Post on 05-Jun-2020
Defeating Malaria Together
Partnering to develop new products Siem Reap, Cambodia – 24-26 February 2015 Timothy Wells, PhD ScD Chief Scientific Officer
Defeating Malaria Together
PRODUCTS WITH IMPACT
INVESTING IN OPENNESS
NEW PRODUCTS ON THE HORIZON
WORKING TOGETHER TO INCREASE IMPACT
Resistance against both artemisinin and the partner drug is a concern
Pyramax recrudescence in Pailin (2007-2008) 3.3% day 28; 10.2% day 42 NB: Pursat (2013) piperaquine IC50 increasing, but mefloquine IC50 and PfMDR1 copy numbers decreasing. 3
Day 3: ‘artesunate’
Day 28: ‘partner’
ACT efficacy Pailin,
Cambodia
Approved ACTs: fighting back against resistance
Eurartesim (Sigma-Tau) DHA-piperaquine
EMA approved 2011 Cambodia 2013
NCl
HNN
N O
N
OH
Pyramax (Shin Poong) Pyronaridine-artesunate
EMA article 58 2012 Cambodia 2014
NCl
N
N
NN
N
Cl
Collaborations giving high impact affordable products
25 million vials distributed
Affordable chemoprevention now
Start with the end in mind: Target Product Profiles for the medicine
Long-acting post treatment prophylaxis
Radical cure
Transmission blocking
Long acting Causal liver or slow onset asexual
Different MOA to SERCaP
SERCaP single exposure
radical cure and prophylaxis
SEC single exposure
chemoprotection
Alonso P et al., A research agenda for malaria eradication: drugs PLoS Med 8(1): e1000402 Target Candidate Profiles: Burrows JN et al., Malaria J. 12:187 (2013)
Fast clearance of parasitaemia
Start with the end in mind Target Candidate Profiles for the molecules
Long-acting post treatment prophylaxis
Radical cure
Transmission blocking
Long acting Causal liver or slow onset asexual
Different MOA to SERCaP
SERCaP single exposure
radical cure and prophylaxis
SEC single exposure
chemoprotection
Alonso P et al., A research agenda for malaria eradication: drugs PLoS Med 8(1): e1000402 Target Candidate Profiles: Burrows JN et al., Malaria J. 12:187 (2013)
TCP1
TCP3b
TCP2
TCP3a
TCP4 Fast clearance
of parasitaemia
Target Product Profiles Medicines for malaria eradication
Long-acting post treatment prophylaxis
Radical cure
Transmission blocking
Long acting Causal liver or slow onset asexual
Different MOA to SERCaP
SERCaP single exposure
radical cure and prophylaxis
Alonso P et al., A research agenda for malaria eradication: drugs PLoS Med 8(1): e1000402 Target Candidate Profiles: Burrows JN et al., Malaria J. 12:187 (2013)
TCP1
TCP3b
TCP2
TCP3a
Fast clearance of parasitaemia
Many of the new compounds have both:
they kill fast, with plasma concentrations above
MIC for >7 days
New medicines: building on an existing template
O
OO
OZ03 OZ277/ RBx11160
reduce logP improve solubility
O
OO
NHO
NH2
OZ439
Decrease interaction with ferrous iron (single electron)
O
O OO
OH H
H
O
OO O
N
O
Nature, 2004, 430, 900 PNAS, 2011, 108(11), 4400
Better embryo safety Better granulocyte safety Active vs artesunate resistance
New medicines: building on new templates
KAE609
NH
NH
NH
Br
O
Singleton “Hit” EC50 NF54 90nM
EC50 NF54 9.2nM Clint (hu, m) unstable
NH
NH
NHO
Cl
7- to 6- ring Enantiomer Bromo- to chloro- EC50 NF54 0.7nM
Clint (hu, m) stable ED90 Pb 2.7mg/kg
NH
NH
NHO
Cl
F
ClFix metabolic Instability with halo-substitution
Science, 2010, 1175; J Med Chem 2010, 53, 5155
Data can predict whether compounds kill resistant strains in humans
12
Time after administration (h) 0 24 48 72 96 120 144 168
1
10
100
1000
10000
Dru
g c
once
ntra
tion
(ng/
mL)
800 mg OZ439
OZ439 threshold
DHA threshold
100 mg DHA
NH
NH
NHO
Cl
F
Cl
N
N
N
N
HN
SF5
FF
KAE609 Novartis, Swiss Tropical, Wellcome Trust Development with Novartis
DSM265 Dallas, Swiss Tropical Monash
Development with Takeda, GHIT
Many options for new combinations in phase II studies now
KAF156 Novartis, Swiss Tropical, Wellcome
Development with Novartis
OZ439 Nebraska, Swiss Tropical, Monash
Development with Sanofi
Single Dose 300 mg Tafenoquine Relapse-free Efficacy at 6 months
37.5%
57.7% 54.1% (p=0.16)
89.2% (p<0.0001
)
91.9% (p<0.0001)
77.3% (p=0.0004)
Phase III study currently ongoing including Anlong Veng Referral Hospital, Oddar Meancheay Province. Regulatory Submission planned for 2016
Malaria Box 400 compounds 200 research groups worldwide Sharing our resources with the world
MMV048 University of Cape Town Republic of South Africa
P218 Biotec
Kingdom of Thailand
Partnering with countries to develop medicines
SO2Me
N
NH2NF3C
New mechanism of action: PI-4kinase
Human Volunteer studies Cape Town, May 2014
First time for a new molecule to be tested first in Africa
Next generation DHFR inhibitor: replaces pyrimethamine
Currently in preclinical safety testing
Study in human volunteers in Thailand 2016
The pipeline has moved a long way from 2008
In registration Preclinical
Research Translational Development Patient
exploratory Human
volunteers Lead optimisation Approved* Patient confirmatory
KAE609 NGBS consortium
Falcipains GSK/UCSF
Artimisone UHKST
Artesunate Injection WRAIR
MK 4815 (Merck)
GSK 932121 GSK
Tafenoquine GSK
OZ 439 Monash/UNMC/STI
Pyronaridine AS Shin Poong
DHA-PQP Sigma-Tau
Macrolides GSK
(+) Mefloquine Treague
Artemether Lumefantrine
Novartis
4-pyridone GSK
DHODH UTSW/UW/Monash
DHFR BIOTEC/Monash/
LSHTM
1
APM
20% 68% 10% Submission Probability
2015+ 2013 2017+ >90% 2011
Isoquine LSTH/GSK
to 2015 Research
Miniportfolio Novartis
1 Project Novartis
Miniportfolio GSK
Miniportfolio Sanofi
Aminopyridines UCT
Heterocycles Campinas
Heterocycles St
Jude/Rutgers/USF
Heterocycles Celgene
3 Projects GSK
Oxaboroles Anacor
Tetraoxanes LSTM/Liverpool
DHODH UTSW/UW/Monash
Orthologue Leads Sanofi
Open Source Drug Discovery
Sydney
Amino-alcohols Merck Serono
Screening Daiichi-Sankyo
Other Projects 15 Projects
Screening Takeda
Screening Eisai
Pathogen Box MMV
Research Lead optimisation Registration Phase IIa Phase IIb/III
OZ439/PQP Sanofi
Tafenoquine GSK
Pyronaridine-
Artesunate Paediatric
Shin Poong/Iowa
DHA-
Piperaquine Paediatric Sigma-Tau
KAE609 Novartis
KAF156 Novartis
In registration Development
Patient exploratory Patient confirmatory Phase IV Post Approval
Preclinical Phase I
MMV253 (Astrazeneca)
MMV048 UCT/TIA
P218 DHFR BIOTEC
SJ733 St Jude/Eisai (Rutgers/NIH)
MMV121 (Dundee)
Translational Pr eclinical Human volunteers
OZ439/FQ Sanofi
Rectal Artesunate CIPLA/Strides Acrolab/TDR
Artesunate for injection
Guilin
Artemether- Lumefantrine Dispersible
Novartis
Pyronaridine-Artesunate Shin Poong
DHA- Piperaquine
Sigma-Tau
1
2
3
Research Lead
optimisation
Under review *
Development Patient
exploratory Patient
confirmatory
Translational
Preclinical Human
volunteers
5
4
Access
Artesunate Amodiaquine
Sanofi/DNDi
Artesunate- Mefloquine CIPLA/DNDi
Sulfadoxine Pyrimethamine+
Amodiaquine Guilin
PA92 (Drexel/UW/GNF)
GSK030 GSK
DSM265 Takeda/GHIT
20% 68% 10% Submission Probability
2020+ 2018+ 2022+ >90% 2016
and there are major challenges ahead
SINGLE DOSE CURE TO AUGMENT OR REPLACE ACTS
SAFETY IN EXPECTANT
MOTHERS AND NEW BORN
BABIES
MEDICINES TO PROTECT FOR
EVERYONE
SAFELY PREVENTING THE
RELAPSE OF VIVAX MALARIA
For MMV our network is our intangible asset
Our partnerships are our greatest strength
Defeating Malaria Together
PRODUCTS WITH IMPACT
INVESTING IN OPENNESS
NEW PRODUCTS ON THE HORIZON
WORKING TOGETHER TO INCREASE IMPACT