| Primary analysis- | Mean Striatum SBR | A Bayesian repeated measures model of mean striatum SBR over time will be used to compare the slope/progression of active treatment versus the shared placebo arm. The model allows for heterogeneity across individual baseline mean striatum SBR values and individual slopes, heterogeneity across regimens due to minor differences in the inclusion/exclusion criteria or mode of administration, and the ability to leverage the natural history arm (i.e. non-randomized participants). A greater negative slope indicates a reduction in the biomarker and a greater progression rate. A hypothesis test for a smaller progression rate for active treatment versus placebo will be conducted using the Bayesian posterior distribution, with a predefined threshold (e.g. 0.98) required to demonstrate superiority. |
| MDS-UPDRS total score | A Bayesian repeated measures model of MDS-UPDRS total score over time will be used to compare the slope of active treatment versus the shared placebo arm. The model allows for heterogeneity across individual baseline MDS-UPDRS total score values and individual slopes, heterogeneity across regimens due to minor differences in the inclusion/exclusion criteria or mode of administration, and the ability to leverage the natural history arm (i.e. non-randomized participants). A greater positive slope indicates fast symptom accumulation and a greater progression rate. A hypothesis test for a smaller progression rate for active treatment versus placebo will be conducted using the Bayesian posterior distribution, with a predefined threshold (e.g. 0.98) required to demonstrate superiority. |
Progranulin (PGRN)
cxxi) Definition::
| Normal | Progranulin (parent protein) → granulin eNeuro, showed that progranulin enters lysosomes within cells, → it is then broken down to the smaller granulins. Our paper is the first to actually show that mature granulins are made in the lysosome." |
| PD | ↓ Progranulin these were not degraded |
Denali Progranulin PTV: PGRN (DNL593)
Biomarkers of DNL593
| position | Characterization | Qualification | assay | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| HUMAN | In vitro | animal | human | In vitro | Animal | |||||||||
| papers | In house | paper | In house | papers | In house | papers | In house | Paper | In house | Paper | In house | |||
| PGRN | Plasma PGRN can be utilized for patient selection. | O (CSF, correlation between CSF & Plasma) | O | O (KO mice) | Js: will | |||||||||
| BMP | Proxomal PD | Will (CSF of patients) | O 일걸 ptv:pgrn prc1 slide: Validated: BMP change in PGRNdeficient cells and mice | O (brain & CSF, 24h & 96h each) | O | O (brain & CSF, 24h & 96h each) | Fulfilled (qualification yet인데) Ful-filled | |||||||
| TDP-43 | Exploratory | not a prerequisite for clinical development; but important question to understand FTD pathogenesis is due to PGRN deficiency | X (correlation with FTD pathogenesis and progression is unknown) | Will (Pending on preclinical results, further effort may be initiated for TDP43 characterization in human) | GRN mutation (R493X) KI mice exhibit PGRN deficiency & age-dependent TDP43 pathology | will | TDP43 CSF/plasma assay development ongoing Not fulfilled | |||||||
| vMRI | ||||||||||||||
| NFL | O (CSF) | Fulfilled | ||||||||||||
(a) Risk: It has yet to be validated if translatable PK/PD and efficacy biomarkers can link each other.
Mitigation: Correlation of those markers are examined in GRN KO mice and patient’s samples
Mode of action model
- PGRN → Rescue lysosomal dysfunction (abnormal BMP signature) → Reduce Increased NfL (neurodegeneration) [Main path, solid arrow]
- PGRN ⇢ Normalize microglia phenotype (Change in cytokine profile) ⇢ Reduce Increased NfL [Additional path, dashed arrow]
Work flow to see the relationship between biomarkers
- Good PK/PD (BMP) relationship in GRN KO x TfR KI mice
- Yes → Correlation between lysosomal GRN level (or CSF PGRN), CSF BMP, Nf-L levels in GRN KO x TfR KI mice
- Yes → Correlation between CSF/plasma BMP and Nf-L in FTD with GRN mutations
- Yes → CSF/plasma BMP can be utilized as translatable markers to estimate clinical efficacy
- No → If BMP not available, other proximal PD markers should be identified, or the use of distal PD markers should be considered. Candidates: other lipids, sTREM2, cytokines
- No → (same right-side branch as above)
- Yes → Correlation between CSF/plasma BMP and Nf-L in FTD with GRN mutations
- No → (same right-side branch as above)
- Yes → Correlation between lysosomal GRN level (or CSF PGRN), CSF BMP, Nf-L levels in GRN KO x TfR KI mice
(b)
| Priority Tier | Biomarkers | Assay / Implementation party | Sample Type | Targeted timeline |
|---|---|---|---|---|
| #1 | Targeted metabolite/lipid biomarkers: BMP, GalCer, GluCer, Carnitines | LCMS/Denali | CSF/plasma | Q1 2019 |
| #2 | Untargeted lipidomics/metabolomics | LCMS/Denali | CSF/plasma | Data will be submitted to NCRAD for unbinding |
| #1 | NfL | NfL Simoa/Quanterix | CSF/plasma | |
| #1 | Cytokine | Luminex/Eve Tech | CSF/plasma | |
| #1 | sTREM2 | MSD/Denali | CSF/plasma | |
| #1 | Progranulin | ELISA/Denali | CSF/plasma | |
| #2 | GFAP | MSD/Denali | CSF | |
| #3 | Proteomics | Biognosys | CSF |
Figure 13. Scenario for risk mitigation (a) and priority of biomarker activities (b).
PD and PGRN
| Shuji 211023 |
cxxii) PGRN regulates GBA function and Denali's data is corroborated with this scientific evidence as PGRN KO mouse and GRN-FTD patients show up-regulated GluSph. cxxiii) But GBA mutation seems not to have an great impact on PGRN levels. cxxiv) We measured PGRN levels in Gaucher disease patients (type2 and 3). However, decreased PGRN levels were not observed (vs control with similar age). Type2 and 3 GD patients are very young, mostly less than 3 years old. Whether or not they develop GD, they have high PGRN levels. |
|
cxxv) We also tried to measure PGRN levels in GBA-PD patients. However, only one sample had pathogenic GBA mutation, which failed to conclude the link of GBA mutation and PGRN. cxxvi) Meanwhile, in PD, GRN SNP rs5848 that lowers PGRN levels is said to be associated with PD risk. When I previously communicated with Rene, Gil, and Akhil, they said this is an ongoing effort at Denali although it takes a while. | |
| I don't know about MJFF, but If I have found out something, I will let you know. | |
MJF
| animal | https://www.michaeljfox.org/grant/delayed-start-assessment-progranulin-progressive-rodent-model-parkinsons-disease | |
| https://www.michaeljfox.org/grant/assessment-therapeutic-efficacy-progranulin-sub-chronic-animal-model-pd | Neurodyn Inc |
Prophylactic vs Therapeutic
| Midbrain | ISF | CSF | prophylactic | Therapeutically | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| pros | Cons | pros | Cons | |||||||
| Can look at, cleared pre-existing aSyn pathology | Can look at, normalization of TH ie baseline, required for replacement Tx? | |||||||||
Uncertain Spans
- Biomarkers of DNL593 표는 사진에서 셀이 매우 좁고 많아 14-15 column 구조를 분리했으나, 가장자리 열과 PGRN/BMP/TDP-43 행에서 어느 셀에 어떤 마커(“O”, “Will”, “Js: will” 등)가 들어가는지 시각적 정렬이 어렵다.
- Mode of action model 흐름도와 Work flow Yes/No 분기 도식은 사진에서 박스/화살표 구조이며, Yes/No 분기 후 같은 우측 분기로 이어지는지 별도 분기인지 사진만으로는 정확히 단정 어려워 같은 분기로 통합 표시했다.
- BMP 행의 “O 일걸 ptv:pgrn prc1 slide: Validated:” 셀은 Korean 메모형 “일걸”이 그대로 있으며, “Validated:” 뒤에 줄바꿈 후 “BMP change in PGRNdeficient cells and mice”가 이어진다.
- “Fulfilled (qualification yet인데)” 표기는 사진의 “yet” 다음 한글 “인데” 그대로 옮긴다.
- Prophylactic vs Therapeutic 표는 사진 하단에 헤더와 첫 행 일부만 보이고 좌측 행 라벨 셀은 비어 있다; 이어지는 TAK-341, IONIS ASO 행은 다음 사진(184427 또는 그 이후)으로 이어진다.