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Kitasato Univ. Kanji Hosoda
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Microbialchem
Indications and Markets
NASH/NAFLD 16 million patients in USA No approved drug (Very High needs!)
$1.8B (2017)
$21.5B (2025)
CAGR 58.4%
LAL-D (Lysosomal Acid Lipase Deficiency )
19,000 patients worldwide (Rare disease) Only 1 approved drug (High needs!)
$380M (2017)
$954M (2025)
CAGR 10.8%
Hyperlipidemia 95 million patients in USA Various approved drug (Low needs)
$19.3B (2016)
CAGR 2.3%
$22.6B (2022)
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Grand View Research, Inc., Allied market research
Healthy Liver
https://cn-bio.com/disease-modelling/
Fatty Liver +Inflammation +Fibrosis
Cirrhosis Hepatocellular Carcinoma Liver failure (NAFLD) (NASH)
Deficiency of LAL enzyme (LAL enzyme degrade lipids)
Mechanism of NASH/NAFLD and LAL-D
Metabolic syndrome Diabetes mellitus etc..
NASH/NAFLD LAL-D
Accumulation of lipids (Cholesteryl ester, CE)
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Our Target: Novel target isozyme 2 (target 2)
Isozyme Target 1 Target 2
Distribution Various tissues and cells Small intestine and liver
KO mouse
Decrease of CE synthesis in the small
intestine and liver Massive xanthomatosis
(Toxicity) No Toxicity
It is important to selectively inhibit Target 2
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Our Technology: Novel target inhibitor (PRD)
IC50 for Target2 (μM)
(Lo
g IC
50 f
or
Ta
rget1
/ IC
50 f
or
Ta
rget2
) 1. Found natural product
2. Synthesis derivatives (>200)
3. Select lead compounds (PRD)
High activity High selectivity High metabolic stability
Natural product ■
PRD
PRD is the first and only target 2 selective inhibitor
*Target 1 inhibition leads to toxicity (diarrhea and adrenal grand)
IC50 (μM)
Target 1* Target 2 Selectivity (fold)
Natural product >80 0.0700 >1,000
PRD >72.8 0.0118 >6,000
Compound1 18.7 19.1 1
Compound2 8.3 5.9 1.4
Compound3 0.45 102 -200
P2 drop
P3 drop
P2 drop
Company 1
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Company 2
Company 3
PRD decreased lipid level in the animal model Animal: New Zealand White Rabbit (male, 8 weeks old, N = 5 ~ 8)
Diet: High cholesterol diet (0.5% Cholesterol)
Drug: PRD or Atorvastatin (Atorv.)
12 weeks
PRD
(orally administered every morning)
Collect blood every 2 weeks Dissect
(Liver and aortas)
0 -2
High cholesterol diet
(-2 to 12 weeks)
PRD completed in vivo study, mouse, rabbit and monkey. 7
Control (High cholesterol diet)
PRD-A (1 mg/kg/day)
PRD-A (10 mg/kg/day)
PRD-E (1 mg/kg/day)
PRD-E (10 mg/kg/day)
Atorvastatin (1 mg/kg/day)
*p <0.05, N = 5~8
vs Cont. (High cholesterol diet)
PRD decreased total plasma cholesterol
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PRD decreased CE and FC in the liver
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PRD-E PRD-A PRD-E PRD-A
PRDs decreased TG in the liver
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PRD-E PRD-A
Control
(High cholesterol diet)
Control
(regular diet)
High cholesterol diet
+PRD-A (10 mg/kg/day)
PRDs showed inhibition of fatty liver progression
Healthy Liver Fatty Liver
(NAFLD)
Healthy Liver
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In vivo study in LAL-D mouse models
Mouse: LAL knockout mouse (male, 21 days old, N = 5)
Diet: Low fat diet (0.02% cholesterol)
Drug: PRD-A (10 mg/kg/day in the diet)
32 days
Added PRD-A
(10 mg/kg/day in the diet)
Dissect
(Liver and small intestine)
0
Deficiency of LAL enzyme
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Effect of PRD-A on lipid levels in small intestine
CE FC
Deficiency of LAL enzyme
Obtained non-clinical POC 13
PRD-A
CE FC
TC TG TC: Total cholesterol
Effect of PRD-A on lipid levels in the liver
Deficiency of LAL enzyme
PRD-A markedly reduced hepatic CE accumulation in LAL-D mouse model
14 Obtained non-clinical POC PRD-A
Effect of PRD-A on hepatic toxicity
ALT
AST
Deficiency of LAL enzyme
Deficiency of LAL enzyme showed hepatic toxicity.
PRD-A improved hepatic toxicity to normal levels.
15 Obtained non-clinical POC
PRD-A
ALT, AST: hepatic toxicity biomarker
• Change from baseline (LDL, HDL, TG, AST, Liver fat content etc.)
PRD obtained non-clinical POC
• ALT Normalization
PRD confirmed (in LAL-D model mouse)
Competition and PRD advantages
Drugs Administration Frequency
PRD Oral Once daily
Intravenous infusion Once a week in hospital
Only 1 approved drug (KANUMA®) for LAL-D
KANUMA® sales: $65.6M (2017)
$92.0M (2018) 60% UP!!
Target Product Profile
Product Description • Small molecules
• Novel target selective inhibitor (The world’s FIRST and ONLY selective inhibitors)
• Decreased lipid level by a novel mechanism of action
Indications & Usage • LAL-D, NASH/NAFLD, Hyperlipidemia
• Just take medicine everyday at home
• Start from Nonclinical Safety Studies
Dosage & Administration • Orally administration (p.o)
Safety & Toxicity • Decreased lipid level without causing side effects in mouse, rabbit and monkey models
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Development Roadmap 2020-2022 2023-2026 2027-
Manufacture of PRD (GLP & Investigational Drug)
Preclinical study Phase I-II for LAL-D
Safety and POC in Human
Conditional Approval, Launch sales in Japan
Use LAL-D’s study data
First develop as an orphan drug for LAL-D Low cost (<100 participants) and High speed
Phase IIa for Hyperlipidemia
Phase IIa for NASH/NAFLD
Phase III
Development Roadmap 2020-2022 2023-2026 2027-
Manufacture of PRD (GLP & Investigational Drug)
Preclinical study
Safety and POC in Human
We are looking for financing to PRDs’ manufacturing and pre-clinical trials.
＄5M ＄20M
Phase I-II for LAL-D
Conditional Approval, Launch sales in Japan
Phase III
Prof. TOMODA Hiroshi HOSODA Kanji
Graduate School of Pharmaceutical Sciences, Kitasato Univ.
Team
For further information, please contact me! Contact: [email protected]
Microbial chemistry of lipid metabolism
Microbial chemistry
Support
Mentor
Toshio Nagae PeptiDream Inc.
Tomohisa Ninomiya Alchemedicine Inc.
Kyoji Ueda Celgene K.K.
Ken Hirose AJINOMOTO CO., INC.
Program
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