Antimicrobial Drug Developmentin Japan
Keiji Hirai, Ph.D
Senior Advisor
Kyorin Pharmaceutical Co. Ltd.,
Asia Pacific Workshop on AMR in 2021Session III. Strategies for Improving Antimicrobial Drug Development
Discovery of Penicillin by Fleming (1928)
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Discovery of Sulfonamide by Domagk (1935)
Synthetic antibacterial agent
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Discovery of Streptomycin by Waksman(1943)
4Streptomycin was isolated from culture broth of soil-derived streptomyces
Antibiotic
Waksman's method, "screening for antimicrobial activity against test bacteriaby detecting zone of growth inhibition”, was widely adopted by pharmaceuticalindustries and produced the major classes of antibotics over next 20 years.
1930s 1940s 1950s 1960s 1970s 1980s 1990s 2000s 2010s
Sulfonamides
Penicillins
Aminoglycosides
Glycopeptides
Macrolides
Tetracyclines
Chloramphenicol
Lincosamides
Quinolones
Streptogramins
Trimethoprim
(1970s ~ 2000s)Modification of lead compounds (new class) using Medicinal Chemistryto improve their profiles
Target classes:-Beta-lactams
-Penicillins-Cephalosporins-Carbapenems
- Quinolones- Macrolides
Cephalosporins
Carbapenems
“Discovery of new classes era” “Chemical modification era”
:Antibiotic :Synthetic agent5
Colistin 1950
Kanamycin 1957
: Japanese origin
Golden era of antibacterial agents discovery
Chemical class Original lead compounds Japanese origin
[Natural product]
β-Lactams
・Penicillins Penicillin G Piperacillin (1976)
・Cephalosporins CephalosporinC Cefazolin (1969)
・Carbapenems Thienamycin Meropenem (1987)
・β-Lactamase inhibitor Clavulanic acid Tazobactam (1984)
Aminoglycosides Strepmycin Kanamycin (1957)
Amikacin (1972)
Tetracyclines Tetracycline
Chloramphenicols Chloramphenicol
Macrolides Erythromycin Clarithromycin (1984)
Glycopeptides Vancomycin, Teicoplanin
Polypeptides Polymixin B Colistin (1950)
Lipopeptides Daptomycin
[Synthetic chemical]
Sulfonamides Sulfanilamide Sulfamethoxazole(1959)
Quinolones Nalidixic acid Norfloxacin (1977)
Levofloxacin (1987)
Oxazolidinones Linezolid
Chemical classes of antibacterial agents and the agents of Japanese origin in the golden era
Hirai, K : Jap. J Chemotherapy. 2020 68:499-5096
Approved New Antibacterial Agents in Japan(1985 – 2016)
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Why the R&D pipeline is dry?
Three big challenges to development of new antibacterial agents
-Hard to discovery -Hard to development/Regulatory-Low return on investment
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Bottlenecks in the value chain of R&D of antibacterial agents.
Hit /Lead Identification
Regulatory To approval[Clinical trial : Guideline]
No. of patientsSafety, EfficacyEndpoint : Diagnosis
ReimbursementDrug pricing
Market exclusivityIP extension
Lead OptimizationTo PCC selection
[Medicinal Chemistry]Efficacy, Safety, ADME
Discovery Pre-ClinicalClinical(Ph1/2)
Post-marketing
NDAClinical
(Ph2/3)
[POC]
Proof of concept
Lack of New targets
and New lead compounds
Low return of investment
High cost
Hard to patients
recruitment
Low NPV・High R&D cost・Low Marketability・High Manufacturing cost
Crossing the ValleyOf Death
Pre-clinical to clinical(Safety, Formulation, CMC)
Low hanging fruit plucked
Lack of interest and
funding, a brain drain
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Revenue
R&D InvestmentTime
“Push” and “Pull” Incentive for R&D
[Push incentive]for drug discovery stage-Public-private partnership-Public funding ,-Grant-Tax incentive
Product
launch
GenericEntry
[Pull incentive] -Pricing, Reimbursement-IP extension, Market exclusivity-Advance purchase-Prizes, -Patent Buyout-Market entry rewards
Projectlaunch
[Push incentive]for clinical development stage- Funding and supporting - New pathways to facilitate approval
ND4BB (IMI)
GAINAct
BARDA
CARB-X
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Current situation to promoteantimicrobials R&D against AMR in Japan
• Establish new “Public- private partnership (PPP)” for discovery research and development for novel antimicrobials against AMR
- Collaborations of AMED, Industry (JPMA), and academia were started and AMED PPP for Infectious Diseases R&D wasestablished in Sep. 2018.
- AMED supports and promotes R&D activities, such as drugdiscovery researches for AMR.
• Develop incentives for new antimicrobials against AMR - “Pull-incentives” : JPMA submitted to MHLW “Suggestion
from the JPMA on the introduction of Pull incentive* to facilitate of R&D for AMR” in 2019.*model delinked from sales : -Market entry rewards -Transferable Exclusivity Extensions
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Well balanced push and pull incentives
are necessary to promote antimicrobials
R&D against AMR
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