New medicines to drive the
control and eradication of
malaria
Timothy Wells CSO Medicines for Malaria Venture
APPMG December 11th 2013
Defeating Malaria Together
MMV Portfolio: October 2013
Research
Translational
Lead optimisation
Oxaboroles
Anacor
1 Project
Novartis
Preclinical
P218 DHFR
(Biotec/Monash/
LSHTM)
Development
Human
volunteers
Patient
exploratory
DSM265
(UTSW/UW/
Monash)
OZ439
(Monash/UNMC/
STI)
ELQ-300
DHODH
4 Projects
UTSW/UW/Monash
GSK
(USF/
OHSU-VAMC)
Pyrazoles
Orthologue Leads
21A092
DrexelMed/UW
Sanofi
(DrexelMed/UW)
Heterocycles
Whole cell leads
MMV390048
Dundee
AstraZeneca
(UCT)
KAE609
Novartis
KAF156
Novartis
Patient
confirmatory
APM
In
registration
Tafenoquine
Rectal Artesunate
GSK
MMV / WHO-TDR
DHA-PQP
Pediatric
Sulfadoxine
Pyrimethamine +
Amodiaquine
Guilin
4
Sigma-Tau
Approved*
Artemether
Lumefantrine
Novartis
A-L Dispersible
Shin Poong
2
Novartis
Artesunate for
injection
Pyronaridine AS 5
Pediatric
1
3
Guilin
1
Dihydroartemisinin
Piperaquine (DHAPQP)
4
Sigma-Tau
2 Projects
Liverpool
STM/Liverpool Uni
PyronaridineArtesunate
SJ557733
St Jude/Rutgers
Shin Poong
Artesunate
Amodiaquine
Aminopyridines
UCT
6
Sanofi /DNDi
Artesunate
Mefloquine
Cipla/DNDi
1 Brand Coartem®, Generics Ajanta, Cipla, Ipca, Strides
2 Brand Coartem® Dispersible. Generic by Ajanta
3 Brand Artesun®
4 Brand Eurartesim®
5 Brand Pyramax®
6 Brand CoarsucamTM, ASAQ/Winthrop®
7 Also, Acino/Mepha product (co-blistered).
5
Included in MMV portfolio
post registration
*
First approval by regulatory bodies
who are ICH members or observers
or WHO Prequalification
7
MMV Portfolio: October 2013
Research
Translational
Lead optimisation
Oxaboroles
1 Project
Anacor
Novartis
Preclinical
P218 DHFR
(Biotec/Monash/
LSHTM)
ELQ-300
DHODH
4 Projects
UTSW/UW/Monash
GSK
(USF/
OHSU-VAMC)
Pyrazoles
Orthologue Leads
21A092
DrexelMed/UW
Sanofi
(DrexelMed/UW)
Heterocycles
Whole cell leads
MMV390048
Dundee
AstraZeneca
(UCT)
Human
volunteers
DSM265
(UTSW/UW/
Monash)
Development
Patient
exploratory
OZ439
(Monash/UNMC/
STI)
KAE609
Novartis
KAF156
Novartis
Patient
confirmatory
APM
In
registration
Tafenoquine
Rectal Artesunate
GSK
MMV / WHO-TDR
DHA-PQP
Pediatric
Sulfadoxine
Pyrimethamine +
Amodiaquine
Guilin
4
Sigma-Tau
Approved*
Artemether
Lumefantrine
Novartis
A-L Dispersible
Shin Poong
2
Novartis
Artesunate for
injection
Pyronaridine AS 5
Pediatric
1
3
Guilin
1
Dihydroartemisinin
Piperaquine (DHAPQP)
4
Sigma-Tau
2 Projects
Liverpool
STM/Liverpool Uni
SJ557733
St Jude/Rutgers
Aminopyridines
UCT
PyronaridineArtesunate
Shin Poong
Artesunate
Amodiaquine
6
Sanofi /DNDi
Artesunate
Mefloquine
Cipla/DNDi
New chemical entities since 2007
5
New presentations
of existing
molecules
7
MMV Portfolio: October 2013
Research
Translational
Lead optimisation
Oxaboroles
Anacor
1 Project
Novartis
Preclinical
P218 DHFR
(Biotec/Monash/
LSHTM)
Human
volunteers
DSM265
(UTSW/UW/
Monash)
ELQ-300
DHODH
4 Projects
UTSW/UW/Monash
GSK
(USF/
OHSU-VAMC)
Pyrazoles
Orthologue Leads
21A092
DrexelMed/UW
Sanofi
(DrexelMed/UW)
Heterocycles
Whole cell leads
MMV390048
Dundee
AstraZeneca
(UCT)
Development
Patient
exploratory
OZ439
(Monash/UNMC/
STI)
KAE609
Novartis
KAF156
Novartis
Patient
confirmatory
APM
In
registration
Tafenoquine
Rectal Artesunate
GSK
MMV / WHO-TDR
DHA-PQP
Pediatric
Sulfadoxine
Pyrimethamine +
Amodiaquine
Guilin
4
Sigma-Tau
Approved*
Artemether
Lumefantrine
Novartis
A-L Dispersible
Shin Poong
2
Novartis
Artesunate for
injection
Pyronaridine AS 5
Pediatric
1
3
Guilin
1
Dihydroartemisinin
Piperaquine (DHAPQP)
4
Sigma-Tau
2 Projects
Liverpool
STM/Liverpool Uni
PyronaridineArtesunate
SJ557733
St Jude/Rutgers
5
Shin Poong
Artesunate
Amodiaquine
Aminopyridines
UCT
6
Sanofi /DNDi
Artesunate
Mefloquine
Cipla/DNDi
2022+
2020+
2018
2016
10%
20%
68%
>90%
Launch
Probability
7
MMV Portfolio: October 2008
Research
Translational
Lead optimisation
DHFR
BIOTEC/Monash/
LSHTM
Preclinical
OZ 439
Monash/UNMC/STI
DHODH
MK 4815
UTSW/UW/Monash
(Merck)
Human
volunteers
Development
Patient
exploratory
Tafenoquine
GSK
Artesunate
Injection
WRAIR
Isoquine
LSTH/GSK
Artimisone
UHKST
Patient
confirmatory
DHA-PQP
Sigma-Tau
APM
In
registration
Approved*
Artemether
Lumefantrine
Novartis
Pyronaridine AS
Shin Poong
GSK Pyridones
2 compounds
1
(+) Mefloquine
Treague
Novartis
2 compounds
2017+
2015+
2013
2011
10%
20%
68%
>90%
Launch
Probability
Every second a child’s life is transformed
•
•
•
•
•
Coartem-D: Collaboration with Novartis
Taste masked, sweet cherry flavour, dispersible
Twice a day for three days
Approved in 2009; 200 000 000 treatments delivered
Ongoing study of activity in under 5kg patients
Critical Success Factor
Multiple child-friendly treatment options
ftreatment is critical
• DHA-piperaquine
• Collaboration with Sigma•
•
•
9
Tau (Italy)
Approved EMA (2011)
Approved in Cambodia,
Ghana, Burkina Faso,
Tanzania, Mozambique
Superior post-treatment
prophylaxis
• Pyronaridine-artesunate
• Collaboration with Shin•
•
•
Poong (Korea)
Approved EMA article 58
(2012), and Korea
WHO prequalified:
targeting the Mekong
Repeat use study for
submission 2014
Multiple ACTs: providing options
Compound
Artemether
Lumefantrine
Artesunate
Amodiaquine
DHA
Piperaquine
Artesunate
Pyronaridine
Artesunate
Mefloquine
Artemisinin
Naphthoquine
sanofi
aventis/DNDi
(MMV)
sigma-tau/MMV
Shin
Poong/MMV
Farmanguinhos
/DNDi/CIPLA
Mepha
(MMV)
Kunming
65% 35%
Partner
Novartis/MMV
(Generics)
Holley-cotec
First
Approval
1Q’09
4Q’08
4Q’11
1Q’12
2Q’08
’08
Key
Strengths
Experience
>200 million
children
treated
Once per day:
First line
therapy in West
Africa
Long half life
Once per day;
post treatment
prophylaxis
Once per day:
Long half life:
No resistance
in SE Asia
Once per day
Single day
treatment
Paediatric
Dispersible
tablet
Dissolves
Dispersible
tablet for 2014
Granules:
submission
2014
Crushed tablet
Crushed
tablet
Emerging multidrug resistant malaria strains in
Western Cambodia
Development
MMV Response
Parasites showing decreased
response to artesunate
Increased pressure on the
combination partners
Decreasing sensitivity to partner Rapidly deploy new
drugs mefloquine and
combinations: Pyroanaridine in
piperaquine
Cambodia
Accelerate testing of new
classes of molecules in patients
Biological and genetic markers
of parasite resistance are
emerging
Verify that current pipeline is
active against resistant strains.
Develop new models to test
pharmacological activity
11
Medicines can be used against malaria
to treat …
12
and to protect
Protecting small children:
Seasonal Malarial Chemoprotection
Cost-effective protection of children
Draft
•
•
•
•
Sulfadoxine-pyramethamine plus amodiaquine
Once per month; cost <50¢ per year
82% reduction of infection; 57% less all-cause mortality
Manufacturing and Product Access collaboration with
Guilin (China) to support prequalification
• One million treatments in first year (2013)
Wilson AL. A Systematic Review and Meta-analysis of the Efficacy and Safety of Intermittent Preventive Treatment of
Malaria in Children (IPTc). PLoS ONE. 2011;6:e16976.
Cairns M. et al SMC symposium ASTMH (2011)
13
Artesunate: Providing options in severe
malaria
•
•
•
•
•
Artesunate for injection: WHO prequalified 2010
Mortality reduction: 10.9% to 8.5%
Approximately $1 per vial; 12 million vials 2012-3
Managing pharmacovigilance of late onset hemolysis
Next step: artesunate suppositories for pre-referral
treatment (UNITAID, WHO-TDR, WHO-prequalification)
Dondorp AM et al., Artesunate versus quinine in the treatment of severe falciparum malaria in African children
(AQUAMAT); an open label, randomised trial Lancet (2010) 376 1647-57
New medicines for Malaria Eradication
Fast killing
Post treatment
Protection
Radical
cure
Transmission
blocking
SERCaP
single exposure
radical cure and prophylaxis
15
Replacing three
days ACT and 14
days primaquine
with a simpler
therapy
Overcoming
concerns about
resistance
Alonso P et al.,(2011) A research agenda for malaria eradication: drugs PLoS Med. Jan 25;8
16
Strong portfolio of single dose killers:
A new medicine needs two
OZ 439
17
KAE609
DSM265
MMV048
MMV/Sanofi
MMV/Novartis
MMV/Takeda (GHIT) MMV/South Africa
Active in malaria
patients
Active in malaria
patients
Active in infected
volunteers;
First new medicine
from Africa
Redox modulation
PfATP4 sodium
channel blocker
PfDHODH inhibitor
PfPI4kinase inhibitor
Active against
resistant strains
Active against
resistant strains
Active against
resistant strains
Active against
resistant strains
>1010 fold reduction
>1010fold reduction
Potential for
1010fold reduction
New compounds to stop Plasmodium vivax
relapse
Anaemia
Coma
• Not benign: high fevers,
• Relapses – infection
without a mosquito bite
• Current treatment
primaquine: needs 14 days
and G6PD- risk
Proportion of Patients
with Severe Malaria
Deaths from malaria
relapsing, sometimes fatal
RDS
Multiple
Mixed Infections
34% 293 / 871
45%
>1 Criteria
Pure P. vivax
22% 528 / 2,385
Pure P. falciparum
23% 1205 / 5586
40%
mixed
RDS
P. falcip. P. vivax
35%
Coma
SMA
30%
25%
20%
15%
10%
5%
0%
<1
1-4
5-15 15-24 25-44 45+
<1
1-4
5-15 15-24 25-44 45+
<1
1-4
5-15 15-24 25-44 45+
Age Group (Yrs)
• Tafenoquine in phase II
Safety and Efficacy
• Single dose cure
Primaquine
Tjitra E, PLoS Med. 2008 Jun 17;5(6):e128.
Chen, L. H. et al. JAMA 2007;297:2251-2263
18
Tafenoquine
Single Dose Tafenoquine
Relapse-free Efficacy at 6 months
89.2%
(p<0.0001)
57.7%
37.5%
54.1%
(p=0.16)
91.9%
(p<0.0001)
77.3%
(p=0.0004)
Transforming drug discovery
Engineered phenotypic screens
Chemistry:
All available
molecules
•
•
•
•
•
HTS
Whole
parasite
Identify
resistance
New business model
Screened five million compounds: 25’000 hits (1 uM)
Fast: screen to human trials in less than four years
Seven molecules already in clinical or preclinical
Identifies previously overlooked new targets
Rottman M., et al, Science 325 1175-1180 (2010)
Meister S., et al Science 334 1372-1377 (2011)
Gamo FJ, et al., Nature 465 (7296): 305–310 (2010)
Guiguemde WA, et al., Nature 465, 311–315 (2010)
Wells TNC Science 329 1153-1154 (2010)
20
Hits to leads
New
candidate
molecules for
development
MMV collaborates with a majority of pharma
and biotech companies
Compound Collection
Compounds
screened
Number of hits1
Novartis2
810’000
5930
0.73 Yes
GSK
1,986,056
13,533
0.68 Yes
St Jude
309,474
561
0.18 Yes
Pharma A
502,868
3274
0.65 No
Pharma B
155,554
1147
0.74 No
Diversity A
256,263
339
0.13 2013?
Sanofi2
1600
306
19.1 No
Broad Institute
100’000
465
0.47 2013?
Diversity B
35,000
222
0.63 2013?
% Hit-rate Public?
Building a Bayesian model to predict actives from theoretical diversity
1
Exact definitions variable – usually confirmed hit is non-cytotoxic and has IC50 < 2mM
selected inhibited human targets that have orthologues in Plasmodium
2Compounds
Open Access: Empowering neglected disease
drug discovery
• From 20’000 hits to 400
reference compounds
• Open access: supplied to
over 150 groups
•
•
•
•
40% malaria
60% other diseases
PK and metabolism data
Stringent quality controls
malariabox@mmv.org
Malaria Box: transforming open access drug
dsicovery in disease endemic countries
23
www.mmv.org/malariabox
MMV partners with a global network of study sites
O
O
O
O
OO
O
O
O
O
*
24
fast clearance,
long duration
*O volunteers
patients
relapse
prevention
O proof of concept
patients
transmission
blocking
chemoprotection
O volunteers
field demonstration O volunteers
Enhancing Capacity in Pailin, Cambodia (2007)
Testing medicines where resistance is highest
Enhancing capacity in Bagamoyo, Tanzania
Cardiology, challenge models, transmission
The future: Kolla Diba, Gondar, Ethiopia
Preparing for P vivax testing in Africa
PDPs
REDUCE DISEASE AND SUFFERING by focusing international
health R&D efforts and funding on the development of
EFFECTIVE
| AFFORDABLE
IMPACTFUL
MEDICINES
EFFECTIVE
AND
AFFORDABLE| NEW
PRODUCTS
for those
diseases that primarily affect developing country populations.
EFFECTIVE | AFFORDABLE | IMPACTFUL MEDICINES
COARTEM
DISPERSIBLE
EURATESIM
PYRAMAX
ARTESUN
INJECTED
4 medicines registered
from 2009-2013
94-99% efficacy*
for 3 ACTs developed with MMV
COARTEM
DISPERSIBLE
EURARTESIM
PYRAMAX
ARTESUN
INJECTED
4 medicines registered
from 2009-2013
* PCR-adjusted; day 28
22-33%
greater survival
with injected artesunate
vs. iv quinine
COARTEM
DISPERSIBLE
EURARTESIM
PYRAMAX
ARTESUN
INJECTED
4 medicines registered
from 2009-2013
Eurartesim-dispersible
Pyramax-granules
Tafenoquine
OZ439
KAE609
KAF156
DSM265
7 new medicines
in clinical development
1x
CHILDREN
& PREGNANT
WOMEN
SINGLE DOSE
CURES
PREVENTION
OF RELAPSE
TRANSMISSION
BLOCKING
CHEMO
PREVENTION
Addressing unmet medical needs
25 new chemical entities
in pre-clinical development & hit-to-lead / lead optimization
12 WITH ACADEMIA
25 new chemical entities
in pre-clinical development & hit-to-lead / lead optimization
13 WITH PHARMA
25 new chemical entities
in pre-clinical development & hit-to-lead / lead optimization
Providing researchers with
400 anti-malaria compounds
to further R&D in other NTDs
3 chemical series
Providing researchers with
400 anti-malaria compounds
to further R&D in other NTDs
2 tropical diseases
Sleeping sickness
Leishmaniasis
Providing researchers with
400 anti-malaria compounds
to further R&D in other NTDs
EFFECTIVE
| AFFORDABLE | IMPACTFUL MEDICINES
PHARMA
‘IN-KIND’
TOTAL
MMV
=
+
$1.00
$1.50
$2.50
Leveraging donor funds
Before GLP
preclinical
GLP preclinical
Phase I
Phase II
Phase III
Launched
Active
34
5
42
1 4
2
4
9
Terminated
Focusing resources
through early project prioritisation
4
3 2
INDUSTRY
$180 MILLIONS
Industry estimates for clinical
development of an anti-infective
(Tufts)
70%
REDUCTION
MMV
$54 MILLIONS*
Total clinical development costs
for pyronaridine-artesunate
Reducing costs
in clinical development
* Includes direct internal project costs, CRO costs and MMV management & administration costs.
INITIAL
COST
PROPOSAL
Reducing partner & vendor costs
e.g. non-clinical toxicology study
INITIAL
COST
PROPOSAL
73%
REDUCTION
CRO BID
Reducing partner & vendor costs
e.g. non-clinical toxicology study
50%
INITIAL
COST
PROPOSAL
OF CRO BID
13%
OF INITIAL
PROPOSAL
CRO BID
MMV SHARE
Reducing partner & vendor costs
e.g. non-clinical toxicology study
1KG
MEFLOQUINE
Cutting production costs
by improving routes of synthesis
AFTER
NEGOTIATION
WITH MMV
ACT
+ Obligation to launch in
malaria-endemic countries
+ Price targets & cost audits
Negotiating affordable pricing
INJECTABLE ARTESUNATE
Ensuring competitive pricing
by qualifying generic producers
EU 27 cents* to treat one child
* cost for one 3-day course of Coartem-dispersible (Novartis public sector price for malaria-endemic
countries; weighted average treatment regimen 2012; March 1st 2013 exchange rate)
EFFECTIVE
| AFFORDABLE | IMPACTFUL MEDICINES
>212 million treatments
delivered and counting
Coartem Dispersible
60-87 million children cured
200 million treatment courses delivered
* estimates based upon drug distribution data, epidemiology / testing data and clinical efficacy data
(PCR-corrected 28-day cure rate for Coartem Dispersible)
Artesun Injected
79 000 – 95 000
additional lives saved*
12 million vials delivered since WHO pre-qualification
* estimates based upon drug distribution data and clinical efficacy data
MMV is grateful for the financial support from
the following organizations:
57
Single dose cure is a priority:
Three day therapy role where ACTs fail
Districts where
ACTs still effective
Districts where
ACTs have failed
Therapeutic efficacy safely achieved
One Day
 High compliance
 Directly observed therapy
 Low cost of goods
? Need to show activity in
artemisinin resistant malaria
One Day
 High compliance
 Low cost of goods
Three days
 Back-up therapy where

?


?
ACTs fail
No compliance benefit vs.
ACTs
Cost of goods benefit vs.
ACTs
Three Days
Limited interest to replace
ACTs where they are still
active
No compliance benefit vs.
ACTs
Cost of goods benefit vs.
ACTs