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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