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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
3
2
4
Artemether- lumefantrine Dispersible Novartis
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Sulfadoxine pyrimethamine+ amodiaquine Guilin
4
1
3
Artesunate- mefloquine Cipla/DNDi/ Farmanguinhos
SAR121 Sanofi
DSM265 Takeda (UTSW/UW/ Monash)
5
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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