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Defeating Malaria Together
David Reddy PhD, CEO of MMV
Developing next-generation malaria
medicines to address drug resistance
and support malaria elimination efforts
To reduce the burden of
malaria in disease-endemic
countries by discovering,
developing and facilitating
delivery of new, effective and
affordable antimalarial drugs
MMV is a Product Development Partnership (PDP)
Our mission is…
COARTEMDISPERSIBLE
EURARTESIM PYRAMAX
ARTESUNINJECTED
SP-AQ AS-AQ* AS-MQ*
* Transferred from DNDi-led partnership portfolio to MMV-led partnership portfolio 20th May 2015
PYRAMAXGRANULES
MMV:Products launched through our partnerships
Progress in the fight against malaria
2000-2015
GLOBAL
1.2 billioncases averted
6.2 milliondeaths averted*
60%reduction in malaria-related deaths
5.9 millionchildren’s lives saved*
* Difference between actual malaria deaths occurring between 2001 and 2015 versus projected deaths had incidence and mortality
rates remained unchanged since 2000.
Source: UNICEF and WHO. 2015. Achieving the malaria MDG Target. Reversing the incidence of malaria 2000-2015
214 millioncases in 2015
91%deaths occur in
Sub-Saharan Africa
70%of deaths are children
<5 years of age
236 000 – 635 000deaths
Source: UNICEF and WHO. 2015. Achieving the malaria MDG Target. Reversing the incidence of malaria 2000-2015
Malaria remains a public health imperative
Removal of control measures leads to resurgencethe cost of inaction: historical evidence
Source: Investing for a malaria-free world. Action and investment to defeat malaria 2016-2030 (AIM).
WHO Roll Back Malaria (RBM) Partnership 2015.
SUDAN
1975
1977
1979
1981
1983
1985
1987
1989
1991
1993
30%
20%
10%
0%
Program ends
INDIA
1961
1963
1965
1967
1969
1971
1973
1975
1977
1979
1981
1983
4%
8%
12%
0%
Funding withdrawnfollowed by
IRS shortages
THAILAND
1965
1967
1969
1971
1973
1975
1977
1979
1981
1983
1985
1987
8%
6%
4%
2%
0%
Attack phase ends
WHO global technical strategy for malaria vision and objectives 2016-2030
2
Reduce malaria
case incidence
globally
compared with
2015
>40%
>75%
>90%
3
Eliminate
malaria from
countries
in which it was
transmitted
in 2015
>10 countries
>20 countries
>35 countries
4
Prevent
re-establishment
of malaria in all
countries that
are malaria-free
Re-establishment
prevented
1
Reduce malaria
mortality rates
globally
compared with
2015
>40%
>75%
>90%
2020
2025
2030
Source: Global Technical Strategy for Malaria 2016–2030. World Health Organization, June 2015
http://www.who.int/malaria/publications/atoz/9789241564991/en/
Malaria elimination and eradication
We can accelerate the trajectory to malaria eradication by
targeting the human reservoir of infection
in asymptomatic persons combined with synchronous
transmission prevention
Target
the human
parasite
reservoir
Effective
transmission
preventionEradication
Adapted from Alan Magill’s BMGF Analytic Framework for Malaria Eradication
Drugs targeting malaria in 20th Century
Chemotype and related series Biological target Number of molecules
4-aminoquinolines b-haematin 4 (CQ,AQ,PYRO, PIP)
Artemisinins Multiple including haem,
PI3K, ATP6
5 (ART, DHA, ARS,
artemether, arteether)
Amino-alcohols Cytosolic haem? 3 (QUIN, MEF, LUM)
Diaminopyrimidines & diamino-
triazines
DHFR 4 (PYR, trimethoprim, Cl-
and H-cycloguanil)
Anilines DHPS 2 (sulphadoxine,
sulphamethoxazole)
Antibiotics (macrolide, tetracyclines
and lincosamide)
Ribosome 4 (AZI, TET, DOXY, CLIN)
8-aminoquinolines Unknown. Mitochondrial
target?
2 (primaquine, tafenoquine)
Naphthoquinone Cytochrome bc1 1 (Atovaquone)
8 Clinically validated pathways/ chemistry-linked phenotypes
CQ = chloroquine; SP = sulphadoxine-pyrimethamine; M15 = mefloquine 15 mg/kg body weight; M25 = mefloquine
25 mg/kg body weight; Q = quinine; QT = tetracycline; AM = amodiaquine; PQP = DHA-piperaquine
Anti-malaria drug resistanceDeclining cure rates in SE Asia (%)
In Cambodia a 5-10 fold increase in treatment failure rates
Slide courtesy of Professor Nick White; updated to include DHA-piperaquine day 42 efficacy data for Cambodia from WWARN
1975 1980 1985 1990 1995 2000 2005 2010 2015
100
80
60
40
20
CQ SP
Q
M25
AM
M15
QT
% t
reate
d p
atients
cure
dAM
PQP
Start with the end in mindTarget Candidate Profiles for the molecules
SECsingle exposure chemoprotection
TCP1 TCP2 TCP3a TCP3b
Fast clearance of parasitaemia
Long-acting post treatment
prophylaxis
Radical cure
Transmission blocking
Long acting
Causal liver or slow onset asexual
Different MOA to SERCaP
TCP4
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)
SERCaPsingle exposure
radical cure and prophylaxis
A Liver-stage schizonts
B Blood-stage schizonts
C Gametocytes
D Micro- and Macro-gametes/zygotes
E Ookinetes
F Oocysts
G Sporozoites
Radical cure requires clearance
of all forms of the parasite
A Liver-stage schizonts
B Blood-stage schizonts
C Gametocytes
D Micro- and Macro-gametes/zygotes
E Ookinetes
F Oocysts
G Sporozoites
Use of common assays across all projects
P. Cynomolgi hypnozoite assay
BPRC, Netherlands
P. vivax liver stages
Mahidol & USF-SMRU, Thailand;
NCBS, India; UCSD, Peru; BMGF
P. berghei liver stage assay
In vitro: UCSD, USA
In vivo: USF, USA
Blood stage activity
Swiss TPH, Switzerland; Syngene,
India; UCSD, USA & Eskitis, Australia
Parasite reduction rate
GSK Tres Cantos; STPH
in vivo huSCID model
GSK Tres Cantos; STPH
Target ID
BMGF Consortium/Cellzome
Gametocyte assay
BMGF; UCSD; Eskitis; GSK
Gamete formation assay
Imperial College UK
Resistance risk assessment
Columbia University, USA
Fields isolates:
Menzies, Australia, CSRS Côte
d’Ivoire, Tororo, Uganda
Membrane feed assay
TropIQ, Netherlands
GSK, Tres Cantos
HTS Whole parasiteScreened >7 000 000 compounds
Hits to leads25,000 hits (EC50<1 uM)
Identify resistance
New candidatemolecules fordevelopment
Computational model built based on all data
Fastest screen to human trials in less
than four years
Chemistry: All available molecules
Identifies previously overlooked new targets
13in clinical or preclinical
development
Rottman M., et al, Science 325 1175–1180 (2010) | Verras A., et al, Manuscript in preparation
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)
16candidatesdelivered
A transformation in drug discovery
In 2007, 95% of advisors preferred reductionism
MMV candidates targeting malaria in 21st Century
Chemotype and related series Biological Target Number of molecules
Multiple diverse series New - ATP4 4 (KAE609, SJ733,
GSK030, PA92)
Triazolopyrimidine and others New – DHODH 2 (DSM265, DSM421)
Imidazolopiperazine CARL KAF156
Aminopyridine New - PI4K 1 (MMV048)
Quinoline amide New – EF2 1 (MMV121)
Triaminopyrimidine New - V-type H+ ATPase 1 (MMV243)
Quinolone New – bc1 Qi inhibitor 1 (ELQ-300)
Pathways to kill the parasite – doubled in 10 years
25 compounds now identified where no resistance has been generated
2010 2011 2012 2013 2014 2015
KAE609Novartis
AN3661 ELQ-300DSM421
TakedaSJ733
St Jude/ Eisai
Genz-764DDD107498Merck KGaA
AZ412Partner
finalisation
GSK030GSK
P218BIOTEC
KAF156Novartis
DSM-265Takeda
21A092Drexel
MMV390048TIA
GSK692GSK
AN13762Anacor
candidates12 from phenotypic screens | 2 from target HTS | 2 from historical compounds
Delivered candidates cover all TCPs except
anti-relapse
Anti-relapse assays delivering; earliest candidate
in 2018?
Three projects terminated to date (toxicology/ CMC)
Exploring potential partnering
options early
Continued Parked Terminated
CONFIDENTIAL – MMV internal use only
16
New preclinical candidates 2010–2015
Whole cellSt Jude/Rutgers/USF
Translational Product development Access
MiniportfolioNovartis
SJ733(St Jude/Eisai)
MMV048(UCT)
Rectal artesunate *Cipla/Strides/WHO-TDR
PreclinicalPatient
confirmatoryPost approval Human
volunteers
Patient exploratory
Regulatory review
1 projectNovartis
P218(Biotec Thailand)
DSM265UTSW/UW/Monash (Takeda)
TafenoquineGSK
MiniportfolioGSK
2 projectsGSK
MiniportfolioSanofi
Orthologue LeadsSanofi
HeterocyclesUniv. Campinas
TetraoxanesLSTM/Univ. Liverpool
DHODHUTSW/UW/Monash
HeterocyclesTakeda
ScreeningMerck KGaA
Pathogen BoxMMV
Other projects24 projects
HeterocyclesEisai
PA92 (Drexel/UW/GNF)
MMV253(AstraZeneca)
Artefenomel(OZ439)/FQSanofi
Cipargamin(KAE609)Novartis
KAF156Novartis
GSK030GSK
DSM421(UTSW/UW/Monash)
Dihydroartemisinin piperaquinePaediatricSigma-Tau
ResearchLead
optimizationLead
generation
DDD498Merck KGaA(Dundee)
HeterocyclesDaiichi-Sankyo
Diversity oriented SynthesisBroad/Eisai
GSK692GSK
AN13762Anacor
PantothenamidesTropIQ/RUMC/Pansynt
HeterocyclesUCT
HeterocyclesCelgene
Open SourceDrug DiscoveryUniv. Sydney
3
UCT943UCT
1. Brand name: Coartem® Dispersible; 2. Brand name: Artesun®; 3. Brand name: Eurartesim®; 4. Brand name: Pyramax® Tablets & Granules; 5. Brand name: ASAQ Winthrop; 6. Brand name: SPAQ-COTM;
Artesunate for Injection Guilin
Dihydroartemisinin-piperaquine Sigma-Tau
Pyronaridine-artesunateShin Poong
Artesunate-amodiaquineSanofi/DNDi
Artesunate-mefloquineCipla/DNDi/Farmanguinhos
Pyronaridine-artesunate PaediatricShin Poong
3
2
4
6
Artemether-lumefantrineDispersibleNovartis
Sulfadoxinepyrimethamine+amodiaquineGuilin
4
1
5
MMV-supported projects
Predicted & (actual) human half lives,
and resistance
MoA Human dose human t1/2 Resistance Dd2 IC50 fold shift
OZ439 Unknown 800 (24-40) >9 No mutants
KAE609 ATP4 30 16 (40) 7 20
KAF156 Carl 800 (39) 8 100
AN3661 CPSF73 15 x 3 10-12 >9 ?
DSM265 DHOD 400 43 (100) 5.5 800
MMV048 PI4K 20-40 34 (125-237) 6 2
P218 DHFR 35-500 6-45 >9 No mutants
SJ733 ATP4 210-500 8-24 7 300
DDD498 EF2 750 43 6 4810
AZ412 ATP synthase 260/520 36 >9 ?
GSK030 ATP4 1000 11-40 8 632
DSM421 DHOD 215 83 ≤6
AN762 In progress <10/<50 14 6 8
GSK692 Unknown 250/490 34 >9 No mutants
MMV594 PI4K 100-1600 27
MMV943 PI4K 200-400 42
19
Key translational platforms
Measuring the MIC
1011 _
109 _
107_
105_
103_
101_
0 2 4 6 8 10 days
microscopic limit
PCR limit
Tota
l n
um
ber
of para
sites
[Concentration] > MIC
[Concentration] > MIC
[Concentration] > MIC
Controlled human malaria infection (CHMI) modelCollaboration with QIMR-Berghofer
Using the IBSM model
to de-risk and expedite malaria drug development
* IBSM (induced blood-stage malaria)
TCP fit • TCP 1,2, 4
Product vision• Part of a single exposure radical cure
• Potential for chemoprophylaxis
MoA• Plasmodium dihydroorotate dehydrogenase
(DHODH) inhibitor
Key features • Novel mechanism of action
Challenges• Cost of goods for API, and formulation
• Reduced relative activity against P. vivax
Status
• Completed Phase IIa in patients with
P. falciparum or P. vivax malaria
• Completed Phase Ib blood-stage challenge
in combination with OZ439
Next
milestone
• Start sporozoite challenge studies in
Germany, 1Q 2016
• Start direct mosquito bite challenge study in
the USA
MMV Project
Director• Dr Thomas Rückle
DSM265NIH/Takeda
(Univ. of Texas
Southwestern/Univ. of
Washington/Monash Univ.)
Activity of DSM265 against P. falciparum
in the HuSCID mouse model
HuSCID mouse
STPHI Basel
GSK Tres Cantos
DSM265-13-01: FIM, pilot food & IBSM
challenge study (150 mg DSM265 cohort)
Parameter Value
Lag 12–15 hr
MPC (based on PD data and
PK simulation)
1.4 µg/mL
MPC (based on PK/PD from
clinical data)
0.95 µg/mL
(95% CI = 0.68–1.27)
PRR 2.2 (95% CI = 2.0–2.7)
Parasite clearance half-life 6.6 hours
(95% CI = 5.4–7.2)
Predicted human
efficacious dose
320 mg
QIMR-B: 7 subjects received DSM265 and 2 subjects received MQ
Day
1 2 3 4 50
106
102
104
103
105
S1056 MQ1
S1057 Redo
S1058
S1059
S1060
S1064
S1065
S1068 Redo
Average DSM
S1070 MQ2
Pa
rasite
s/m
L
• Single centre, open-label, non-comparative study; site: ACSA, Iquitos, Peru
• Two arms: P. vivax and P. falciparum malaria
• Maximum of 3 cohorts per arm with 10 patients per cohort
• DSM265 administered as single dose
• Starting dose: 400 mg; Sequential adaptive design
• Study clinically complete, data base lock 02/2016
• 45 patients enrolled
DSM265 POC study for treatment
of uncomplicated malaria: study design
P. falciparum 250 mg – Microscopy
P. falciparum 250 mg of DSM265 parasitaemia
F2002
F2003
F2004
F2005
F2008
F2009
F2010
F2007
F2006
F2001
Log p
ara
sites/µ
l
5
4
3
2
1
0
Constants
*non-drug SAE
Rescue
0 24 48 72 200 400 600 800
Never blood smear positive
Stopped based on PCR criteria
P. falciparum 400 mg of DSM265 parasitaemia
Never blood smear positive
Stopped based on PCR criteria
F1002
F1003
F1004
F1005
F1008
F1009
F1010
F1007
F1006
F1001
Time (hours)
Log p
ara
sites/µ
l
P. falciparum 400 mg – Microscopy
5
4
3
2
1
0
0 24 48 72 200 400 600 800
Rescue
Key checkpoints using predictive models
HuSCID mouse
STPHI Basel
GSK Tres Cantos
Human Challenge 150mg
QIMR-Berghofer 2012
Tübingen 2015
Patient PoC 400 mg
Peru 2015
Ethiopia 2017
Partner selection matrix
Factor High Score (5) Low Score (1)
TPP - SERCaP TCP1, 2 and 3 Insufficient TCP1 & 2
Safety Different organ tox & manageable Same organ tox + SAEs
Dev stage Both drugs approved Both preclinical stage
PK- time > MPC Complete overlap > MPC for > 2wk Very short acting + very long acting
Total Dose (mg) <150mg >1200mg
BCS - formulation No challenges Two drugs with bad formulation
Prophylaxis - liver stage Both drugs 3-4wks > MPC Neither has >1 wk prophylaxis
Resistance None to either drug Widespread to 1 or 2 drugs
Food effect No food effect for both Both food effect + severe safety
issue
DDI between partners No predicted DDI Clinically concerning DDI
DDI with other conc-med No predicted DDI Clinically concerning DDI
MOAs Complementary Identical MOA + resistance mutation
IP flexibility Two drugs from same group Owner unwilling to partner
Wes van Voorhis, MD PhD, Stephan Chalon MD PhD
Portfolio evaluation tool for prioritizing partner
drugs for a single-encounter radical cure (SERC)
Mefloq
PQP
FQ
KAF156
0
5
10
15
20
25
30
35
40
TCP1
+TCP2,
3
IP o
wne
r fle
xibi
lty
Proph
ylax
is
Differ
ent M
OA
Mat
ched
Tim
e > M
PC
Dev
Sta
ge
Safet
y/Diff O
rgan
tox
Diff e
limin
mec
h
Qua
ntity
of t
wo
need
ed
No
drug
xdru
g in
tera
ctio
ns
BCS/F
orm
ulat
ion
issu
es
No
food
effe
ct
Res
ista
nce
issu
es
Mefloq Pyronaridine PQP KAE609 FQ DSM265 KAF156 MMV048
Partner drugs for OZ439
March 2016
SERCaP combination score: DSM265
Marketed Drugs Total Score
Piperaquine 79
Atovaq-Proguanil 65
Lumefantrine 64
Pyronaridine 63
Amodiaquine 58
Azithromycin 52
Mefloquine 50
NCEs Total Score
Phase 2 Candidates
OZ439 86
KAE609 85
Ferroquine 65
KAF156 59
Phase1 Candidates
MMV048 70
ACT840 64
Pilot IBSM study with drug combination
DSM265/OZ439: study design and concept
• Single dose of each drug does not eliminate all parasites
• Low doses of OZ439 and DSM265 would allow observation of a
combination effect- Change of PRR
- Apparent MIC
- Proportion with recrudescence
- Time to recrudescence
- Presence of gametocytes
• 2 cohorts, 200/100 mg and 200/50 mg OZ439/DSM265
• Selection of drug combination for further studies
Pilot IBSM study with drug combination
DSM265/OZ439: results
RecrudescenceCohort 1: 200/100 mg OZ439/DSM265: 4/8
Cohort 2: 200/50 mg OZ439/DSM265: 5/5
95% Confidence Interval =
Mean 1.96*SD
DSM265: 100 mg OZ439: 200 mg
DSM265: 150 mg
OZ439: 200 mg
DSM265: 50 mg OZ439: 200 mg
Time (hours)
-100 -50 0 50 100 150 200
0.1
1.0
10.0
100.0
1000.0
% P
ara
site
s r
ela
tive
to
ba
se
line
MMV is grateful for the support of the following
committed donors
35