Innovative medicines for
the control and elimination
of malaria
Timothy N.C Wells, ScD Chief Scientific Officer
Defeating Malaria Together
Malaria: Leading cause of child mortality
•
•
•
•
•
655’000 deaths per year
216 million cases per year
86% in children under five
Targets expectant mothers
£8 billion African GDP; 40% of
health budgets
One child dies every minute from malaria
3
Millenium Development Goals (MDGs)
Reduce Child Mortality Rates
Improve maternal health
Reversal of incidence of malaria and
other major diseases by 2015
Reducing malaria burden would contribute
significantly towards achieving the MDGs
Unwavering focus on unmet needs
Better medicines
for uncomplicated
malaria
Medicines for
vulnerable
populations
Medicines for
malaria elimination
& eradication
Facilitating access to gold-standard medicines
More simple & effective medicines
Medicines for children
Medicines for pregnant women
Treatment for severe malaria
Transmission blocking
Relapse prevention
Chemo-protection
Facilitating access to gold standard medicines
Pressure on the partner drugs; choice is important
Coartem-D: (artemether-lumefantrine with Novartis)
171 million treatments delivered
Testing now in children under 5 kg
Eurartesim: (DHA-piperaquine, with Sigma-Tau)
EMA approved 2011
Now approved in Cambodia, Ghana, Tanzania
Pyramax: (pyronaridine artesunate, with Shin Poong)
EMA approved 2012 (art 58), WHO prequalified
Label extension and granule submission next 12 months
Unwavering focus on unmet needs
Better medicines
for uncomplicated
malaria
Medicines for
vulnerable
populations
Medicines for
malaria elimination
& eradication
Facilitating access to gold-standard medicines
More simple & effective medicines
Medicines for children
Medicines for pregnant women
Treatment for severe malaria
Transmission blocking
Relapse prevention
Chemo-protection
Artesunate: saving lives in severe malaria
•
•
•
•
•
Artesunate for injection (with Guilin)
WHO prequalified 2010
Mortality reduction: 10.9% to 8.5%
Approximately $1 per vial; 6 million vials in first year
Next challenge: artesunate suppositories for pre-referral
treatment
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
Protecting children and expectant mothers
Seasonal Malaria Chemoprotection:
potential 7-8 million less children infected
Once per month; cost <50¢ per year
Options: Amodiaquine + SP
25 million expectant mothers at risk
Protect twice in pregnancy for $1?
Options: Azithromycin-Chloroquine
low price Mefloquine
8
Chico RM et al., Azithromycin-chloroquine and the intermittent preventive treatment of
malaria in pregnancy.2008 Malar J 7:255-60
Unwavering focus on unmet needs
Better medicines
for uncomplicated
malaria
Medicines for
vulnerable
populations
Medicines for
malaria elimination
& eradication
Facilitating access to gold-standard medicines
More simple & effective medicines
Medicines for children
Medicines for pregnant women
Treatment for severe malaria
Transmission blocking
Relapse prevention
Chemo-protection
New medicines for malaria control and
eradication
• Irresistible
• Relapse prevention
• Transmission blocking
• Single dose
• Extremely safe
• Cheap
• Child friendly
A research agenda for malaria eradication: drugs PLoS Med. 2011 Jan 25;8(1)
Target Product profiles: see www.mmv.org
Types of medicine we need
Target Candidate Profiles
1. Fast killers/blood stage
2. Long persisters/blood stage
3. Relapse prevention, transmission blocking
4. Chemoprotection
Ask the parasite: transforming discovery
Chemistry:
All available
molecules
•
•
•
•
•
HTS
Whole
parasite
Hits to leads
Identify
resistance
New
candidate
molecules for
development
New business model
Screened over five million compounds, 25’000 hits
Fast: screen to human trials in less than four years
Five molecules already in clinical or preclinical
Identifies 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)
Discovering, developing and delivering
innovative medicines
Research
Lead Gen
Translational
Lead Opt
Preclinical
Phase I
DSM265
GNF156
Novartis
Novartis
Novartis
miniportfolio
2 Projects
(UTSW/UW/
Monash)
GSK
GSK
Aminoindole
miniportfolio
2 Projects
Broad/Genzyme
Broad/Genzyme
sanofi
miniportfolio
1 Projects
P218 DHFR
Screening
(Biotec/Monash/LSH
sanofi
Antimalarials
Pyrazoles
Orthologue screen
Dundee
(DrexelMED/UW)
Screening
DHODH
UTSW/UW/
Monash
OZ439
Azithromycin
chloroquine
(Monash/UNMC/
STI)
NITD609
Novartis
Pfizer
Tafenoquine
GSK
Pyramax
Paediatric
MMV048
St
Jude/Rutgers/USF
AstraZeneca
Phase IIb/III
(University of Cape
Town)
Anitmalarials
Pfizer
Actelion
ACTXXX
Development
Phase IIa
Shin Poong/University
of iowa
Eurartesim®
Paediatric
sigma tau
TM)
Registration
Phase IV
Coartem®-D
Novartis
Pyramax
Shin
Poong/University of
Iowa
Artesunate for
injection
Guilin
Eurartesim®
sigma tau
ELQ-300
(USF/OHSU-VAMC)
ASAQ Winthrop
sanofi /DNDi
Kinases
Monash
Oxaboroles
Anacor
SP-AQ
Guilin
Other Projects
15 Projects
2019+
2018+
2017+
2015+
10%
20%
68%
>90%
Launch
Probability
New fast killers: the front-line of eradication
OZ439
EC50 NF54 1.3nM
P. berghei oral 1x30mg/kg curative
•
•
•
•
KAE609
EC50 NF54 0.7nM
ED90 Pb 2.7mg/kg
OZ439: long acting peroxide; artemisinin replacement
Still active when the parasite wakes up
KAE609: fast acting, first new target in 20 years
Both in Phase II with potential for single dose curative
combination
New medicines for transmission blocking
Key
compounds
from blood
stage HTS
Membrane
feeding in vitro
Proof of
concept
(membrane
feeding ex vivo)
Asymptomatic
Carrier study
Village based
Existing medicines
• Primaquine kills the gametocytes at safe doses
• Ivermectin kills the insect forms
New medicines
• 8 molecules in preclinical to phase II
• Are any of these as good or better than primaquine?
• Clinical test being validated (Tanzania)
• 25’000 blood stage hits to follow up on if not
Radical Cure of Plasmodium vivax
Anaemia
Coma
• Not benign: high fevers,
•
•
P roportion of P atie nts
M ix e d In fe c tio n s
with S e v e re M alaria
Deaths from malaria
•
•
relapsing, sometimes fatal
80 million cases per year
Relapses – infection
without a mosquito bite
Current treatment
primaquine: needs 14 days
and G6PD- risk
Tafenoquine in phase II
efficacy/safety studies (data
July 2013) with GSK
RDS
Multiple
34% 293 / 871
45%
mixed
2 2 % 5 2 8 / 2 ,3 8 5
23% 1205 / 5586
40%
>1 C rite ria
P u re P . v iv a x
P u re P . fa lc ip a ru m
RD S
P. falcip. P. vivax
35%
C oma
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
A g e G ro u p (Yrs )
Primaquine
Tjitra E, PLoS Med. 2008 Jun 17;5(6):e128.
Chen, L. H. et al. JAMA 2007;297:2251-2263
Tafenoquine
45+
Finding new anti-relapse therapies for P vivax
Screen asexual
stage
P yoelii
infected
HepG2/liver
cells (25k)
P. cynomolgi
infected
rhesus
hepatocytes
• Dormant form: hypnozoite
• Fast track: test exisiting molecules
• First new class of compounds could
enter phase I in 2014
• New clinical model to test for relapse
directly (Indonesia)
PoC
Primate model,
Human relapse
Open Access: Empowering Research
Available Now
Further details malariabox@mmv.org
Malaria Box: new leads for other diseases
Trypanosoma
brucei
EC50 <125 nM
Plasmodium
falciparum
EC50 = 50 nM
1000
10
10
Mean PO
1
0.1
1
2
3
4 5 6
Time (h)
7
8
9
1
0.1
Concentration (μM)
10
0
Mean PO
Mean PO
Concentration (μM)
100
Concentration (μM)
Leishmania
infantum
EC50 = 1000 nM
1
0.1
0.01
0.01
0
1
2
3
4
5
6
7
8
9
Time (h)
Single oral exposure mice PK (140 uM/kg, n=3)
In collaboration with DNDi and University of Antwerp (Prof. L. Maes) Unpublished data
0
1
2
3
4 5 6
Time (h)
7
8
9
Value through efficiency
COMPETENCIES
INNOVATION
PRODUCTIVITY
EFFICIENCY
HEALTH IMPACT
Reducing clinical development costs
Industry estimates for
clinical development of
an anti-infective (Tufts)
Industry: £120m
MMV: £29m
Total clinical development costs for
pyronaridine-artesunate
March 1st 2013 exchange rate
Value through efficiency
COMPETENCIES
INNOVATION
PRODUCTIVITY
EFFICIENCY
HEALTH IMPACT
Leveraging donor funds
Committed
$87 million
2008-2013* (£53.7 million)
DFID
£ 1.00
$475 million
Other donors
£ 5.46
Benefits to other donors:
 MMV manages funds that cannot be provided directly to Pharma by the donor
 MMV provides one-stop-shop for donors: strategy, management, reporting
* Total funds received & committed as of March 2013
Total
£ 6.46
Value through efficiency
COMPETENCIES
INNOVATION
PRODUCTIVITY
EFFICIENCY
HEALTH IMPACT
Leveraging donor funds
Pharma’s ‘in-kind’ support
MMV
£1.00
Pharma ‘in-kind’
£1.50
Total
£2.50
Better medicines for more
people at affordable prices
UK 23 pence* to cure 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)
Thank you