Pipeline of GD & GBA-PD

program / target	study	population	route / note	CSF/serum ratio	visible total / TE note	visible free / PD note
Prasinezumab	SAD	HV	iv			↓ 96%
Prasinezumab	MAD	PD	iv	0.3 (w9)		↓ 97% (the highest dose); monomeric a-syn in CSF did not change (due to its low affinity to monomeric aSyn). At the time, Prothena had no assay for a-syn aggregates in CSF
TAK-341	P2 (MSA)					This assay (MSD) was used in SAD and MAD studies and will be set up the same fashion to support ph2 in MSA (priority)
TAK-341	MAD	PD
TAK-341	SAD	HV	iv

MEDI1341 MAD / TAK-341 POM Evidence

아래: slide 20220112 TAK-341 POM and Ph2 planning discussion - 011222
Mean (SD) % Change from Baseline for Free a-synuclein in CSF
Following Multiple Intravenous Doses of MEDI1341 or Placebo
 
O-D(?) the fraction of aSYN that can bind TAK-341 is slightly <50% of the total in human.
Human

visible dose	serum Cmax / exposure fragments	serum aSyn / CSF aSyn fragments	visible summary note
1200 mg	202, 8080	64.3, 34.3	-47.2% ... -47.3% ...
2400 mg	441, 18800	144.9, 30.8	-68.9% / -68.1% style fragment
4800 mg	...	...	-86.5% style fragment
4500 mg	...	...	...

TAK-341 Preclinical Rat And NHP CSF a-Syn Evidence

rat / WT / iv / 1w / 13w
Figure 14
Free α-synuclein in rat
rapid & robust suppression
 
C: Rat Total α-synuclein (Study AB21095 [BS001397-80])
no change
 
A: Rat Free α-synuclein (Study AB21095 [BS001397-80])
 
NHP / WT / iv / 1w / 13w
increase
 
D: Monkey Total α-synuclein (Study AB21096 [BS001397-85])
no change
 
B: Monkey Free α-synuclein (Study AB21096 [BS001397-85])
Cyno
CSF Concentration (ng/mL): 132, 293, 760

Within the planned human dose range of 70 to 4200 mg, it is not anticipated that the maximum exposure will exceed a Cmax of 2800 ng/mL or an AUC∞ of 4100 ng*day/mL, the exposure achieved at the NOAEL in cynomolgus monkeys

Clinical Studies: SAD HV

Clinical studies (아래표는 옛날+최신)

row / study	design	milestone	PK/PD
SAD / HV	A Randomized, Double-blind, Placebo-controlled Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single Ascending Doses of MEDI1341 in HV		[Initial human PK/PD modelling]; 약 plasma- aSyn Plasma - asyn CSF; objective: ① examine the historic PK/PD prediction based on monkey data, ② estimate the extent of free CSF aSYN reduction in the subsequent cohorts, and ③ determine if the modification of the SAD and/or MAD design is needed to capture the full PK/PD relationship.

[results]
At 4500mg, there is slightly more aSYN than TAK-341

Molarity / Relative Concentration Calculation

analyte	observed A	MW B	molarity A/B	relative conc
αSYN in CSF	194.4	14500	1.34E-11 (0.013407)	6.19
341 in CSF	320.5	148000	2.17E-12 (0.002166)	1

Observed (ng/L): A
MW (g/mol): B
Molarity=A/B=the moles of a solute (molecule)/L
=the molar concentration of a solution.

Clinical Studies: MAD PD

row / study	design	milestone	PK/PD
MAD / PD	PD, iv, 8w DB treatment period. Each subject will receive three 60-minute intravenous infusions of MEDI1341 or placebo during the treatment period, with 4 weeks between infusions (1 infusion on each of Days 1, 29, and 57).	(20190613 scenario 1, POM=e POC): ↓ >50% CSF Asyn (at trough concentration of drug) # 성공여부는 50%감소로 하지만, 2상 dose는 maximal reduction 일으키는 dose로 하겠다는 것.	[Fully developed human PK/PD modelling] Objective: ① predict the relationship of free CSF aSYN to TAK-341 exposure at steady state, ② estimate the dose regimens that provide maximal free CSF aSYN reduction, and ③ facilitate dose selection for planned phase 2/3 trials in PD and MSA indications.

Cohort 1 (1200mg)
DEC data review
Cohort 2 (2400 mg)
DEC data review
Cohort 3 (4800mg)
 
Note
N=12 per cohort (N=9 MEDI1341, N=3 placebo)
The Dose Escalation Committee (DEC) will review blinded safety, tolerability, pharmacokinetic, and pharmacodynamic data before progression to the next higher dose level occurs.
After Cohort 1, implementation of the planned higher dose-level cohorts will be decided in the context of the totality of available nonclinical and clinical data.
The doses for Cohorts 2 and 3 may be adjusted based on data from Cohort 1.

secondary: α-syn levels (total in plasma, free in cerebrospinal fluid)
tertiary: MDS-UPDRS assessments
To collect blood and CSF samples to explore the potential effects of MEDI1341 on relevant biomarkers in subjects with PD: Possible examples include (RNA) (transcript, microRNA), proteins (eg, synaptic proteins, oligomeric α-syn, p-aSyn, α-syn fragments, exosomal proteins, tau, amyloid 1-42, broad proteomics), and metabolomics/lipidomics

CSF sampling is done on the baseline (ie day -49 to -2), day 61, day 85
 
Possible blood and CSF exploratory biomarkers include RNA (transcript, microRNA), proteins (eg, synaptic proteins, oligomeric aSyn, p-aSyn, a-syn fragments, exosomal proteins, tau, amyloid 1-42, broad proteomics, and metabolomics/lipidomics

MSA Study Note

row / study	design	milestone	PK/PD / biomarker
MSA study	An interim analysis for possible futility and/or efficacy analysis and/or sample size re-estimation may be conducted after approximately 40% of subjects have completed 52 weeks of treatment	FPI in 202207,	BM: NFL

aSyn Programs Table Start

aSyn programs
 
Target entry
To Explore target validity
PS
To Explore asset feasibility
LGE
LG
PE
Commit to Medicine Discovery
CN
CS
Commit to clinical asset
Early Dev Entry
Commit to Medicine development
IND
 
Target
incubator
Assay dev
Hit finding
TV
Hit-to-lead

Uncertain Spans

location	text/status	reason
navigation path	TAK-341 (MEDI1341) > Clinical studies	Inferred from visible nav headings and body content; active highlight is not clear enough to prove exact subsection.
top comparison table	original column headers	The top/left edge of the table is cut off, so the full schema must be recovered from adjacent photos.
Prasinezumab MAD row	0.3 (w9) and ↓97% (the highest dose)	Both engines agree broadly, but the table cell is small and partially wrapped.
TAK-341 POM mini-table	dose rows and percent-change values	Text is very small; values are preserved as figure evidence and only obvious fragments are transcribed.
preclinical graph units	Cmax of 2800 ng/mL and AUC∞ of 4100 ng*day/mL	OCR rendered the unit glyph poorly; visual reading suggests ng, but manual confirmation is needed.
clinical dose schema	Cohort 2 (2400 mg) / Cohort 3 (4800mg)	Values look clear in the crop, but the photo angle and highlight make exact digits high-risk.
MSA study row	FPI in 202207	Visible but may be shorthand for 2022-07; left row label is partly cut by the next-page boundary.