T B i n n o v a t i o n f o r t o m o r r o w .T B i n n o v a t i o n f o r t o m o r r o w .

Update on Delamanid and OPC-167832

WGND MeetingThe Hague

Oct 24, 2018

Jeffrey Hafkin M.D.

Proprietary and Confidential

Access to Delamanid is Continuously Increasing

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Nearly 10,000 patient courses of delamanid supplied for treatment in 80 countries for compassionate use, expanded access programs, or under normal programmatic conditions, including

28/30 WHO High MDR-TB burden countries

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Proprietary and Confidential

Access to Delamanid is Continuously Increasing

− Regulatory Status • Approvals: China, EU, Hong Kong, India, Indonesia, Japan, South Korea, Philippines,

Turkey, Turkmenistan• NDAs submitted: Peru, Russian Federation, South Africa, Ukraine, World Health

Organization – Prequalification (WHO-PQ)• NDA preparation: Brazil, Mongolia, Uzbekistan, Kazakhstan

− Data Sharing for WHO Guideline Development Review• Trials 232/233 & Trial 213

− Commercial Partnerships• Mylan (South Africa, India, other high-burden countries)

Technology transfer initiated• R-Pharm (Russian Federation and CIS)

Technology transfer option• Global Drug Facility (Global Fund to Fight AIDS, TB and Malaria eligible countries)

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Proprietary and Confidential

Delamanid Collaborative Studies: Key Themes

− Optimize use of delamanid as part of safer, shorter, broad-spectrum regimens• All oral (i.e. injectable free) regimens• Combining delamanid with bedaquiline• Empiric pan-TB regimen

− Pediatric MDR-TB

− Latent TB infection

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Proprietary and Confidential

Collaborative Studies

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Sponsor Study title Started ()

Seoul National University Hospital

MDR-END: Treatment Shortening of MDR-TB Using Existing and New Drugs

US NIH ACTG 5343: Evaluating the safety, tolerability, and pharmacokinetics of bedaquiline and delamanid, alone and in combination, for Drug-Resistant Pulmonary Tuberculosis

UNITAID/MSF/PIH

endTB: OBR vs. 5 different 6-month treatment shortening, injectable-free regimens

US NIH IMPAACT 2005: DLM for MDR/HIV paediatric patients w/o injectable

USAID Evaluate six-month regimen (DLM + BDQ + LZD) for patients with drug resistance to isoniazid, rifampicin and a quinolone.

US NIH A5300B/PHOENIx: Protecting households on exposure to newly diagnosed index Multidrug-Resistant Tuberculosis patients

Proprietary and Confidential

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• OPC-167832 is a 3,4-dihydrocarbostyril derivative

• Otsuka has experience andsuccess with carbostyril compounds

Introduction to OPC-167832

NH

O

Carbostyril structure

NH

O

O NN

NN

( Anti

platelet

agents )

Pletal 1988

NH

OOH

NH

HO.

HCl

Meptin 1980

( β

-Stimulant )

NH

O

O NHOH .

HCl

( β

-Blocker )Mikelan

1980

NH

O

O N N

Cl Cl

ABILIFY 2006

( Schizopherenia

)

NH

O

O N N

REXULTI 2015( Schizopherenia

)

S

NH

O

HN

CO2H

OCl

Mucosta 1990

( Stomach ulcer )

NH

O

O

anti -TB drug

Proprietary and Confidential

New Anti-TB Compound: OPC-167832

− Inhibition of decaprenylphosphoryl-β-D-ribose 2’-oxidase (DprE1), an enzyme involved in the cell wall biosynthesis

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OPC-167832

Modified from Crellin PK et al., PLoS One. 2011 Feb 8;6(2):e16869.

Proprietary and Confidential

In-vitro Pharmacology of OPC-167832

• MIC for Mycobacterium tuberculosis (MTB):0.00024 to 0.002 μg/mL

• Frequency of spontaneous resistance:2.60 × 10-9 to 1.52 × 10-7 for MTB H37Rv at 16 × MIC

• Bactericidal against growing and intracellular bacilli

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Proprietary and Confidential

In-vivo Efficacy Pharmacology

In mouse model of chronic TB:• OPC-167832 shows potent antimycobacterial activity

Effective dose 1.25 mg/kg

OPC-167832 plus delamanid, in combination with other anti-TB drugs, more effective than standard regimens for DS/MDR-TB

Results suggest OPC-167832/DLM regimens have potential to shorten treatment period and improve treatment outcomes

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Proprietary and Confidential

Trial 323-201-00001: “SAD” Study

− First in human, single ascending dose study of OPC-167832 completed

− 6 dose levels of OPC-167832 (from 30mg to 480mg), administered to cohorts of 8 subjects each for a total of 48 healthy subjects• Exposures dose proportional• No safety signals observed

Proprietary and Confidential

Trial 323-201-00003: “MAD/EBA Study”

Phase 1b/2a, active-controlled, randomized, open-label trial to evaluate the safety, tolerability, pharmacokinetics, and efficacyof multiple oral doses of OPC-167832 tablets in subjects with uncomplicated, smear-positive, drug-susceptible pulmonarytuberculosis

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ClinicalTrials.gov Identifier: NCT03678688

Proprietary and Confidential

Trial 323-201-00003: Study Design

STAGE 1

− 72 subjects randomized to 4sequential cohorts (14 OPC-167832 + 4 RHEZ):1. 10 mg OPC-167832 or RHEZ2. 30 mg OPC-167832 or RHEZ3. 90 mg OPC-167832 or RHEZ4. 270 mg OPC-167832 or

RHEZ

STAGE 2

− 53 subjects randomized to 1 of 4 treatments groups (15:15:15:8 ratio):• Low dose OPC-167832 & 200

mg delamanid• High dose OPC-167832 & 200

mg delamanid• 200 mg delamanid• RHEZ

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Proprietary and Confidential

Other Ongoing Steps in Development Process

• Regimen selection to be guided by: Mouse models in Otsuka labs Hollow fiber model studies in collaboration with CPTR Marmoset model studies in collaboration with NIH

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