Post on 12-Mar-2020
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Drug discovery
Role and significance of academia
Toshio MIYATA
Tohoku University Graduate School of Medicine
United Centers for Advanced Research
and Translational Medicine (ART)
The 13th Kitasato University - Harvard School of Public Health Symposium
Inhibitors to plasminogen activator inhibitor (PAI)-1
Example
What can academia contribute ?
Our strategy, goal, framework, status…
95 compounds
Hit compounds TM5007
3000 compounds
Docking simulation
28 compounds
Biological screening
Filter selection (size/charge)
Lead compound TM5275
75 compoundsHit-to-lead synthesis
Virtual screening
Chemical synthesis
In silico discovery of PAI-1 inhibitors2,240,000 compounds
0.3 mg/kgIn vivo efficacy
(anti-thrombosis)
Cmax:17.0 μM
Tmax:2 hr
T1/2:3.9 hr
PK (rat, 5mg/kg)
Tmax:4 hr
T1/2:8.2 hr
Cmax:106.5 μM
PK (monkey, 3mg/kg)
IC50
2.82 μM
0.3 mg/kg
Cmax:5.7 μM
Tmax:18 hrT1/2:>198 hr
PK (rat, 50mg/kg)
10 mg/kg
Cmax:34.2 μMTmax:2 hrT1/2:25 hr
PK (rat, 50mg/kg)
Cmax:17.9 μM
Tmax:1 hrT1/2:2.3 hr
PK (rat, 5mg/kg)
1 mg/kg
In vivo efficacy
(anti-thrombosis)
IC50 IC50 IC50
7.94 μM6.47 μM 3.58 μM
Hit TM5007 Lead TM5275 TM5441
In vivo efficacy
(anti-thrombosis)
In vivo efficacy
(anti-thrombosis)
TM5509
300 mg/kg
O
NH
O
NHSS
S S
OOH OH
O
NH
O O
O N
N
Cl
OH
O
75NCEs 166NCEs 207NCEs
Clinical candidate
Hit to lead, lead optimization to a clinical candidate
Newly synthesized over 500 compounds
A panel of GLP pre-clinical studies
A manufacture of the GMP-grade investigational drug (tablet)
Leaching test:Good dissolutionStability test:Unwrapped tablet was stable for 3 months in accelerating test of 40℃ and 75 % relative humidity.
Pathophysiologicalresearch
Target validation
Hit compound(HTS, in silico)
Academia can undertake up to Ph-IIa…
Lead optimization
GMP synthesisformulation
GLPPre-clinical
Phase I (PK, PD) and II (POC)
これまでの実績(個人シーズ)
PMDA戦略相談・事前面談 3件
PMDA戦略相談・対面助言 3件
医師主導治験(未承認薬)Ph-1,2a 3件
治験外臨床研究(未承認薬)Ph-2a 1件
オーファン申請(共同) 1件
企業導出 2件
厚生労働省 先駆けパッケージ戦略 2014 6月17日
What is the advantage and significance of drug discovery in
academia ?
Open innovation…
A PAI-1 inhibitor regenerates bone marrow and vascular endotheliumBlood 119, 2012
PAI-1 inhibitors improved the mortality and
promoted rapid hematopoietic recovery
C57BL6/J recipient mice, 9Gy TBI, WBM transplantation
0d 7d 21d 28d14d
Treatment Evaluation Evaluation
0
10
20
30
40
Cont 10 100 1 3 10
WBC count (x102/µl)
0
20
40
60
80
100
Cont 10 100 1 3 10
PLT count (x105/µl)
0
10
20
30
40
Cont 10 100 1 3 10
BM MNC (x106/µl)
0.0
0.3
0.6
0.9
1.2
Cont 10 100 1 3 10
plasma active tPA (ng/ml)
0
20
40
60
80
Cont 10 100 1 3 10
plasma total MMP9 (μg/ml)
0
100
200
300
400
Cont 10 100 1 3 10
plasma c-KitLigand (pg/ml)
tPA TM5275 TM5509 (mg/kg) tPA TM5275 TM5509 (mg/kg) tPA TM5275 TM5509 (mg/kg)
tPA TM5275 TM5509 (mg/kg) tPA TM5275 TM5509 (mg/kg) tPA TM5275 TM5509 (mg/kg)
Stem Cell, 2013PAI-1 inhibitor
Irradiation
Blood count Blood count
A PAI-1 inhibitor retards the development of senescence and protects organ
structure and function while prolonging the lifespan in the klotho mouse.
Proc Natl Acad Sci USA, in press
PAI-1 is a critical up-stream factor of
senescence-messaging secretome
(SMS)
Proc Natl Acad Sci USA 2012
Nature Reviews Cancer 2009
Cell regeneration
PAI-1
inhibition
Fibrinolysis
Inhibition of plasminogen activator inhibitor 1 (PAI-1)
Anti-senescence
Anti-thrombosis
Anti-aging
Anti-fibrosis
Kidney disease
Cellregeneration
Anti-inflammation
PAI-1inhibitors
Nature Review Nephrology 2014
Potential applications of our PAI-1 inhibitors
ATVB 2007
ATVB 2007
JCBMF 2010
Circulation 2013
PNAS 2014Blood 2012
Stem Cell 2013
ARCMB 2012
ATVB 2013
ATVB 2013
Open resources
What can academia contributein the futute?
PK, Pharmacokinetics (what the body does to the drug)
Microdosing (phase 0)
Efficiently develop FIH-class drug with lower costs and greater probabilities…?
Significance of ‘exploratory early clinical studies’ in humans !
PD, Pharmacodynamics (what the drug does to the body)
Biomarkers, molecular imaging
Tox, Toxicity
Renal biomarkers for drug toxicities
POC, Proof of concept (efficacy in humans)
Pharmacogenomics (PGx), surrogate end points
Miyata et al. Nature Review Nephrology, 2014
Phase I
Phase 0
Phase I
Phase IIa
A total dose of 100μg as a single dose or divided doses in any subject including patients.
The requirements of pharmaco-toxicological studies are minimum, depending upon the amount or duration of exposure, e.g., a single-dose toxicity study in rodents.
For the conventional phase I, a full program of pharmaco-toxicological studies under the GLP regulation is required
Microdosing test
ICH Harmonized Tripartate Guideline M3(R2)
PK, Pharmacokinetics (what the body does to the drug)
Microdosing (phase 0)Phase 0
Phase I pharmacokinetics of a PAI-1 inhibitor TM5509M
icro
dosi
ng
Q
Is it possible to evaluate early a drug’s pharmacodynamics from analyses of blood or urine specimens? Often NO
Can we directly assess pathological events in situ in the tissue (e.g., inflammation, fibrosis, hypoxia, oxidative stress)? Potentially Yes
How can we evaluate a drug’s pharmacodynamics as early as possible?
Oxygen status is visible non-invasively in human kidney
by blood oxygen dependent level (BOLD)-MRI
Control Water load
Miyata et al, Nature Review Nephrology, 2011
PD, Pharmacodynamics (what the drug does to the body)
Biomarkers, molecular imagingPhase I
POC, Proof of concept (efficacy in humans)
Pharmacogenomics (PGx)Phase IIa
This is not the case with human studies: age, nationality, lifestyle, food …
Pharmacogenomics (PGx)
Normal responder
Weak responder
No responder
Potential side effect
Experimental mice are homogeneous:age, gender, genotype, food …
PAI-1 polymorphism
Does this genetic difference affect the efficacy, optimal
dose, and toxicity of a PAI-1 inhibitor?
PAI-1 GGGG
4G-type
Gene Higher PAI-1 Conc.
TM5509Partial Inhibition
PAI-1 GGGGG
5G-type
Gene Lower PAI-1 Conc.
TM5509Complete Inhibition
PGx-based dose adjustment
PAI-1 Genotypes Frequency in Japanese Plasma PAI-1 conc. Dose of TM5509
4G/4G 40 % 87 ng/mL 100 mg ?
4G/5G 50 % 62 ng/mL 75 mg ?
5G/5G 10 % 42 ng/mL 50 mg ?
Q
Does the genetic difference of metabolizing enzymes of a
PAI-1 inhibitor TM5509 affect the efficacy or side effect?Q
PAI-1 inhibitorTM5509
Patients withCYP2C9 3*/3*
Low activity mutant
・Normal metabolizer・Relatively low blood concentration?
・Poor metabolizer・Relatively high blood concentration?
Prediction of PK, tox, and efficacyGenetic analyses of target molecule
or metabolizing enzymes
Patients withCYP2C9 1*/1*
Wild Type
Efficient clinical trials for POC with pharmacogenomics (PGx)
PAI-1 inhibitorTM5509
(FIH class)
Metabolizing enzymeCYP2C9
Normal responder without side effect
No responder
Potential side effect
Pharmacogenomics (PGx)
Target protein
Phase 0 Phase I Phase IIa Phase IIb Phase III
Towards a more efficient strategy and framework
‘From Serendipity to Rationality’
Biomarker and molecular imaging (PD or
Tox)
Validated surrogate endpoints (Big data)
Pharmacogenomics (PGx)
Collaboration of regulatory authorities
Global networking of clinical trials
Microdosing test (PK)