Confidential – For Celgene Internal Use Only

Tim Wells, CSO, MMV

Defeating Malaria Together

Artefenomel/ferroquine Phase 2 Development Program Bali | 11 – 12 October 2017

Confidential – For Celgene Internal Use Only

New Combinations for Case Management

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Translational Product development Access Preclinical Patient

confirmatory Post approval Human volunteers

Patient exploratory

Regulatory review

Research Candidate Profiling

Lead optimisation

OZ609 Nebraska, Monash, STPHI

P218 Janssen, (Biotec Thailand)

MMV253 Zydus Cadila

M5717 Merck KGaA

AN13762 (Anacor)

UCT943 H3D Cape Town

SJ733 Kentucky/Eisai

MMV048 (UCT)

Artefenomel/ Ferroquine Sanofi

Cipargamin Novartis

KAF156/ Lumefantrine Novartis

Tafenoquine GlaxoSmithKline

Dihydroartemisinin piperaquine Paediatric Sigma-Tau/Pierre Fabre

Rectal artesunate Cipla/Strides/WHO-TDR

Dihydroartemisinin- piperaquine Sigma-Tau /Pierre Fabre

Artesunate for Injection Guilin

Pyronaridine- artesunate Shin Poong

Artesunate- amodiaquine Sanofi/DNDi

Pyronaridine- artesunate granules Shin Poong

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2

4

Artemether- lumefantrine Dispersible Novartis

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Sulfadoxine pyrimethamine+ amodiaquine Guilin

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1

3

Artesunate- mefloquine Cipla/DNDi/ Farmanguinhos

SAR121 Sanofi

DSM265 Takeda (UTSW/UW/ Monash)

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Footnotes: Included in MMV portfolio after product approval; Global Fund Expert Review Panel (ERP) reviewed product – permitted for time-limited procurement, while regulatory/WHO prequalification review is ongoing. WHO Prequalified OR approved/positive opinion by regulatory bodies who are ICH members/observers. MMV support to projects may include financial, in-kind, and advisory activities Brand names 1: Coartem® Dispersible; 2: Artesun®; 3: Eurartesim®; 4: Pyramax® tablets or granules; 5: ASAQ/Winthrop®; 6: SPAQ-COTM; * For infants 3 – 12 months, ** for children 13-60 months

Rectal artesunate Cipla/Strides/WHO-TDR

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Sulfadoxine pyrimethamine+ amodiaquine ** Guilin

Injectable Prodrug Calibr

Miniportfolio 3 series GSK

SFK59 series H3D Cape Town

DHODH backups UTSW/UW/Monash

Open Source Series University of Sydney

Purines Celgene

DHODH Broad/Eisai

Phenotypic Lead Eisai

Phe tRNA lygase Broad Institute/Eisai

Pantothenates TropIQ/RUMC

Phenotypic Lead Daiichi-Sankyo

Molecular Target DDU Dundee

Confidential – For Celgene Internal Use Only

Artefenomel-Ferroquine

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ferroquine (FQ; SSR97193)

+ artefenomel (OZ439)

Two independent mechanisms of action, active against resistance

O

OO O

N

O

NCl

HN N

Fe

Artefenomel: Charman S.A. et al, (2011) Proc Natl Acad Sci U S A. 108(11):4400–5 Ferroquine: Delhaes L, Biot C, et al., (2002) Chembiochem. 3(5):418–23

Ferroquine + artefenomel: potential to shorten therapy and overcome resistance

Confidential – For Celgene Internal Use Only

Artefenomel Kills Artemisinin Resistant Strains

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DHA

OZ277

OZ439 OZ609

Baumgärtner F., et al., Malaria Journal (2017) 16, 45 Also Straimer J, et al., MBio. (2017) 8(2) be00172–17.

Confidential – For Celgene Internal Use Only

Artefenomel in Controlled Human Malaria Infection (HCMI) Model

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McCarthy JS, et al., (2016) J Antimicrob Chemother. 71(9):2620–7

500 mg dose causes 10,000-fold drop in parasites over 48 h, a parasite half-life of 3.6 h

Confidential – For Celgene Internal Use Only

Artefenomel in Patients

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Parasite clearance half lives were 4.1–5.3 h for P. falciparum and 2.3–3.2h for P. vivax

0

2,000

4,000

6,000

8,000

10,000

12,000

14,000

16,000

18,000

20,000

-1 4 9 14 19 24 29

200 mg

400 mg

800 mg

1,200 mg

Time /h

para

site

s /m

l

0

2,000

4,000

6,000

8,000

10,000

12,000

14,000

16,000

18,000

-1 4 9 14 19 24 29

200 mg

400 mg

800 mg

1,200 mg

P. falciparum P. vivax

para

site

s /m

l Time /h

Phyo AP, et al., (2016) Lancet Infect Dis. 16(1):61–69.

Confidential – For Celgene Internal Use Only

Activity in Patients with Artesunate Resistance

Phyo AP, et al., (2016) Lancet Infect Dis. 16(1):61–69.

Confidential – For Celgene Internal Use Only

Ferroquine in CHMI Model

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McCarthy J. et al., (2016) Malaria Journal 15:469.

800 mg FQ: 162-fold reduction in 48 h; half life = 6.5 h Time above Minimal Parasiticidal Concentration = 454 h

Confidential – For Celgene Internal Use Only

Ferroquine in Patients

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Supan C, Mombo-Ngoma G, et al., (2017) Am J Trop Med Hyg. 97(2):514–525.

PP population FQ/AS (daily dose) FQ alone

n total = 325 patients 2 mg/kg (100mg) (n=70)

4 mg/kg (200mg) (n=74)

6 mg/kg (300mg) (n=72)

4 mg/kg (200mg) (n=68)

PCR corrected ACPR at Day 28* 68/70 91.7% 74/74 100.0% 70/72 97,2% 48/68 70,6%

95% Clopper-Pearson CI 90.0.–99.7 95.1–100.0 90.3–99.7 47.9–75.2

Parasite clearance times only reported for FQ/AS groups

Confidential – For Celgene Internal Use Only

Artefenomel-Ferroquine

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Artefenomel: Charman S.A. et al, (2011) Proc Natl Acad Sci U S A. 108(11):4400–5 Ferroquine: Delhaes L, Biot C, et al., (2002) Chembiochem. 3(5):418–23

Artefenomel (OZ439) – Novel aromatic trioxolane – “Fast” killer & high efficacy on

parasite clearance – No cross resistance – Intermediate half life (4–5

days)

+

O

OO O

N

O

NCl

HN N

Fe

Ferroquine + artefenomel: potential to shorten therapy and overcome resistance

Ferroquine (SSR97193) – 4 aminoquinoline – “Slow” Killer with sustained

sterilization – No cross resistance – Long half life (>30 days; >40

days for active metabolite

Confidential – For Celgene Internal Use Only

Artefenomel-ferroquine: Phase 2b ‘FALCI’ Trial

«A randomized, double blind, study to investigate the efficacy, safety, tolerability and pharmacokinetics of a single dose regimen of ferroquine (FQ) with Artefenomel (OZ439) in adults and children with uncomplicated Plasmodium falciparum malaria» • Locations: 17 sites in 7 countries (6 in Africa, 1 in Asia) • Sample Size: up to 662 (4 treatment arms) • IMP formulations (oral): FQ capsules, artefenomel+TPGS in sachets • Completion in early 2019: Dosing 5–14 yo’s completed; next step 2–5

yo’s

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For patients ≥35 kg, 4 doses of FQ will be assessed along with a fixed dose of OZ439; Weight-adjusted doses for OZ439 & FQ for patients < 35 kg

• FQ at 400 mg and OZ439 800 mg OD in single dose

• FQ at 600 mg and OZ439 800 mg OD in single dose

• FQ at 900 mg and OZ439 800 mg OD in single dose

• FQ at 1200 mg and OZ439 800 mg OD in single dose

Confidential – For Celgene Internal Use Only

Artefenomel-ferroquine: Remaining Phase 2 Program

• Additional Phase 2 trial to fulfill ‘combination rule’ requirement • FQ dose held constant and OZ439 dose varied

• Design based on measuring exposure response

• Sites overlapping with FALCI sites

• Launch in Q1 2018; completion in 2019

• Additional optimization work to hone in on best formulation for Phase 3

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Confidential – For Celgene Internal Use Only

Conclusions

• OZ439 & FQ – two novel agents with different MoA’s deep in Phase 2 development

• Encouraging clinical data generated on both molecules as mono-therapies (CHMI model & clinical trials) and in combination trials

• Modelling/simulation of doses required to cure non-immune patients suggests single dose cure may be achievable

• Randomized, double-blind, Phase 2b ‘FALCI’ trial to test combination in patients as young as 6 mos. underway in 17 sites

• Additional randomized trial to fulfill requirement for combination rule (FQ set dose; OZ439 varied dosing) to launch in Q1 2019

• Formulation work to optimise exposure of artefenomel as pathway to formulation selection for Phase 3 is ongoing in parallel

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