Translational Modeling Using A Reference Drug (Beloranib)

Top scatter axis labels (clipped continuation from preceding photo, evidence-only):

%BWL
Peak NMet-14-3-3γ
0    0.5    1    1.5    2
-5   0   5

• If the data from PBMC PD study could be used to predict a target tissue PD?

(TE) PD 가 Translationable 한가?
PBMC 적어도 CSF data 가 있어야 하지.

⊞ Translational modeling (and prediction of clinical efficacy) using a reference drug (that has clinical data)

Questions

• BID가 QD보다 효과 크구나.

Figure labels (Panel A — DIO Efficacy on two dose schedules; Panel B — Translational PK/E Model; evidence-only):

A   DIO Efficacy on two dose schedules
    x: Day  (0, 7, 14, 21, 28)
    y: % Body Weight Change  (10 → -30)
    Series:
      - Vehicle
      - 0.1 mg/kg Beloranib BIW x4w
      - 0.3 mg/kg Beloranib BIW x4w
      - 1.0 mg/kg Beloranib BIW x4w
      - 0.1 mg/kg Beloranib QD x28d
 
B   Translational PK/E Model
    x: Beloranib Cavg (ng/mL)  (0 → 2)
    y: Total %BWL  (0 → 50)
    Series:
      - BID sim
      - QD sim
      - BIW sim
      - BIW in DIO
      - QD in DIO
      - BIW in human

A: [(MAD 임상자료있는) reference drug 의 mouse 에서의 dose-(Chronic) Efficacy], cf] BID 없고 BIW 임 수의.
B; (MAD 임상자료있는) reference drug 의 human 에서의 PK-(Chronic) Efficacy

Beloranib PK and Receptor Occupancy

• how muchMetAP2 needs to be inhibitor-bound (ie occupied) to cause downstream effects?

[Method]
Occupancy assay: measures 'free' unbound target in blood from mice following drug treatment using ELISA

Figure labels (Beloranib PK and Receptor Occupancy plot, evidence-only):

A   Beloranib
    PK and Receptor Occupancy
    y (left):  MetAP2 Occupancy   (with `100% RO Control` and `Vehicle` reference lines)
    y (right): PK (ng/ml)  (0.1 → 100)
    x:         Time after dose (hours)  (0 2 4 6 8 10 20 30 40 50)
    Series:
      ⌬ 0.1 mg/kg Beloranib RO (study 1)
      ▲ 0.1 mg/kg Beloranib PK (study 1)
      ⌬ 0.1 mg/kg Beloranib RO (study 2)

해석:
- MetAP2 is maximally occupied with inhibitor (approx. 100%) from 2 to 8 hours post-dose, in blood from mice treated with 0.1 mg/kg beloranib
- Occupancy decreased to approx. 85% at 24 hours and approached vehicle levels at 48 hours postdose

[PK vs Occupancy]

• average weekly beloranib exposure and the average MetAP2 occupancy (for twice-weekly and daily dosing regimens over a range of doses in DIO mice)

occupancy saturated at submaximal levels for the less frequent schedule (ie QD 에서는 (Occupancy 가) saturation 되는구나 그래서 Efficacy 적...)

[Exposure vs Occupancy]

Figure labels (Panel B — Exposure vs Occupancy, evidence-only):

B
y: Avg %Occupancy  (0 → 100)
x: Beloranib Cavg (ng/mL)  (0 → 2)
Series:
  - BIW sim
  - QD sim
  - BIW in DIO
  - QD in DIO
  - Human equivalent

• more frequent dose schedule resulting in greater occupancy and efficacy

Repeated A/B Panels (Bottom Of Page)

Figure labels (DIO Efficacy A and Translational PK/E Model B, repeated; evidence-only):

A   DIO Efficacy on two dose schedules
    (same x/y/series as the top A panel: Vehicle, 0.1 BIW, 0.3 BIW, 1.0 BIW, 0.1 QD)
 
B   Translational PK/E Model
    (same x/y/series as the top B panel: BID sim, QD sim, BIW sim, BIW in DIO, QD in DIO, BIW in human)

• more frequent dose schedule resulting in greater occupancy and

Uncertain Spans

location	text/status	reason
Translational modeling heading	⊞ collapse marker	A small Word section-collapse glyph is visible to the left of the heading; rendered here as ⊞.
reference-drug annotation under panels	cf] BID 없고 BIW 임 수의.	Trailing 수의 reads ambiguously between 수의/수의/숫자 in the photo; preserved verbatim.
top scatter	first-author / context for the %BWL vs Peak NMet-14-3-3γ figure	Only the lower-right tail is on this page; full figure title and source appear on the preceding photo.
Korean Efficacy comment under [PK vs Occupancy]	trailing word after Efficacy 적	The right edge clips the rest of the sentence; preserved as Efficacy 적....