WGND Meeting The Hague Oct 24, 2018

Update on Delamanid and OPC-167832

Jeffrey Hafkin M.D.

TB innovation for tomorrow. Access to Delamanid is Continuously Increasing

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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2 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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3 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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4 Collaborative Studies

Sponsor Study title Started () Seoul National MDR-END: Treatment Shortening of MDR-TB Using Existing and New Drugs  University Hospital 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/ endTB: OBR vs. 5 different 6-month treatment shortening, injectable-free  PIH 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

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5 Introduction to OPC-167832

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

O l C O N O HN H Cl Cl CO H O 2 N N N O • Otsuka has H L - ABI IFY 2006 N O anti TB drug c zo eren a H ( S hi ph i )

ucos a experience and M t 1990 ( Stomach ulcer ) N O H S O success with N O N N H

Carbostyril structure REXULTI 2015 carbostyril ( Schizopherenia )

N N HO N O N N . O compounds H . H N OH HCl HCl

O N O N H N O H OH H

e an e a Mik l 1980 Meptin 1980 Pl t l 1 988 - - n a e e Proprietarya en s and Confidential ( β Blocker ) ( β Stimulant ) ( A ti pl t l t g t )

6 New Anti-TB Compound: OPC-167832

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

OPC-167832

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

7 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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8 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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9 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 efficacy of multiple oral doses of OPC-167832 tablets in subjects with uncomplicated, smear-positive, drug-susceptible pulmonary tuberculosis

ClinicalTrials.gov Identifier: NCT03678688

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11 Trial 323-201-00003: Study Design

STAGE 1 STAGE 2 − 72 subjects randomized to 4 − 53 subjects randomized to 1 sequential cohorts (14 OPC- of 4 treatments groups 167832 + 4 RHEZ): (15:15:15:8 ratio): 1. 10 mg OPC-167832 or RHEZ • Low dose OPC-167832 & 200 2. 30 mg OPC-167832 or RHEZ mg delamanid 3. 90 mg OPC-167832 or RHEZ • High dose OPC-167832 & 200 4. 270 mg OPC-167832 or mg delamanid RHEZ • 200 mg delamanid • RHEZ

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12 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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