Sample size estimation, Tx Paradigm, Biomarker Usage Map, DMPK PK/PD, Translational questions, Tempo code 43/6-100
Top header carry-over
| AAV-GBA | GBA mRNA | GBA protein | GBA activity |
|---|
Experimental Medicine
- GBA+PD vs GBA-PD,
- GBA+PD인데, gba activity 충분군과 부족군으로 나뉘서 결과봄.
Ambroxol: gba activity 충분군과 부족군으로 나뉘서 결과봄?
근데 venglustat 자료보면 26주까지 GlcSph 떨어지므로, 짧게 보는 EM 불가능?
Phase I
- Population
- PD군이라야 하겠지! HV should not have increased GBA protein safety perspective
Tx Paradigm
| Tx | GBA activity | GlcCer | GlcSph | 현상 | goal | Ambroxol | Venglustat |
|---|---|---|---|---|---|---|---|
| To | Incremental만 (Gegg et al. 2012) 2-fold upregulation of GBA (어떤 환자에서는 여러 fold 증가일 텐데 safety?!) | 15% 증가 (-20-60%, SN, cerebellum, putamen) 모두 제거 | PD ↓ GBA-PD 제거 | (?(what if too much?)) | Venglustat 는 maximal reduction 도모하잖나? | ||
| To normal level | Same as normal control | Same as above | downstream 위주로 생각하지, 어차피 지금 상류와 하류 사이에 quantitative correlation 이 잘안 된다 | ||||
down stream 위주로 생각하자, 어차피 지금 상류와 하류 사이에 quantitative correlation 이 잘안 된다
- GD: GlcSph를 최대로 없애야 함
- PD: aSyn 을 최대로 없애야 함
- Motor: 남은 aSyn이 cell-to-cell transmission 할 테니 max로 없애야 하지 않나
- OS: 최대로 없애야 하지 않나? b/c downstream 은 amplification 되므로
Biomarker Usage Map: GBA activator in PD (Takeda)
Quantitative relationship between biomarkers → DMPK, QCP, & QS
| Lane | PS Patient Selection Genotype/phenotype | PK Pharmacokinetics Drug Concentration | TE Target Engagement Target Occupancy | TF Target Function | PD Pharmacodynamic Physiologic Pathway Modulation | DR Disease-Related Pathophysiologic Pathway Modulation | Clinical Endpoints |
|---|---|---|---|---|---|---|---|
| Clinical | mutant early PD | Plasma, CSF concs | GBA activator PET | GBA activity CSF/Plasma | GlcCer and GlcSph | aSyn PET CSF aSyn Neurodegeneration DATScan, vMRI | MDS-UPDRS, MoCA (MoCA: Montreal Cognitive Assessment) |
| Translational link across species: Allometric Scaling | |||||||
| Non-Clinical | GBA+PD TG mouse model | PK Plasma, CSF concs (DMPK) | GBA activator PET ligand Brain/CSF/Plasma | TF GBA activity brain/CSF/Plasma | GlcCer and GlcSph brain/CSF/Plasma | aSyn (brain) | In vitro iPSC In vivo WT & Animal Models Human Experimental Medicine Study |
Key Question to enable quantitative decision-making in EPOC study
- How much TE needed to change PD / DR biomarkers by a magnitude likely to predict a clinically meaningful effect?
- Increasing confidence in ability to answer this as move from left to right, with vertical integration at each step
The main preclinical research hypothesis: for LGE proposal, is it reducing aSyn (then what species, or is it spreading?), or would we have to prepare for an alternative mechanism (ie some other mechanism that’s independent of aSyn)
Target degree of biological effect
- For LGE proposal, I think we will stick to aSyn reduction though we have not had any data or platform yet.
How do we determine a effective dose?
- If we can establish the PD animal model in which a-Syn reduction is observed in AAV-GBA, then we will estimate the correlation between vg quantity or GBA expression and the degree of aSyn reduction. Then we will translate the data comparing NHP biodistribution data and calculate the effective dose.
- Or, if we cannot establish the PD model either in vitro or in vivo, it would be really difficult to estimate the dose. In that case, we will start at the highest dose with which NHP does not show any toxicity.
Target symptom domain
Target occupancy
Any other unmet needs from preclinical perspective
NHP Translational Model — DMPK’s PK/PD
| Plasma exposure | Brain exposure | |
|---|---|---|
| brain plasma CCC | plasma | |
| GBA activity | brain plasma CSF | |
| GlcCer brain plasma | ||
| GlcSph brain plasma CSF |
Key question to DMPK
Human 에서 GlcSph plasma change 로 GlcSph brain change 예측 가능한가?
GCSi 에서 구축한 걸로 (slide 103~) GBA activator 에도 적용가능하는가?
| Background | ↑ GlcSph ↑ A-syn level/spread |
|---|---|
| Outcomes | |
| No drug | ↑ GlcSph ↑ A-syn level/spread 확인 |
| Drug | GCSi? |
| Therapeutic outcome | |
| (PD) CSF calibration | A-syn PET, regional correlation between GlcSph and A-syn 진행중인 NHP Model 에서 CSF에서 a-syn 이 안 변할 수도 있는데, 그 때를 대비하여, 대신 GlcSph 변화의 CSF biomarker 로서의 utility 를 평가할 수 있음. |
| GD | CSF calibration of changes of GlcSph, GBA activity, (GBA expression은 NHP Bioditribution study 에서 보겠지) GBA activity 수십배 증가를 model해야 하는데 (CBE 로 WT MICE 에서 prevail이 한 사례있음), Smid 참고할 것, venglustat은 GCSi 라서 다를 수 있음. |
Translational questions
Genetics
- complete penetrance suggests presence of modifiers. How do we identify such modifiers to garner insights into potential therapeutic targets and patient enrichment / stratification strategies?
- Will different mutations within the GBA gene lead to differential effects on PD phenotypes. 5,6?
Translational
- How much of an increase (both amount and duration of increase) in GCase is needed to see efficacy?
- (prevention 이 아니라) early PD 에서는, Existing GlcSph 도 clear 해야 하므로 많이 필요할 수도 있겠다.
- What is the potential liability of increasing GCase activity and depleting GlcSph in CNS?
- clear association with GBA activity level and phenotype (motor & cognitive) (2019 PPMI annual meeting)
Biomarker
- Could alpha-syn serve as a good biomarker in GCase targeting trials?
Clinical trial
- What is the optimal patient population for Phase 1 and Phase 2/PoC trials?
- How can you enrich for a population most likely to respond to GCase activation?
- Would GCase targeted therapies work in idiopathic PD?
- What clinical outcome measures should be used for Phase 2/PoC trials?
- What should be the duration of the PoC trial?
Executive summary: tempo code 43/6-100
| LGE | PE | CN | PDE | CS | IND |
|---|---|---|---|---|---|
| 202406 | 2025 | 202505 | 202512 | 202612 | |
| PQR on 24-Apr NSRB on 20240606 PE on 20-Jun |
Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
| Biomarker Usage Map | flowchart layout | the flowchart visual structure is approximated as a 3-row HTML table; some left/right lane labels may need image-level review. |