work with external partner to complete IND submission process and complete regulatory requirements to proceed to human PET studies | IND enabling | 0.05 | ||||
Project Team — Function Table (start)
| Process stage (Project Team Operational Lead) | Project | Function | |||
|---|---|---|---|---|---|
| ANCEL PET Chemistry | NSTM (PJ-TML, Biology) | DMPK | PTS Imaging | ||
| 1. Preliminary discussion (NSTM PJ-TML) | DMD MTV GBA-PD gene therapy Parkin | - Discuss PET tracer viability and expected outcome | |||
| 2. PET Steering committee (NSTM PJ-TML) | - Obtain endorsement to start PET discovery | ||||
| 3. B__ measurement (PTS Imaging) | MAP4K4 PKR NLRP3 | - Characterize compound - Select and provide ³H-compound | - Provide data (e.g., target region, animal model, availability of KO animal) | - Select species and model for B__ study and PET discovery - Arrange brain sample - Measure B__ in rodent, NHP, and human | |
| 4. Ligand optimization (ANCEL PET Chemistry) | MAP4K4 | - Identify lead series - Optimize and characterize compounds | |||
| 5. In vivo LCMS uptake (DMPK) | MAP4K4 | - Select and provide compound | Provide appropriate animal model information to be used | Design study Run animal study - Analyze sample - Check metabolite | |
| 6. In vivo preclinical (PTS Imaging) | IP6Ks | - Provide precursor and | - Design study | - Design study - Run PET imaging | |
| 5. Clinical translation (PTS Imaging) | - Run PET imaging | ||||
Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
| Budget table, PET Tractability row Funding division General cell | NSTM (이건 translational이니까 확실) | The Korean parenthetical is partially obscured by red coloring; reading is consistent with OCR but the trailing token 확실 is shortened to two glyphs in the source. |
| Budget table, In vivo Preclinical Mil$ (=OKY) NLRP3 cell | Bob (E-013, CAMH/Invicro)와 CRO tracking에: $226,931 | The dollar amount appears on a wrapped line at the column edge; verified against the cohort cell across two crops. |
| Project Team table | B__ measurement row label | The character following B is rendered as a small italic subscript (likely Bmax) but is partially clipped where the row joins the ANCEL PET Chemistry column; transcribed with the visible underscore placeholder. |