innovative medicines for the control and elimination of malaria timothy n.c wells, scd chief...
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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
Millenium Development Goals (MDGs)
Reducing malaria burden would contribute significantly towards achieving the MDGs
3
Reversal of incidence of malaria and other major diseases by 2015
Reduce Child Mortality Rates
Improve maternal health
Unwavering focus on unmet needs
Medicines for children
Treatment for severe malaria
Medicines for pregnant womenMedicines for vulnerable populations
Facilitating access to gold-standard medicines
More simple & effective medicines
Better medicines for uncomplicated malaria
Transmission blocking
Relapse prevention
Chemo-protection
Medicines for malaria elimination & eradication
Facilitating access to gold standard medicines
Pressure on the partner drugs; choice is important
Coartem-D: (artemether-lumefantrine with Novartis) 171 million treatments deliveredTesting now in children under 5 kg
Eurartesim: (DHA-piperaquine, with Sigma-Tau)EMA approved 2011Now approved in Cambodia, Ghana, Tanzania
Pyramax: (pyronaridine artesunate, with Shin Poong)EMA approved 2012 (art 58), WHO prequalifiedLabel extension and granule submission next 12 months
Unwavering focus on unmet needs
Medicines for children
Treatment for severe malaria
Medicines for pregnant womenMedicines for vulnerable populations
Facilitating access to gold-standard medicines
More simple & effective medicines
Better medicines for uncomplicated malaria
Transmission blocking
Relapse prevention
Chemo-protection
Medicines for malaria elimination & eradication
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
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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
Chico RM et al., Azithromycin-chloroquine and the intermittent preventive treatment of malaria in pregnancy.2008 Malar J 7:255-60
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.
Unwavering focus on unmet needs
Medicines for children
Treatment for severe malaria
Medicines for pregnant womenMedicines for vulnerable populations
Facilitating access to gold-standard medicines
More simple & effective medicines
Better medicines for uncomplicated malaria
Transmission blocking
Relapse prevention
Chemo-protection
Medicines for malaria elimination & eradication
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
HTSWhole parasite
Hits to leads
Identify resistance
• 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)
New candidate molecules for development
Discovering, developing and delivering innovative medicines
RegistrationPreclinicalResearch Translational Development
Lead Opt Phase IIaPhase ILead Gen Phase IVPhase IIb/III
Novartisminiportfolio
Novartis2 Projects
MMV048(University of Cape
Town)
Artesunate for injectionGuilin
Coartem®-DNovartis
GSKminiportfolio
Broad/Genzymeminiportfolio
OxaborolesAnacor
Other Projects15 Projects
sanofi Orthologue screen
KinasesMonash
PfizerScreening
GSK2 Projects
NITD609Novartis
OZ439(Monash/UNMC/
STI)
Azithromycin chloroquine
Pfizer
PyramaxShin
Poong/University of Iowa
ASAQ Winthropsanofi /DNDi
AstraZenecaScreening
GNF156Novartis
DSM265(UTSW/UW/
Monash)
AminoindoleBroad/Genzyme
Eurartesim® sigma tau
AnitmalarialsSt
Jude/Rutgers/USF
TafenoquineGSK
P218 DHFR(Biotec/Monash/
LSHTM)
AntimalarialsDundee
DHODHUTSW/UW/
Monash
PyramaxPaediatric
Shin Poong/University of iowa
Eurartesim® Paediatricsigma tau
sanofi1 Projects
Pyrazoles(DrexelMED/UW)
ELQ-300(USF/OHSU-VAMC)
ActelionACTXXX
20% 68%10%
LaunchProbability
2018+ 2017+2019+
>90%
2015+
SP-AQGuilin
New Chemical E
ntities
New fast killers: the front-line of eradication
• 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
OZ439EC50 NF54 1.3nMP. berghei oral 1x30mg/kg curative
O
OOO
N
O
KAE609 EC50 NF54 0.7nMED90 Pb 2.7mg/kg
NH
NH
NHO
Cl
F
Cl
New medicines for transmission blocking
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
Key compounds from blood stage HTS
Membrane feeding in vitro
Proof of concept
(membrane feeding ex vivo)
Asymptomatic Carrier studyVillage based
Radical Cure of Plasmodium vivax
• Not benign: high fevers, 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
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
<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)
Proportion of Patients with Severe Malaria
>1 Criteria
RDS
Coma
SMA
Pure P. falciparum 23% 1205 / 5586
Pure P. vivax 22% 528 / 2,385
Mixed Infections 34% 293 / 871
P. falcip. P. vivax mixed
AnaemiaComa
RDSMultiple
Tjitra E, PLoS Med. 2008 Jun 17;5(6):e128. Chen, L. H. et al. JAMA 2007;297:2251-2263
Dea
ths
from
mal
aria
N
HN
O
NH2
O
F FF
O
N
HN
O
NH2
Tafenoquine
Primaquine
Finding new anti-relapse therapies for P vivax
• 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)
Screen asexual stage
P yoelii infected
HepG2/liver cells (25k)
P. cynomolgi infected rhesus
hepatocytes
PoCPrimate model, Human relapse
0 1 2 3 4 5 6 7 8 90.1
1
10
100
1000
Mean PO
Time (h)Co
nce
ntr
atio
n (
μM
)
0 1 2 3 4 5 6 7 8 90.01
0.1
1
10
Mean PO
Time (h)
Co
nce
ntr
atio
n (
μM
)
0 1 2 3 4 5 6 7 8 90.01
0.1
1
10Mean PO
Time (h)
Co
nce
ntr
atio
n (
μM
)
Single oral exposure mice PK (140 uM/kg, n=3)
Malaria Box: new leads for other diseases
In collaboration with DNDi and University of Antwerp (Prof. L. Maes) Unpublished data
Plasmodium falciparum EC50 = 50 nM
Trypanosoma bruceiEC50 <125 nM
Leishmania infantumEC50 = 1000 nM
MMV: £29m
Industry: £120m
Value through efficiency
EFFICIENCYPRODUCTIVITYCOMPETENCIES
Reducing clinical development costs
INNOVATION
Total clinical development costs forpyronaridine-artesunate
Industry estimates forclinical development ofan anti-infective (Tufts)
HEALTH IMPACT
March 1st 2013 exchange rate
Value through efficiency
EFFICIENCYPRODUCTIVITYCOMPETENCIES
Leveraging donor funds
INNOVATION
DFID£ 1.00
Other donors£ 5.46
Total£ 6.46
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
Committed2008-2013*
$475 million$87 million(£53.7 million)
HEALTH IMPACT
* Total funds received & committed as of March 2013
Value through efficiency
EFFICIENCYPRODUCTIVITYCOMPETENCIES
Leveraging donor funds
INNOVATION
Pharma’s ‘in-kind’ support
MMV£1.00
Pharma ‘in-kind’£1.50
Total£2.50
HEALTH IMPACT
* cost for one 3-day course of Coartem-dispersible (Novartis public sector price for malaria-endemiccountries; weighted average treatment regimen 2012; March 1st 2013 exchange rate)
Better medicines for morepeople at affordable prices
UK 23 pence* to cure one child
Thank you