PRC-PRC Memo; LDE; Ph 3 studies are placeholders; Phase3 study; markers around 10 Jul28 and 13 Jun29
Clinical Studies
PD Gait ePoC
30 Nov20 - 22 Feb23
Clinical Studies
PD Ph2 Dose ranging/Ph3 Studies (2)
30 Jul24 - 31 May28
Clinical Studies
PD Long Term Safety
29 Jan25 - 22 Nov29
Clinical Studies
DDI (2) Studies for CYP3A4
14 Sep22 - 09 May23
Clinical Studies
IND/NDA Submission/Approval
IND; Remove Partial CH; EOP2/EMA-HTA
Clinical Studies
hADME Study
14 Apr23 - 09 Feb24
CMC
CTM for ePOC
01 Oct18 - 31 May20
CMC
DS/DP development for Ph3*
30 Aug22 - 31 Aug23
CMC
API & CTM for Ph3 (pilot scale)*
30 Aug22 - 25 Jul24
CMC
CTM for Ph3 (2nd supply)
01 Jul24 - 03 Apr25
CMC
DS/DP registration stability
01 Jul24 - 29 Oct27
Toxicology
26W Rat
30 Aug22 - 09 Aug23
Toxicology
39W NHP
30 Aug22 - 12 Oct23
Toxicology
Definitive EFDs
30 Aug22 - 25 Feb23
Toxicology
Male/female Fertility
30 Aug22 - 27 Mar23
Toxicology
TG car study + DRF-SPA
28 Mar23 - 29 May25
Toxicology
2 year rat car study
29 Jul24 - 27 Nov27
*Raw material ordering and some DS/DP development begin in 2021. Initiating 6 month prior (Jan 2022) will be additional 0.8 OY.*hADME, Asian bridging, tQT studies will be conducted after successful ePOC. LDE 1 month after DDI studies."Reg team is exploring fast track, and Ph3 digital tools
Timeline of TAK-071
TM of TAK-071
(20201211 TAK-071 CDP_NSRB_11Dec2020.docx) Potential IIR or Takeda-sponsored biomarker study: Currently, there is no biomarker for the TAK-071 program, and none is used in the 2002 study. The team has interacted extensively with Dr. Lewis Lipsitz, Chair of Gerontology at Beth Israel Hospital whose research program is focused on falls in cognitively impaired elderly patients. His group has identified resting state fMRI imaging correlates of gait variability in elderly subjects. Resting state EEG or fMRI could be a useful biomarker to explore dose-response relationships in this regard to improve the choice of doses to test in the Ph2b study. A IIR or Takeda-sponsored study can be considered if study 2002 is positive.
Activation of expression of (IFN) response genes in the nucleus
downstream effects
↑ type I Interferons (ie a product of STING activation); ↑ microglia recruitment; ↑ apoptosis; neurodegeneration
{Matsui, 2021 #1541} 그런데 (cGAS말고도) 다른 NUCLEIC ACID sensor molecule많다: IFI16, DDX41, TLR9, AIM2, DHX9, ZBP1, MRE11, DHX36, (즉 cGas억제해도 이런 것들이 보상적으로 오르면 어쩔?)
Evidence
row / context
text
Loss of LRRK2
↑ DRP1 phosphorylation
Evidence / Human / postmortem
{Matsui, 2021 #1541} Fig5b, sPD medulla oblongata에서 ↑ (cytosolic) ds mt DNA (postmortem)
Niigata plan
Postmortem brain sample from Niigata univ: IHC of cGAS results in FY21 4q; Niigata univ: Will not look at cGAMP & STING
cGAS / cGAMP questions
cGAS protein?; cGAMP level?
serum / patient
{Borsche, 2020 #1044} patient에서 오르긴 했으나 overlap
Korean interpretation
제일 가능성 높은 군에서 이러니 mtDNA를 sPD에서의 stratification BM으로 쓰기는 난망
Borsche cohort note
{Borsche, 2020 #1044} - German cohort: n=15 Parkin-PD 와 Pink1-PD 섞인 (각 구성 UNKNOWN) - Italian cohort: n=19 Parkin-PD 와 Pink1-PD 섞인 (각 구성 UNKNOWN)
Borsche 2020 IL6 / PRKN / PINK1 Figure
- Total 34명: 중 parkin 23명, PINK1 11명, h&y 2.6, disease duration 18.1 y, age 51.3Analysing PRKN and PINK1 mutation carriers separately, we did not detect any difference between IL6 levels, neither in biallelic nor in heterozygous mutation carriers (Supplementary Fig. 2). This was true for both the German (Supplementary Fig. 2A and C) and the Italian cohorts (Supplementary Fig. 2B and D).
Uncertain Spans
location
text/status
reason
page label
Page 44 of 50
Apple Vision and PaddleOCR agree for this statusbar, but adjacent synthesized pages previously showed Page 34 of 40; keep exact OCR-visible value pending manual check.
nav path
TAK-071 > Mechanism
Inferred from body heading and nav entries. The page also includes Timeline of TAK-071, TM of TAK-071, and the start of cGAS > MOA cGAS, so the active highlight should be manually confirmed.
TAK-071 mechanism comparator
C?) AChEIs...
Row label is partly cut/unclear; the mechanism sentence is readable but the leading marker is uncertain.
timeline title
PD Falls and cognition Timelines - Base Plan
The right edge of the title is visible, but the left/center title is slightly blurred.
timeline row labels
PD Gait ePoC, TG car study + DRF-SPA, DS/DP registration stability
Small text; OCR engines disagree slightly on capitalization/spelling.
timeline dates
all activity date ranges
Many dates are small; copied only when legible in both image/OCR evidence.
footnote
0.8 OY, tQT, fast track, Ph3 digital tools
Small text at the bottom of the timeline; preserve visible wording pending review.
TM paragraph
A IIR, study 2002, Dr. Lewis Lipsitz
Text is readable but line-wrapped and partly near the right photo edge.
cGAS title
=mb21d1
Visible as typed, but gene symbol may require normalization before KB use.
