drugs for treatment and chemoprevention of malaria · rectal artesunate1 project *...
TRANSCRIPT
Drugs for treatment and chemoprevention of malaria
Tim Wells Chief Scientific Officer MMV
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Ideal Product has several activities
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 12187 (2013)
bull Clears blood stages rapidly
bull Long acting
bull Blocks transmission
bull Kills dormant forms
bull Active against all current and emerging resistance
bull Safe enough to give to all
Malaria Drug Resistance
bull Artemisinin resistance in the Mekong slower rate of killing parasites
bull Puts pressure on partner drugs multidrug resistance
4 Noedl H et al (2008) N Engl J Med 359 2619-20 Dondorp AM et al (2009) N Engl J Med 361455-67 Ariey F et
al Nature 2014 50550-5 Straimer Jet al Science 2015 347428-31
Thailand
t12 = 4h
Cambodia
t12 = 6h
2009
Focus on simplifying treatment or fighting resistance
Dis
tric
ts w
he
re
AC
Ts h
ave
fai
led
One Dose Split Dose
One Dose Split Dose
Dis
tric
ts w
he
re A
CTs
st
ill e
ffe
ctiv
e
Back-up therapy where ACTs fail
Some compliance benefit vs ACTs
Cost of goods benefit vs ACTs
Limited interest to replace ACTs where they are still active
No compliance benefit vs ACTs
Cost of goods benefit vs ACTs
High compliance Low cost of goods
High compliance Directly observed therapy Low cost of goods Need to show activity in
artemisinin resistant malaria
6
Balancing Efficacy and Safety
Time
Drug
concentration
Minimum inhibitory
concentration
Safety threshold
Increasing the drug dose
increases the chance of
side effects
1
Ideally the compound needs to be
active (above the minimum
threshold) for 28 days or more
IV Artesunate Univ Tuumlbingen
OZ439 MonashUNMCSTI
MK4815 (Merck)
2008
Translational Product development Access
3 projects Novartis
Preclinical Patient
confirmatory Post approval
Human volunteers
Patient exploratory
Regulatory review
2 projects GSK
5 projects BroadGenzyme
Immucillins Albert Einstein
Quinolones USF
4 projects Other screenings
3 projects Natural products
Research Lead
optimization Lead
generation
Heterocyclic Hit to Lead TDRPharmacopeia
DHFR BIOTECMonash
LSHTM
4 projects GSK
DHODH UTSWUWMonash
Aminoindoles BroadGenzyme
2 projects Novartis
Ozaonides MonashUNMCSTI
1
Artemether- lumefantrine Dispersible Novartis
Isoquine GSK
Pyronaridine-Artesunate Shin Poong
Tafenoquine GSK
DHA-Piperaquine Sigma-Tau
2 compounds GSK Pyridones
Artemisone UHKST
(+)-Meflonquine Treague
2 compounds Novartis
31 March 2016
Whole cell St JudeRutgersUSF
Translational Product development Access
Miniportfolio Novartis
SJ733 St JudeEisai
MMV048 UCT
Rectal Artesunate CiplaStridesWHO-TDR
Preclinical Patient
confirmatory Post approval Human
volunteers
Patient exploratory
Regulatory review
1 project Novartis
P218 (BIOTEC Thailand)
DSM265 UTSWUW Monash
Tafenoquine GSK
Miniportfolio GSK
2 projects GSK
Miniportfolio Sanofi
Orthologue Leads Sanofi
Heterocycles Univ Campinas
Tetraoxanes LSTMUniv Liverpool
DHODH UTSWUWMonash
Heterocycles Takeda
Screening Merck Serono
Pathogen Box MMV
Other projects 24 projects
Heterocycles Eisai
PA92 (DrexelUWGNF)
MMV253 (AstraZeneca)
OZ439FQ Sanofi
KAE609
Novartis
KAF156 Novartis
Artesunate for injection Guilin
Dihydroartemisinin- piperaquine Sigma-Tau
Pyronaridine- artesunate Shin Poong Univ of Iowa
Artesunate- amodiaquine Sanofi DNDi
Artesunate- mefloquine
CiplaDNDi Farmanguinhos
GSK030 GSK
DSM421
(UTSWUW Monash)
Pyronaridine- artesunate Paediatric Shin Poong Univ of Iowa
Sulfadoxine - pyrimethamine + amodiaquine Guilin
Dihydroartemisinin piperaquine Paediatric Sigma-Tau
Research Lead
optimization Lead
generation
3
1
2
4
5
6
DDD498 Merck Serono (Dundee)
Heterocycles Daiichi-Sankyo
Diversity oriented Synthesis BroadEisai
GSK692 GSK
AN13762 Anacor
Artemether- lumefantrine Dispersible Novartis
Pantothenamides TropIQRUMC Pansynt
Heterocycles UCT
Heterocycles Celgene
Open Source Drug Discovery Univ Sydney
4
3
2016
16 new candidates 2009-2016
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Building on an existing template
OZ03 OZ277 RBx11160
Reduce logP Improve solubility
OZ439
Decrease interaction with ferrous iron (single electron)
Vennerstrom JL et al Nature 2004430(7002)900ndash4 Charman SA et al PNAS 2011108(11)4400ndash5
Less potent on embryos and on granulocytes Active vs artesunate resistance
1
Molecular Design DHODH
DSM1 EC50 3D7 79 nM No oral efficacy
DSM191 EC50 3D7 220 nM ED90 Pf SCID 57 mgkg
DSM265 EC50 3D7 8 nM ED90 Pf SCID 81 mgkg
Coteron JM et al J Med Chem 201154(15)5540ndash61
bull Phase IIa completed December 2015
2
Optimising phenotypic hits 3
New targets from parasite screening
Chemotype and related series
New Biological Target
Molecules
Multiple diverse series
ATP4 Na channel KAE609 SJ733 GSK030 PA92
Imidazolopiperazine CARL KAF156
Triazolopyrimidine DHODH DSM265 (DSM421)
Aminopyridine PI4K MMV048 (UCT943)
Quinoline eEF2 DDD498
Triaminopyrimidine V-type H+ ATPase AZ412
Target Identification Consortium 50 compounds from Malaria Box 10-15 new targets Collection of lsquoirresistable scaffoldsrsquo
New Chemotypes by calculation
14
Sequence alignments Homology modelsdocking
Prioritization of new chemistry Validating models to drive
compound design
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Standard Phase II data Response in patients for first 36h
log10PRR(48h) P falciparum 276 -362 log10PRR(48h) P vivax 392-480
16
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
20000
-1 4 9 14 19 24 29
200 mg
400 mg
800 mg
1200 mg
Time h
pa
rasite
s m
l
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
-1 4 9 14 19 24 29
200 mg
400 mg
800 mg
1200 mg
P falciparum P vivax
pa
rasite
s m
l
Time h
Measuring the MIC clinically
17
1011 _
109 _
107_
105_
103_
101_
0 2 4 6 8 10 days
microscopic
limit
PCR limit
Tota
l num
ber
of para
sites
[Concentration] gt MIC
[Concentration] gt MIC
[Concentration] gt MIC
119875119905 = 119875119905
0
119866 minus 1198630 119862119905119867(119862119905
119867 + 11986811986250119867 119889119905
Early data in CHMI models saves time and money
18
Thai Patients (100 mg) Australian Volunteers (100-500mg)
1 month per cohort 1 centre All year round
6 months 4 centres seasonal
19
Human volunteer challenge ndash early readout that the drug works
150 mg DSM265 predicts Human Effective Dose as
400 mg
Day
1 2 3 4 5 0
106
102
104
103
105
S1056 MQ1 S1057 Redo S1058 S1059 S1060 S1064 S1065 S1068 Redo Average DSM S1070 MQ2
Para
site
sm
L
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Candidate selection
Pre- clinical
Transition to human
Phase I
Phase III
Phase IIa
End of Phase IIa
Phase IIb
Candidate Profiling
DDI Phase I
Initiate Phase III
New Chemical
Entity
SRA filing
Discovery and
Candidate Profiling
bull in vitro and in vivo
activity
bull DMPK
bull Solid state
characterization
bull SaltForm screen Phase IIb (adult and
pediatric pts)
bull Safety tolerability
bull Dose finding
bull Contribution of each
agent to the efficacy of
the combination (FDA
rule)
bull Efficacy (ACPR Day 28
and 42)
Discovery
Phase I (hv) and Phase
IIa (adult pts)
bull Single agent
- Safety
- PK
- Parasite clearance and
time to recrudescence
(up to Day 28)
bull Combination
- Safety
- Drug-Drug interactions
- PKPD modeling
Development for combination medicine
21
Preclinical
formulation
Phase III (adult and
pediatric pts)
bull Safety tolerabiliyt
bull Confirm efficacy of
fixed dose
combination (ACPR
Day 28 42 and 63)
Single agent
Combination (with Pharma Partner)
Phase I and Phase IIa
formulation
Phase IIb loose
combination or dose
scalable formulation
Phase III FDC market
formulation
Preclinical
bull GLP Tox
bull DMPK
bull Pre-formulation
studies
Next steps find the right partner
22
WHO guidance differentiated partner to protect against resistance
bull trusted friend or beautiful stranger
bull Can you afford to wait for the next best thing
Differentiated partner protects against resistance trusted friend or beautiful stranger can you afford to wait for the next best thing
Find the right
partner
httpsplusmathsorgcontentkissing-frog-mathematicians-guide-mating
Partner selection Matrix
23
Factor High Score (5) Low Score (1)
TPP - SERCap TCP1 2 and 3 Insufficient TCP1 amp 2
Safety Different organ tox amp manageable Same organ tox + SAEs
Dev Stage Both drugs approved Both preclinical stage
PK- time gt MPC Complete overlap gt MPC for gt 2wk Very short acting + very long acting
Total Dose (mg) lt150mg gt1200mg
BCS -Formulation No challenges Two drugs with bad formulation
Prophylaxis-Liver Stage Both drugs 3-4wks gt MPC Neither has gt1 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 Challon MD PhD
0
5
10
15
20
25
30
35
40
Mefloq Pyronaridine PQP KAE609 FQ DSM265 KAF156 MMV048
Partner selection matrix
24
Newer Newest
Two new combination phase II studies are ongoing
Options for clinical development
Phase IIb One day ndash three days Adults and children
Dose range to satisfy FDA combination rule
2017-18
Single Dose Phase III program
Confirm safety 2019-20
Single dose cohort safe
and gt95 efficacy
Multiple dose Phase III program
Confirm safety 2019-20
Three day cohort safe
and gt95 efficacy
Launch single dose cure
2021
Launch multiple dose
cure 2021
Phase III with three drug
combination 2021- 2
Drug interaction studies with third partner (at risk)
Eliminating the last parasite
Are medicines safe and well tolerated enough to use in subjects with
bull Repeated infection
bull asymptomatic infection
bull undiagnosed early pregnancies
bull in HIV patients (co-medication immunosuppresed)
bull malnutrition
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
A glass half full ndash How we are doing
Blood stage killers fast and long acting
610
Chemoprevention liver schizonticides
510
Transmission blocking safely sparing primaquine
410
Relapse Prevention 810
A glass half full ndash How we are doing
Blood stage killers fast and long acting safe and well tolerated for asymptomatics
310
Chemoprevention liver schizonticides once per month once per season
2510
Transmission blocking safely sparing primaquine
410
Relapse Prevention in G6PD- individuals
010
If you want to go fast go alone If you want to go far go together
Our partnerships are our greatest strength
32
Drugs for treatment and chemoprevention of malaria
Tim Wells Chief Scientific Officer MMV
Products with impact
Molecule
Lumefantrine 4 x 480 mg 2000 mg over 3 days
900 960
Artemether 4 x 80 mg 455
Ferroquine 3 x 200 mg 794
KAF156 1 x 800 mg 67
DSM265 1 x 400 mg 89
PCR corrected
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Ideal Product has several activities
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 12187 (2013)
bull Clears blood stages rapidly
bull Long acting
bull Blocks transmission
bull Kills dormant forms
bull Active against all current and emerging resistance
bull Safe enough to give to all
Malaria Drug Resistance
bull Artemisinin resistance in the Mekong slower rate of killing parasites
bull Puts pressure on partner drugs multidrug resistance
4 Noedl H et al (2008) N Engl J Med 359 2619-20 Dondorp AM et al (2009) N Engl J Med 361455-67 Ariey F et
al Nature 2014 50550-5 Straimer Jet al Science 2015 347428-31
Thailand
t12 = 4h
Cambodia
t12 = 6h
2009
Focus on simplifying treatment or fighting resistance
Dis
tric
ts w
he
re
AC
Ts h
ave
fai
led
One Dose Split Dose
One Dose Split Dose
Dis
tric
ts w
he
re A
CTs
st
ill e
ffe
ctiv
e
Back-up therapy where ACTs fail
Some compliance benefit vs ACTs
Cost of goods benefit vs ACTs
Limited interest to replace ACTs where they are still active
No compliance benefit vs ACTs
Cost of goods benefit vs ACTs
High compliance Low cost of goods
High compliance Directly observed therapy Low cost of goods Need to show activity in
artemisinin resistant malaria
6
Balancing Efficacy and Safety
Time
Drug
concentration
Minimum inhibitory
concentration
Safety threshold
Increasing the drug dose
increases the chance of
side effects
1
Ideally the compound needs to be
active (above the minimum
threshold) for 28 days or more
IV Artesunate Univ Tuumlbingen
OZ439 MonashUNMCSTI
MK4815 (Merck)
2008
Translational Product development Access
3 projects Novartis
Preclinical Patient
confirmatory Post approval
Human volunteers
Patient exploratory
Regulatory review
2 projects GSK
5 projects BroadGenzyme
Immucillins Albert Einstein
Quinolones USF
4 projects Other screenings
3 projects Natural products
Research Lead
optimization Lead
generation
Heterocyclic Hit to Lead TDRPharmacopeia
DHFR BIOTECMonash
LSHTM
4 projects GSK
DHODH UTSWUWMonash
Aminoindoles BroadGenzyme
2 projects Novartis
Ozaonides MonashUNMCSTI
1
Artemether- lumefantrine Dispersible Novartis
Isoquine GSK
Pyronaridine-Artesunate Shin Poong
Tafenoquine GSK
DHA-Piperaquine Sigma-Tau
2 compounds GSK Pyridones
Artemisone UHKST
(+)-Meflonquine Treague
2 compounds Novartis
31 March 2016
Whole cell St JudeRutgersUSF
Translational Product development Access
Miniportfolio Novartis
SJ733 St JudeEisai
MMV048 UCT
Rectal Artesunate CiplaStridesWHO-TDR
Preclinical Patient
confirmatory Post approval Human
volunteers
Patient exploratory
Regulatory review
1 project Novartis
P218 (BIOTEC Thailand)
DSM265 UTSWUW Monash
Tafenoquine GSK
Miniportfolio GSK
2 projects GSK
Miniportfolio Sanofi
Orthologue Leads Sanofi
Heterocycles Univ Campinas
Tetraoxanes LSTMUniv Liverpool
DHODH UTSWUWMonash
Heterocycles Takeda
Screening Merck Serono
Pathogen Box MMV
Other projects 24 projects
Heterocycles Eisai
PA92 (DrexelUWGNF)
MMV253 (AstraZeneca)
OZ439FQ Sanofi
KAE609
Novartis
KAF156 Novartis
Artesunate for injection Guilin
Dihydroartemisinin- piperaquine Sigma-Tau
Pyronaridine- artesunate Shin Poong Univ of Iowa
Artesunate- amodiaquine Sanofi DNDi
Artesunate- mefloquine
CiplaDNDi Farmanguinhos
GSK030 GSK
DSM421
(UTSWUW Monash)
Pyronaridine- artesunate Paediatric Shin Poong Univ of Iowa
Sulfadoxine - pyrimethamine + amodiaquine Guilin
Dihydroartemisinin piperaquine Paediatric Sigma-Tau
Research Lead
optimization Lead
generation
3
1
2
4
5
6
DDD498 Merck Serono (Dundee)
Heterocycles Daiichi-Sankyo
Diversity oriented Synthesis BroadEisai
GSK692 GSK
AN13762 Anacor
Artemether- lumefantrine Dispersible Novartis
Pantothenamides TropIQRUMC Pansynt
Heterocycles UCT
Heterocycles Celgene
Open Source Drug Discovery Univ Sydney
4
3
2016
16 new candidates 2009-2016
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Building on an existing template
OZ03 OZ277 RBx11160
Reduce logP Improve solubility
OZ439
Decrease interaction with ferrous iron (single electron)
Vennerstrom JL et al Nature 2004430(7002)900ndash4 Charman SA et al PNAS 2011108(11)4400ndash5
Less potent on embryos and on granulocytes Active vs artesunate resistance
1
Molecular Design DHODH
DSM1 EC50 3D7 79 nM No oral efficacy
DSM191 EC50 3D7 220 nM ED90 Pf SCID 57 mgkg
DSM265 EC50 3D7 8 nM ED90 Pf SCID 81 mgkg
Coteron JM et al J Med Chem 201154(15)5540ndash61
bull Phase IIa completed December 2015
2
Optimising phenotypic hits 3
New targets from parasite screening
Chemotype and related series
New Biological Target
Molecules
Multiple diverse series
ATP4 Na channel KAE609 SJ733 GSK030 PA92
Imidazolopiperazine CARL KAF156
Triazolopyrimidine DHODH DSM265 (DSM421)
Aminopyridine PI4K MMV048 (UCT943)
Quinoline eEF2 DDD498
Triaminopyrimidine V-type H+ ATPase AZ412
Target Identification Consortium 50 compounds from Malaria Box 10-15 new targets Collection of lsquoirresistable scaffoldsrsquo
New Chemotypes by calculation
14
Sequence alignments Homology modelsdocking
Prioritization of new chemistry Validating models to drive
compound design
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Standard Phase II data Response in patients for first 36h
log10PRR(48h) P falciparum 276 -362 log10PRR(48h) P vivax 392-480
16
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
20000
-1 4 9 14 19 24 29
200 mg
400 mg
800 mg
1200 mg
Time h
pa
rasite
s m
l
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
-1 4 9 14 19 24 29
200 mg
400 mg
800 mg
1200 mg
P falciparum P vivax
pa
rasite
s m
l
Time h
Measuring the MIC clinically
17
1011 _
109 _
107_
105_
103_
101_
0 2 4 6 8 10 days
microscopic
limit
PCR limit
Tota
l num
ber
of para
sites
[Concentration] gt MIC
[Concentration] gt MIC
[Concentration] gt MIC
119875119905 = 119875119905
0
119866 minus 1198630 119862119905119867(119862119905
119867 + 11986811986250119867 119889119905
Early data in CHMI models saves time and money
18
Thai Patients (100 mg) Australian Volunteers (100-500mg)
1 month per cohort 1 centre All year round
6 months 4 centres seasonal
19
Human volunteer challenge ndash early readout that the drug works
150 mg DSM265 predicts Human Effective Dose as
400 mg
Day
1 2 3 4 5 0
106
102
104
103
105
S1056 MQ1 S1057 Redo S1058 S1059 S1060 S1064 S1065 S1068 Redo Average DSM S1070 MQ2
Para
site
sm
L
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Candidate selection
Pre- clinical
Transition to human
Phase I
Phase III
Phase IIa
End of Phase IIa
Phase IIb
Candidate Profiling
DDI Phase I
Initiate Phase III
New Chemical
Entity
SRA filing
Discovery and
Candidate Profiling
bull in vitro and in vivo
activity
bull DMPK
bull Solid state
characterization
bull SaltForm screen Phase IIb (adult and
pediatric pts)
bull Safety tolerability
bull Dose finding
bull Contribution of each
agent to the efficacy of
the combination (FDA
rule)
bull Efficacy (ACPR Day 28
and 42)
Discovery
Phase I (hv) and Phase
IIa (adult pts)
bull Single agent
- Safety
- PK
- Parasite clearance and
time to recrudescence
(up to Day 28)
bull Combination
- Safety
- Drug-Drug interactions
- PKPD modeling
Development for combination medicine
21
Preclinical
formulation
Phase III (adult and
pediatric pts)
bull Safety tolerabiliyt
bull Confirm efficacy of
fixed dose
combination (ACPR
Day 28 42 and 63)
Single agent
Combination (with Pharma Partner)
Phase I and Phase IIa
formulation
Phase IIb loose
combination or dose
scalable formulation
Phase III FDC market
formulation
Preclinical
bull GLP Tox
bull DMPK
bull Pre-formulation
studies
Next steps find the right partner
22
WHO guidance differentiated partner to protect against resistance
bull trusted friend or beautiful stranger
bull Can you afford to wait for the next best thing
Differentiated partner protects against resistance trusted friend or beautiful stranger can you afford to wait for the next best thing
Find the right
partner
httpsplusmathsorgcontentkissing-frog-mathematicians-guide-mating
Partner selection Matrix
23
Factor High Score (5) Low Score (1)
TPP - SERCap TCP1 2 and 3 Insufficient TCP1 amp 2
Safety Different organ tox amp manageable Same organ tox + SAEs
Dev Stage Both drugs approved Both preclinical stage
PK- time gt MPC Complete overlap gt MPC for gt 2wk Very short acting + very long acting
Total Dose (mg) lt150mg gt1200mg
BCS -Formulation No challenges Two drugs with bad formulation
Prophylaxis-Liver Stage Both drugs 3-4wks gt MPC Neither has gt1 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 Challon MD PhD
0
5
10
15
20
25
30
35
40
Mefloq Pyronaridine PQP KAE609 FQ DSM265 KAF156 MMV048
Partner selection matrix
24
Newer Newest
Two new combination phase II studies are ongoing
Options for clinical development
Phase IIb One day ndash three days Adults and children
Dose range to satisfy FDA combination rule
2017-18
Single Dose Phase III program
Confirm safety 2019-20
Single dose cohort safe
and gt95 efficacy
Multiple dose Phase III program
Confirm safety 2019-20
Three day cohort safe
and gt95 efficacy
Launch single dose cure
2021
Launch multiple dose
cure 2021
Phase III with three drug
combination 2021- 2
Drug interaction studies with third partner (at risk)
Eliminating the last parasite
Are medicines safe and well tolerated enough to use in subjects with
bull Repeated infection
bull asymptomatic infection
bull undiagnosed early pregnancies
bull in HIV patients (co-medication immunosuppresed)
bull malnutrition
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
A glass half full ndash How we are doing
Blood stage killers fast and long acting
610
Chemoprevention liver schizonticides
510
Transmission blocking safely sparing primaquine
410
Relapse Prevention 810
A glass half full ndash How we are doing
Blood stage killers fast and long acting safe and well tolerated for asymptomatics
310
Chemoprevention liver schizonticides once per month once per season
2510
Transmission blocking safely sparing primaquine
410
Relapse Prevention in G6PD- individuals
010
If you want to go fast go alone If you want to go far go together
Our partnerships are our greatest strength
32
Drugs for treatment and chemoprevention of malaria
Tim Wells Chief Scientific Officer MMV
Products with impact
Molecule
Lumefantrine 4 x 480 mg 2000 mg over 3 days
900 960
Artemether 4 x 80 mg 455
Ferroquine 3 x 200 mg 794
KAF156 1 x 800 mg 67
DSM265 1 x 400 mg 89
PCR corrected
Ideal Product has several activities
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 12187 (2013)
bull Clears blood stages rapidly
bull Long acting
bull Blocks transmission
bull Kills dormant forms
bull Active against all current and emerging resistance
bull Safe enough to give to all
Malaria Drug Resistance
bull Artemisinin resistance in the Mekong slower rate of killing parasites
bull Puts pressure on partner drugs multidrug resistance
4 Noedl H et al (2008) N Engl J Med 359 2619-20 Dondorp AM et al (2009) N Engl J Med 361455-67 Ariey F et
al Nature 2014 50550-5 Straimer Jet al Science 2015 347428-31
Thailand
t12 = 4h
Cambodia
t12 = 6h
2009
Focus on simplifying treatment or fighting resistance
Dis
tric
ts w
he
re
AC
Ts h
ave
fai
led
One Dose Split Dose
One Dose Split Dose
Dis
tric
ts w
he
re A
CTs
st
ill e
ffe
ctiv
e
Back-up therapy where ACTs fail
Some compliance benefit vs ACTs
Cost of goods benefit vs ACTs
Limited interest to replace ACTs where they are still active
No compliance benefit vs ACTs
Cost of goods benefit vs ACTs
High compliance Low cost of goods
High compliance Directly observed therapy Low cost of goods Need to show activity in
artemisinin resistant malaria
6
Balancing Efficacy and Safety
Time
Drug
concentration
Minimum inhibitory
concentration
Safety threshold
Increasing the drug dose
increases the chance of
side effects
1
Ideally the compound needs to be
active (above the minimum
threshold) for 28 days or more
IV Artesunate Univ Tuumlbingen
OZ439 MonashUNMCSTI
MK4815 (Merck)
2008
Translational Product development Access
3 projects Novartis
Preclinical Patient
confirmatory Post approval
Human volunteers
Patient exploratory
Regulatory review
2 projects GSK
5 projects BroadGenzyme
Immucillins Albert Einstein
Quinolones USF
4 projects Other screenings
3 projects Natural products
Research Lead
optimization Lead
generation
Heterocyclic Hit to Lead TDRPharmacopeia
DHFR BIOTECMonash
LSHTM
4 projects GSK
DHODH UTSWUWMonash
Aminoindoles BroadGenzyme
2 projects Novartis
Ozaonides MonashUNMCSTI
1
Artemether- lumefantrine Dispersible Novartis
Isoquine GSK
Pyronaridine-Artesunate Shin Poong
Tafenoquine GSK
DHA-Piperaquine Sigma-Tau
2 compounds GSK Pyridones
Artemisone UHKST
(+)-Meflonquine Treague
2 compounds Novartis
31 March 2016
Whole cell St JudeRutgersUSF
Translational Product development Access
Miniportfolio Novartis
SJ733 St JudeEisai
MMV048 UCT
Rectal Artesunate CiplaStridesWHO-TDR
Preclinical Patient
confirmatory Post approval Human
volunteers
Patient exploratory
Regulatory review
1 project Novartis
P218 (BIOTEC Thailand)
DSM265 UTSWUW Monash
Tafenoquine GSK
Miniportfolio GSK
2 projects GSK
Miniportfolio Sanofi
Orthologue Leads Sanofi
Heterocycles Univ Campinas
Tetraoxanes LSTMUniv Liverpool
DHODH UTSWUWMonash
Heterocycles Takeda
Screening Merck Serono
Pathogen Box MMV
Other projects 24 projects
Heterocycles Eisai
PA92 (DrexelUWGNF)
MMV253 (AstraZeneca)
OZ439FQ Sanofi
KAE609
Novartis
KAF156 Novartis
Artesunate for injection Guilin
Dihydroartemisinin- piperaquine Sigma-Tau
Pyronaridine- artesunate Shin Poong Univ of Iowa
Artesunate- amodiaquine Sanofi DNDi
Artesunate- mefloquine
CiplaDNDi Farmanguinhos
GSK030 GSK
DSM421
(UTSWUW Monash)
Pyronaridine- artesunate Paediatric Shin Poong Univ of Iowa
Sulfadoxine - pyrimethamine + amodiaquine Guilin
Dihydroartemisinin piperaquine Paediatric Sigma-Tau
Research Lead
optimization Lead
generation
3
1
2
4
5
6
DDD498 Merck Serono (Dundee)
Heterocycles Daiichi-Sankyo
Diversity oriented Synthesis BroadEisai
GSK692 GSK
AN13762 Anacor
Artemether- lumefantrine Dispersible Novartis
Pantothenamides TropIQRUMC Pansynt
Heterocycles UCT
Heterocycles Celgene
Open Source Drug Discovery Univ Sydney
4
3
2016
16 new candidates 2009-2016
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Building on an existing template
OZ03 OZ277 RBx11160
Reduce logP Improve solubility
OZ439
Decrease interaction with ferrous iron (single electron)
Vennerstrom JL et al Nature 2004430(7002)900ndash4 Charman SA et al PNAS 2011108(11)4400ndash5
Less potent on embryos and on granulocytes Active vs artesunate resistance
1
Molecular Design DHODH
DSM1 EC50 3D7 79 nM No oral efficacy
DSM191 EC50 3D7 220 nM ED90 Pf SCID 57 mgkg
DSM265 EC50 3D7 8 nM ED90 Pf SCID 81 mgkg
Coteron JM et al J Med Chem 201154(15)5540ndash61
bull Phase IIa completed December 2015
2
Optimising phenotypic hits 3
New targets from parasite screening
Chemotype and related series
New Biological Target
Molecules
Multiple diverse series
ATP4 Na channel KAE609 SJ733 GSK030 PA92
Imidazolopiperazine CARL KAF156
Triazolopyrimidine DHODH DSM265 (DSM421)
Aminopyridine PI4K MMV048 (UCT943)
Quinoline eEF2 DDD498
Triaminopyrimidine V-type H+ ATPase AZ412
Target Identification Consortium 50 compounds from Malaria Box 10-15 new targets Collection of lsquoirresistable scaffoldsrsquo
New Chemotypes by calculation
14
Sequence alignments Homology modelsdocking
Prioritization of new chemistry Validating models to drive
compound design
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Standard Phase II data Response in patients for first 36h
log10PRR(48h) P falciparum 276 -362 log10PRR(48h) P vivax 392-480
16
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
20000
-1 4 9 14 19 24 29
200 mg
400 mg
800 mg
1200 mg
Time h
pa
rasite
s m
l
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
-1 4 9 14 19 24 29
200 mg
400 mg
800 mg
1200 mg
P falciparum P vivax
pa
rasite
s m
l
Time h
Measuring the MIC clinically
17
1011 _
109 _
107_
105_
103_
101_
0 2 4 6 8 10 days
microscopic
limit
PCR limit
Tota
l num
ber
of para
sites
[Concentration] gt MIC
[Concentration] gt MIC
[Concentration] gt MIC
119875119905 = 119875119905
0
119866 minus 1198630 119862119905119867(119862119905
119867 + 11986811986250119867 119889119905
Early data in CHMI models saves time and money
18
Thai Patients (100 mg) Australian Volunteers (100-500mg)
1 month per cohort 1 centre All year round
6 months 4 centres seasonal
19
Human volunteer challenge ndash early readout that the drug works
150 mg DSM265 predicts Human Effective Dose as
400 mg
Day
1 2 3 4 5 0
106
102
104
103
105
S1056 MQ1 S1057 Redo S1058 S1059 S1060 S1064 S1065 S1068 Redo Average DSM S1070 MQ2
Para
site
sm
L
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Candidate selection
Pre- clinical
Transition to human
Phase I
Phase III
Phase IIa
End of Phase IIa
Phase IIb
Candidate Profiling
DDI Phase I
Initiate Phase III
New Chemical
Entity
SRA filing
Discovery and
Candidate Profiling
bull in vitro and in vivo
activity
bull DMPK
bull Solid state
characterization
bull SaltForm screen Phase IIb (adult and
pediatric pts)
bull Safety tolerability
bull Dose finding
bull Contribution of each
agent to the efficacy of
the combination (FDA
rule)
bull Efficacy (ACPR Day 28
and 42)
Discovery
Phase I (hv) and Phase
IIa (adult pts)
bull Single agent
- Safety
- PK
- Parasite clearance and
time to recrudescence
(up to Day 28)
bull Combination
- Safety
- Drug-Drug interactions
- PKPD modeling
Development for combination medicine
21
Preclinical
formulation
Phase III (adult and
pediatric pts)
bull Safety tolerabiliyt
bull Confirm efficacy of
fixed dose
combination (ACPR
Day 28 42 and 63)
Single agent
Combination (with Pharma Partner)
Phase I and Phase IIa
formulation
Phase IIb loose
combination or dose
scalable formulation
Phase III FDC market
formulation
Preclinical
bull GLP Tox
bull DMPK
bull Pre-formulation
studies
Next steps find the right partner
22
WHO guidance differentiated partner to protect against resistance
bull trusted friend or beautiful stranger
bull Can you afford to wait for the next best thing
Differentiated partner protects against resistance trusted friend or beautiful stranger can you afford to wait for the next best thing
Find the right
partner
httpsplusmathsorgcontentkissing-frog-mathematicians-guide-mating
Partner selection Matrix
23
Factor High Score (5) Low Score (1)
TPP - SERCap TCP1 2 and 3 Insufficient TCP1 amp 2
Safety Different organ tox amp manageable Same organ tox + SAEs
Dev Stage Both drugs approved Both preclinical stage
PK- time gt MPC Complete overlap gt MPC for gt 2wk Very short acting + very long acting
Total Dose (mg) lt150mg gt1200mg
BCS -Formulation No challenges Two drugs with bad formulation
Prophylaxis-Liver Stage Both drugs 3-4wks gt MPC Neither has gt1 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 Challon MD PhD
0
5
10
15
20
25
30
35
40
Mefloq Pyronaridine PQP KAE609 FQ DSM265 KAF156 MMV048
Partner selection matrix
24
Newer Newest
Two new combination phase II studies are ongoing
Options for clinical development
Phase IIb One day ndash three days Adults and children
Dose range to satisfy FDA combination rule
2017-18
Single Dose Phase III program
Confirm safety 2019-20
Single dose cohort safe
and gt95 efficacy
Multiple dose Phase III program
Confirm safety 2019-20
Three day cohort safe
and gt95 efficacy
Launch single dose cure
2021
Launch multiple dose
cure 2021
Phase III with three drug
combination 2021- 2
Drug interaction studies with third partner (at risk)
Eliminating the last parasite
Are medicines safe and well tolerated enough to use in subjects with
bull Repeated infection
bull asymptomatic infection
bull undiagnosed early pregnancies
bull in HIV patients (co-medication immunosuppresed)
bull malnutrition
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
A glass half full ndash How we are doing
Blood stage killers fast and long acting
610
Chemoprevention liver schizonticides
510
Transmission blocking safely sparing primaquine
410
Relapse Prevention 810
A glass half full ndash How we are doing
Blood stage killers fast and long acting safe and well tolerated for asymptomatics
310
Chemoprevention liver schizonticides once per month once per season
2510
Transmission blocking safely sparing primaquine
410
Relapse Prevention in G6PD- individuals
010
If you want to go fast go alone If you want to go far go together
Our partnerships are our greatest strength
32
Drugs for treatment and chemoprevention of malaria
Tim Wells Chief Scientific Officer MMV
Products with impact
Molecule
Lumefantrine 4 x 480 mg 2000 mg over 3 days
900 960
Artemether 4 x 80 mg 455
Ferroquine 3 x 200 mg 794
KAF156 1 x 800 mg 67
DSM265 1 x 400 mg 89
PCR corrected
Malaria Drug Resistance
bull Artemisinin resistance in the Mekong slower rate of killing parasites
bull Puts pressure on partner drugs multidrug resistance
4 Noedl H et al (2008) N Engl J Med 359 2619-20 Dondorp AM et al (2009) N Engl J Med 361455-67 Ariey F et
al Nature 2014 50550-5 Straimer Jet al Science 2015 347428-31
Thailand
t12 = 4h
Cambodia
t12 = 6h
2009
Focus on simplifying treatment or fighting resistance
Dis
tric
ts w
he
re
AC
Ts h
ave
fai
led
One Dose Split Dose
One Dose Split Dose
Dis
tric
ts w
he
re A
CTs
st
ill e
ffe
ctiv
e
Back-up therapy where ACTs fail
Some compliance benefit vs ACTs
Cost of goods benefit vs ACTs
Limited interest to replace ACTs where they are still active
No compliance benefit vs ACTs
Cost of goods benefit vs ACTs
High compliance Low cost of goods
High compliance Directly observed therapy Low cost of goods Need to show activity in
artemisinin resistant malaria
6
Balancing Efficacy and Safety
Time
Drug
concentration
Minimum inhibitory
concentration
Safety threshold
Increasing the drug dose
increases the chance of
side effects
1
Ideally the compound needs to be
active (above the minimum
threshold) for 28 days or more
IV Artesunate Univ Tuumlbingen
OZ439 MonashUNMCSTI
MK4815 (Merck)
2008
Translational Product development Access
3 projects Novartis
Preclinical Patient
confirmatory Post approval
Human volunteers
Patient exploratory
Regulatory review
2 projects GSK
5 projects BroadGenzyme
Immucillins Albert Einstein
Quinolones USF
4 projects Other screenings
3 projects Natural products
Research Lead
optimization Lead
generation
Heterocyclic Hit to Lead TDRPharmacopeia
DHFR BIOTECMonash
LSHTM
4 projects GSK
DHODH UTSWUWMonash
Aminoindoles BroadGenzyme
2 projects Novartis
Ozaonides MonashUNMCSTI
1
Artemether- lumefantrine Dispersible Novartis
Isoquine GSK
Pyronaridine-Artesunate Shin Poong
Tafenoquine GSK
DHA-Piperaquine Sigma-Tau
2 compounds GSK Pyridones
Artemisone UHKST
(+)-Meflonquine Treague
2 compounds Novartis
31 March 2016
Whole cell St JudeRutgersUSF
Translational Product development Access
Miniportfolio Novartis
SJ733 St JudeEisai
MMV048 UCT
Rectal Artesunate CiplaStridesWHO-TDR
Preclinical Patient
confirmatory Post approval Human
volunteers
Patient exploratory
Regulatory review
1 project Novartis
P218 (BIOTEC Thailand)
DSM265 UTSWUW Monash
Tafenoquine GSK
Miniportfolio GSK
2 projects GSK
Miniportfolio Sanofi
Orthologue Leads Sanofi
Heterocycles Univ Campinas
Tetraoxanes LSTMUniv Liverpool
DHODH UTSWUWMonash
Heterocycles Takeda
Screening Merck Serono
Pathogen Box MMV
Other projects 24 projects
Heterocycles Eisai
PA92 (DrexelUWGNF)
MMV253 (AstraZeneca)
OZ439FQ Sanofi
KAE609
Novartis
KAF156 Novartis
Artesunate for injection Guilin
Dihydroartemisinin- piperaquine Sigma-Tau
Pyronaridine- artesunate Shin Poong Univ of Iowa
Artesunate- amodiaquine Sanofi DNDi
Artesunate- mefloquine
CiplaDNDi Farmanguinhos
GSK030 GSK
DSM421
(UTSWUW Monash)
Pyronaridine- artesunate Paediatric Shin Poong Univ of Iowa
Sulfadoxine - pyrimethamine + amodiaquine Guilin
Dihydroartemisinin piperaquine Paediatric Sigma-Tau
Research Lead
optimization Lead
generation
3
1
2
4
5
6
DDD498 Merck Serono (Dundee)
Heterocycles Daiichi-Sankyo
Diversity oriented Synthesis BroadEisai
GSK692 GSK
AN13762 Anacor
Artemether- lumefantrine Dispersible Novartis
Pantothenamides TropIQRUMC Pansynt
Heterocycles UCT
Heterocycles Celgene
Open Source Drug Discovery Univ Sydney
4
3
2016
16 new candidates 2009-2016
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Building on an existing template
OZ03 OZ277 RBx11160
Reduce logP Improve solubility
OZ439
Decrease interaction with ferrous iron (single electron)
Vennerstrom JL et al Nature 2004430(7002)900ndash4 Charman SA et al PNAS 2011108(11)4400ndash5
Less potent on embryos and on granulocytes Active vs artesunate resistance
1
Molecular Design DHODH
DSM1 EC50 3D7 79 nM No oral efficacy
DSM191 EC50 3D7 220 nM ED90 Pf SCID 57 mgkg
DSM265 EC50 3D7 8 nM ED90 Pf SCID 81 mgkg
Coteron JM et al J Med Chem 201154(15)5540ndash61
bull Phase IIa completed December 2015
2
Optimising phenotypic hits 3
New targets from parasite screening
Chemotype and related series
New Biological Target
Molecules
Multiple diverse series
ATP4 Na channel KAE609 SJ733 GSK030 PA92
Imidazolopiperazine CARL KAF156
Triazolopyrimidine DHODH DSM265 (DSM421)
Aminopyridine PI4K MMV048 (UCT943)
Quinoline eEF2 DDD498
Triaminopyrimidine V-type H+ ATPase AZ412
Target Identification Consortium 50 compounds from Malaria Box 10-15 new targets Collection of lsquoirresistable scaffoldsrsquo
New Chemotypes by calculation
14
Sequence alignments Homology modelsdocking
Prioritization of new chemistry Validating models to drive
compound design
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Standard Phase II data Response in patients for first 36h
log10PRR(48h) P falciparum 276 -362 log10PRR(48h) P vivax 392-480
16
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
20000
-1 4 9 14 19 24 29
200 mg
400 mg
800 mg
1200 mg
Time h
pa
rasite
s m
l
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
-1 4 9 14 19 24 29
200 mg
400 mg
800 mg
1200 mg
P falciparum P vivax
pa
rasite
s m
l
Time h
Measuring the MIC clinically
17
1011 _
109 _
107_
105_
103_
101_
0 2 4 6 8 10 days
microscopic
limit
PCR limit
Tota
l num
ber
of para
sites
[Concentration] gt MIC
[Concentration] gt MIC
[Concentration] gt MIC
119875119905 = 119875119905
0
119866 minus 1198630 119862119905119867(119862119905
119867 + 11986811986250119867 119889119905
Early data in CHMI models saves time and money
18
Thai Patients (100 mg) Australian Volunteers (100-500mg)
1 month per cohort 1 centre All year round
6 months 4 centres seasonal
19
Human volunteer challenge ndash early readout that the drug works
150 mg DSM265 predicts Human Effective Dose as
400 mg
Day
1 2 3 4 5 0
106
102
104
103
105
S1056 MQ1 S1057 Redo S1058 S1059 S1060 S1064 S1065 S1068 Redo Average DSM S1070 MQ2
Para
site
sm
L
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Candidate selection
Pre- clinical
Transition to human
Phase I
Phase III
Phase IIa
End of Phase IIa
Phase IIb
Candidate Profiling
DDI Phase I
Initiate Phase III
New Chemical
Entity
SRA filing
Discovery and
Candidate Profiling
bull in vitro and in vivo
activity
bull DMPK
bull Solid state
characterization
bull SaltForm screen Phase IIb (adult and
pediatric pts)
bull Safety tolerability
bull Dose finding
bull Contribution of each
agent to the efficacy of
the combination (FDA
rule)
bull Efficacy (ACPR Day 28
and 42)
Discovery
Phase I (hv) and Phase
IIa (adult pts)
bull Single agent
- Safety
- PK
- Parasite clearance and
time to recrudescence
(up to Day 28)
bull Combination
- Safety
- Drug-Drug interactions
- PKPD modeling
Development for combination medicine
21
Preclinical
formulation
Phase III (adult and
pediatric pts)
bull Safety tolerabiliyt
bull Confirm efficacy of
fixed dose
combination (ACPR
Day 28 42 and 63)
Single agent
Combination (with Pharma Partner)
Phase I and Phase IIa
formulation
Phase IIb loose
combination or dose
scalable formulation
Phase III FDC market
formulation
Preclinical
bull GLP Tox
bull DMPK
bull Pre-formulation
studies
Next steps find the right partner
22
WHO guidance differentiated partner to protect against resistance
bull trusted friend or beautiful stranger
bull Can you afford to wait for the next best thing
Differentiated partner protects against resistance trusted friend or beautiful stranger can you afford to wait for the next best thing
Find the right
partner
httpsplusmathsorgcontentkissing-frog-mathematicians-guide-mating
Partner selection Matrix
23
Factor High Score (5) Low Score (1)
TPP - SERCap TCP1 2 and 3 Insufficient TCP1 amp 2
Safety Different organ tox amp manageable Same organ tox + SAEs
Dev Stage Both drugs approved Both preclinical stage
PK- time gt MPC Complete overlap gt MPC for gt 2wk Very short acting + very long acting
Total Dose (mg) lt150mg gt1200mg
BCS -Formulation No challenges Two drugs with bad formulation
Prophylaxis-Liver Stage Both drugs 3-4wks gt MPC Neither has gt1 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 Challon MD PhD
0
5
10
15
20
25
30
35
40
Mefloq Pyronaridine PQP KAE609 FQ DSM265 KAF156 MMV048
Partner selection matrix
24
Newer Newest
Two new combination phase II studies are ongoing
Options for clinical development
Phase IIb One day ndash three days Adults and children
Dose range to satisfy FDA combination rule
2017-18
Single Dose Phase III program
Confirm safety 2019-20
Single dose cohort safe
and gt95 efficacy
Multiple dose Phase III program
Confirm safety 2019-20
Three day cohort safe
and gt95 efficacy
Launch single dose cure
2021
Launch multiple dose
cure 2021
Phase III with three drug
combination 2021- 2
Drug interaction studies with third partner (at risk)
Eliminating the last parasite
Are medicines safe and well tolerated enough to use in subjects with
bull Repeated infection
bull asymptomatic infection
bull undiagnosed early pregnancies
bull in HIV patients (co-medication immunosuppresed)
bull malnutrition
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
A glass half full ndash How we are doing
Blood stage killers fast and long acting
610
Chemoprevention liver schizonticides
510
Transmission blocking safely sparing primaquine
410
Relapse Prevention 810
A glass half full ndash How we are doing
Blood stage killers fast and long acting safe and well tolerated for asymptomatics
310
Chemoprevention liver schizonticides once per month once per season
2510
Transmission blocking safely sparing primaquine
410
Relapse Prevention in G6PD- individuals
010
If you want to go fast go alone If you want to go far go together
Our partnerships are our greatest strength
32
Drugs for treatment and chemoprevention of malaria
Tim Wells Chief Scientific Officer MMV
Products with impact
Molecule
Lumefantrine 4 x 480 mg 2000 mg over 3 days
900 960
Artemether 4 x 80 mg 455
Ferroquine 3 x 200 mg 794
KAF156 1 x 800 mg 67
DSM265 1 x 400 mg 89
PCR corrected
Focus on simplifying treatment or fighting resistance
Dis
tric
ts w
he
re
AC
Ts h
ave
fai
led
One Dose Split Dose
One Dose Split Dose
Dis
tric
ts w
he
re A
CTs
st
ill e
ffe
ctiv
e
Back-up therapy where ACTs fail
Some compliance benefit vs ACTs
Cost of goods benefit vs ACTs
Limited interest to replace ACTs where they are still active
No compliance benefit vs ACTs
Cost of goods benefit vs ACTs
High compliance Low cost of goods
High compliance Directly observed therapy Low cost of goods Need to show activity in
artemisinin resistant malaria
6
Balancing Efficacy and Safety
Time
Drug
concentration
Minimum inhibitory
concentration
Safety threshold
Increasing the drug dose
increases the chance of
side effects
1
Ideally the compound needs to be
active (above the minimum
threshold) for 28 days or more
IV Artesunate Univ Tuumlbingen
OZ439 MonashUNMCSTI
MK4815 (Merck)
2008
Translational Product development Access
3 projects Novartis
Preclinical Patient
confirmatory Post approval
Human volunteers
Patient exploratory
Regulatory review
2 projects GSK
5 projects BroadGenzyme
Immucillins Albert Einstein
Quinolones USF
4 projects Other screenings
3 projects Natural products
Research Lead
optimization Lead
generation
Heterocyclic Hit to Lead TDRPharmacopeia
DHFR BIOTECMonash
LSHTM
4 projects GSK
DHODH UTSWUWMonash
Aminoindoles BroadGenzyme
2 projects Novartis
Ozaonides MonashUNMCSTI
1
Artemether- lumefantrine Dispersible Novartis
Isoquine GSK
Pyronaridine-Artesunate Shin Poong
Tafenoquine GSK
DHA-Piperaquine Sigma-Tau
2 compounds GSK Pyridones
Artemisone UHKST
(+)-Meflonquine Treague
2 compounds Novartis
31 March 2016
Whole cell St JudeRutgersUSF
Translational Product development Access
Miniportfolio Novartis
SJ733 St JudeEisai
MMV048 UCT
Rectal Artesunate CiplaStridesWHO-TDR
Preclinical Patient
confirmatory Post approval Human
volunteers
Patient exploratory
Regulatory review
1 project Novartis
P218 (BIOTEC Thailand)
DSM265 UTSWUW Monash
Tafenoquine GSK
Miniportfolio GSK
2 projects GSK
Miniportfolio Sanofi
Orthologue Leads Sanofi
Heterocycles Univ Campinas
Tetraoxanes LSTMUniv Liverpool
DHODH UTSWUWMonash
Heterocycles Takeda
Screening Merck Serono
Pathogen Box MMV
Other projects 24 projects
Heterocycles Eisai
PA92 (DrexelUWGNF)
MMV253 (AstraZeneca)
OZ439FQ Sanofi
KAE609
Novartis
KAF156 Novartis
Artesunate for injection Guilin
Dihydroartemisinin- piperaquine Sigma-Tau
Pyronaridine- artesunate Shin Poong Univ of Iowa
Artesunate- amodiaquine Sanofi DNDi
Artesunate- mefloquine
CiplaDNDi Farmanguinhos
GSK030 GSK
DSM421
(UTSWUW Monash)
Pyronaridine- artesunate Paediatric Shin Poong Univ of Iowa
Sulfadoxine - pyrimethamine + amodiaquine Guilin
Dihydroartemisinin piperaquine Paediatric Sigma-Tau
Research Lead
optimization Lead
generation
3
1
2
4
5
6
DDD498 Merck Serono (Dundee)
Heterocycles Daiichi-Sankyo
Diversity oriented Synthesis BroadEisai
GSK692 GSK
AN13762 Anacor
Artemether- lumefantrine Dispersible Novartis
Pantothenamides TropIQRUMC Pansynt
Heterocycles UCT
Heterocycles Celgene
Open Source Drug Discovery Univ Sydney
4
3
2016
16 new candidates 2009-2016
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Building on an existing template
OZ03 OZ277 RBx11160
Reduce logP Improve solubility
OZ439
Decrease interaction with ferrous iron (single electron)
Vennerstrom JL et al Nature 2004430(7002)900ndash4 Charman SA et al PNAS 2011108(11)4400ndash5
Less potent on embryos and on granulocytes Active vs artesunate resistance
1
Molecular Design DHODH
DSM1 EC50 3D7 79 nM No oral efficacy
DSM191 EC50 3D7 220 nM ED90 Pf SCID 57 mgkg
DSM265 EC50 3D7 8 nM ED90 Pf SCID 81 mgkg
Coteron JM et al J Med Chem 201154(15)5540ndash61
bull Phase IIa completed December 2015
2
Optimising phenotypic hits 3
New targets from parasite screening
Chemotype and related series
New Biological Target
Molecules
Multiple diverse series
ATP4 Na channel KAE609 SJ733 GSK030 PA92
Imidazolopiperazine CARL KAF156
Triazolopyrimidine DHODH DSM265 (DSM421)
Aminopyridine PI4K MMV048 (UCT943)
Quinoline eEF2 DDD498
Triaminopyrimidine V-type H+ ATPase AZ412
Target Identification Consortium 50 compounds from Malaria Box 10-15 new targets Collection of lsquoirresistable scaffoldsrsquo
New Chemotypes by calculation
14
Sequence alignments Homology modelsdocking
Prioritization of new chemistry Validating models to drive
compound design
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Standard Phase II data Response in patients for first 36h
log10PRR(48h) P falciparum 276 -362 log10PRR(48h) P vivax 392-480
16
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
20000
-1 4 9 14 19 24 29
200 mg
400 mg
800 mg
1200 mg
Time h
pa
rasite
s m
l
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
-1 4 9 14 19 24 29
200 mg
400 mg
800 mg
1200 mg
P falciparum P vivax
pa
rasite
s m
l
Time h
Measuring the MIC clinically
17
1011 _
109 _
107_
105_
103_
101_
0 2 4 6 8 10 days
microscopic
limit
PCR limit
Tota
l num
ber
of para
sites
[Concentration] gt MIC
[Concentration] gt MIC
[Concentration] gt MIC
119875119905 = 119875119905
0
119866 minus 1198630 119862119905119867(119862119905
119867 + 11986811986250119867 119889119905
Early data in CHMI models saves time and money
18
Thai Patients (100 mg) Australian Volunteers (100-500mg)
1 month per cohort 1 centre All year round
6 months 4 centres seasonal
19
Human volunteer challenge ndash early readout that the drug works
150 mg DSM265 predicts Human Effective Dose as
400 mg
Day
1 2 3 4 5 0
106
102
104
103
105
S1056 MQ1 S1057 Redo S1058 S1059 S1060 S1064 S1065 S1068 Redo Average DSM S1070 MQ2
Para
site
sm
L
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Candidate selection
Pre- clinical
Transition to human
Phase I
Phase III
Phase IIa
End of Phase IIa
Phase IIb
Candidate Profiling
DDI Phase I
Initiate Phase III
New Chemical
Entity
SRA filing
Discovery and
Candidate Profiling
bull in vitro and in vivo
activity
bull DMPK
bull Solid state
characterization
bull SaltForm screen Phase IIb (adult and
pediatric pts)
bull Safety tolerability
bull Dose finding
bull Contribution of each
agent to the efficacy of
the combination (FDA
rule)
bull Efficacy (ACPR Day 28
and 42)
Discovery
Phase I (hv) and Phase
IIa (adult pts)
bull Single agent
- Safety
- PK
- Parasite clearance and
time to recrudescence
(up to Day 28)
bull Combination
- Safety
- Drug-Drug interactions
- PKPD modeling
Development for combination medicine
21
Preclinical
formulation
Phase III (adult and
pediatric pts)
bull Safety tolerabiliyt
bull Confirm efficacy of
fixed dose
combination (ACPR
Day 28 42 and 63)
Single agent
Combination (with Pharma Partner)
Phase I and Phase IIa
formulation
Phase IIb loose
combination or dose
scalable formulation
Phase III FDC market
formulation
Preclinical
bull GLP Tox
bull DMPK
bull Pre-formulation
studies
Next steps find the right partner
22
WHO guidance differentiated partner to protect against resistance
bull trusted friend or beautiful stranger
bull Can you afford to wait for the next best thing
Differentiated partner protects against resistance trusted friend or beautiful stranger can you afford to wait for the next best thing
Find the right
partner
httpsplusmathsorgcontentkissing-frog-mathematicians-guide-mating
Partner selection Matrix
23
Factor High Score (5) Low Score (1)
TPP - SERCap TCP1 2 and 3 Insufficient TCP1 amp 2
Safety Different organ tox amp manageable Same organ tox + SAEs
Dev Stage Both drugs approved Both preclinical stage
PK- time gt MPC Complete overlap gt MPC for gt 2wk Very short acting + very long acting
Total Dose (mg) lt150mg gt1200mg
BCS -Formulation No challenges Two drugs with bad formulation
Prophylaxis-Liver Stage Both drugs 3-4wks gt MPC Neither has gt1 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 Challon MD PhD
0
5
10
15
20
25
30
35
40
Mefloq Pyronaridine PQP KAE609 FQ DSM265 KAF156 MMV048
Partner selection matrix
24
Newer Newest
Two new combination phase II studies are ongoing
Options for clinical development
Phase IIb One day ndash three days Adults and children
Dose range to satisfy FDA combination rule
2017-18
Single Dose Phase III program
Confirm safety 2019-20
Single dose cohort safe
and gt95 efficacy
Multiple dose Phase III program
Confirm safety 2019-20
Three day cohort safe
and gt95 efficacy
Launch single dose cure
2021
Launch multiple dose
cure 2021
Phase III with three drug
combination 2021- 2
Drug interaction studies with third partner (at risk)
Eliminating the last parasite
Are medicines safe and well tolerated enough to use in subjects with
bull Repeated infection
bull asymptomatic infection
bull undiagnosed early pregnancies
bull in HIV patients (co-medication immunosuppresed)
bull malnutrition
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
A glass half full ndash How we are doing
Blood stage killers fast and long acting
610
Chemoprevention liver schizonticides
510
Transmission blocking safely sparing primaquine
410
Relapse Prevention 810
A glass half full ndash How we are doing
Blood stage killers fast and long acting safe and well tolerated for asymptomatics
310
Chemoprevention liver schizonticides once per month once per season
2510
Transmission blocking safely sparing primaquine
410
Relapse Prevention in G6PD- individuals
010
If you want to go fast go alone If you want to go far go together
Our partnerships are our greatest strength
32
Drugs for treatment and chemoprevention of malaria
Tim Wells Chief Scientific Officer MMV
Products with impact
Molecule
Lumefantrine 4 x 480 mg 2000 mg over 3 days
900 960
Artemether 4 x 80 mg 455
Ferroquine 3 x 200 mg 794
KAF156 1 x 800 mg 67
DSM265 1 x 400 mg 89
PCR corrected
6
Balancing Efficacy and Safety
Time
Drug
concentration
Minimum inhibitory
concentration
Safety threshold
Increasing the drug dose
increases the chance of
side effects
1
Ideally the compound needs to be
active (above the minimum
threshold) for 28 days or more
IV Artesunate Univ Tuumlbingen
OZ439 MonashUNMCSTI
MK4815 (Merck)
2008
Translational Product development Access
3 projects Novartis
Preclinical Patient
confirmatory Post approval
Human volunteers
Patient exploratory
Regulatory review
2 projects GSK
5 projects BroadGenzyme
Immucillins Albert Einstein
Quinolones USF
4 projects Other screenings
3 projects Natural products
Research Lead
optimization Lead
generation
Heterocyclic Hit to Lead TDRPharmacopeia
DHFR BIOTECMonash
LSHTM
4 projects GSK
DHODH UTSWUWMonash
Aminoindoles BroadGenzyme
2 projects Novartis
Ozaonides MonashUNMCSTI
1
Artemether- lumefantrine Dispersible Novartis
Isoquine GSK
Pyronaridine-Artesunate Shin Poong
Tafenoquine GSK
DHA-Piperaquine Sigma-Tau
2 compounds GSK Pyridones
Artemisone UHKST
(+)-Meflonquine Treague
2 compounds Novartis
31 March 2016
Whole cell St JudeRutgersUSF
Translational Product development Access
Miniportfolio Novartis
SJ733 St JudeEisai
MMV048 UCT
Rectal Artesunate CiplaStridesWHO-TDR
Preclinical Patient
confirmatory Post approval Human
volunteers
Patient exploratory
Regulatory review
1 project Novartis
P218 (BIOTEC Thailand)
DSM265 UTSWUW Monash
Tafenoquine GSK
Miniportfolio GSK
2 projects GSK
Miniportfolio Sanofi
Orthologue Leads Sanofi
Heterocycles Univ Campinas
Tetraoxanes LSTMUniv Liverpool
DHODH UTSWUWMonash
Heterocycles Takeda
Screening Merck Serono
Pathogen Box MMV
Other projects 24 projects
Heterocycles Eisai
PA92 (DrexelUWGNF)
MMV253 (AstraZeneca)
OZ439FQ Sanofi
KAE609
Novartis
KAF156 Novartis
Artesunate for injection Guilin
Dihydroartemisinin- piperaquine Sigma-Tau
Pyronaridine- artesunate Shin Poong Univ of Iowa
Artesunate- amodiaquine Sanofi DNDi
Artesunate- mefloquine
CiplaDNDi Farmanguinhos
GSK030 GSK
DSM421
(UTSWUW Monash)
Pyronaridine- artesunate Paediatric Shin Poong Univ of Iowa
Sulfadoxine - pyrimethamine + amodiaquine Guilin
Dihydroartemisinin piperaquine Paediatric Sigma-Tau
Research Lead
optimization Lead
generation
3
1
2
4
5
6
DDD498 Merck Serono (Dundee)
Heterocycles Daiichi-Sankyo
Diversity oriented Synthesis BroadEisai
GSK692 GSK
AN13762 Anacor
Artemether- lumefantrine Dispersible Novartis
Pantothenamides TropIQRUMC Pansynt
Heterocycles UCT
Heterocycles Celgene
Open Source Drug Discovery Univ Sydney
4
3
2016
16 new candidates 2009-2016
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Building on an existing template
OZ03 OZ277 RBx11160
Reduce logP Improve solubility
OZ439
Decrease interaction with ferrous iron (single electron)
Vennerstrom JL et al Nature 2004430(7002)900ndash4 Charman SA et al PNAS 2011108(11)4400ndash5
Less potent on embryos and on granulocytes Active vs artesunate resistance
1
Molecular Design DHODH
DSM1 EC50 3D7 79 nM No oral efficacy
DSM191 EC50 3D7 220 nM ED90 Pf SCID 57 mgkg
DSM265 EC50 3D7 8 nM ED90 Pf SCID 81 mgkg
Coteron JM et al J Med Chem 201154(15)5540ndash61
bull Phase IIa completed December 2015
2
Optimising phenotypic hits 3
New targets from parasite screening
Chemotype and related series
New Biological Target
Molecules
Multiple diverse series
ATP4 Na channel KAE609 SJ733 GSK030 PA92
Imidazolopiperazine CARL KAF156
Triazolopyrimidine DHODH DSM265 (DSM421)
Aminopyridine PI4K MMV048 (UCT943)
Quinoline eEF2 DDD498
Triaminopyrimidine V-type H+ ATPase AZ412
Target Identification Consortium 50 compounds from Malaria Box 10-15 new targets Collection of lsquoirresistable scaffoldsrsquo
New Chemotypes by calculation
14
Sequence alignments Homology modelsdocking
Prioritization of new chemistry Validating models to drive
compound design
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Standard Phase II data Response in patients for first 36h
log10PRR(48h) P falciparum 276 -362 log10PRR(48h) P vivax 392-480
16
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
20000
-1 4 9 14 19 24 29
200 mg
400 mg
800 mg
1200 mg
Time h
pa
rasite
s m
l
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
-1 4 9 14 19 24 29
200 mg
400 mg
800 mg
1200 mg
P falciparum P vivax
pa
rasite
s m
l
Time h
Measuring the MIC clinically
17
1011 _
109 _
107_
105_
103_
101_
0 2 4 6 8 10 days
microscopic
limit
PCR limit
Tota
l num
ber
of para
sites
[Concentration] gt MIC
[Concentration] gt MIC
[Concentration] gt MIC
119875119905 = 119875119905
0
119866 minus 1198630 119862119905119867(119862119905
119867 + 11986811986250119867 119889119905
Early data in CHMI models saves time and money
18
Thai Patients (100 mg) Australian Volunteers (100-500mg)
1 month per cohort 1 centre All year round
6 months 4 centres seasonal
19
Human volunteer challenge ndash early readout that the drug works
150 mg DSM265 predicts Human Effective Dose as
400 mg
Day
1 2 3 4 5 0
106
102
104
103
105
S1056 MQ1 S1057 Redo S1058 S1059 S1060 S1064 S1065 S1068 Redo Average DSM S1070 MQ2
Para
site
sm
L
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Candidate selection
Pre- clinical
Transition to human
Phase I
Phase III
Phase IIa
End of Phase IIa
Phase IIb
Candidate Profiling
DDI Phase I
Initiate Phase III
New Chemical
Entity
SRA filing
Discovery and
Candidate Profiling
bull in vitro and in vivo
activity
bull DMPK
bull Solid state
characterization
bull SaltForm screen Phase IIb (adult and
pediatric pts)
bull Safety tolerability
bull Dose finding
bull Contribution of each
agent to the efficacy of
the combination (FDA
rule)
bull Efficacy (ACPR Day 28
and 42)
Discovery
Phase I (hv) and Phase
IIa (adult pts)
bull Single agent
- Safety
- PK
- Parasite clearance and
time to recrudescence
(up to Day 28)
bull Combination
- Safety
- Drug-Drug interactions
- PKPD modeling
Development for combination medicine
21
Preclinical
formulation
Phase III (adult and
pediatric pts)
bull Safety tolerabiliyt
bull Confirm efficacy of
fixed dose
combination (ACPR
Day 28 42 and 63)
Single agent
Combination (with Pharma Partner)
Phase I and Phase IIa
formulation
Phase IIb loose
combination or dose
scalable formulation
Phase III FDC market
formulation
Preclinical
bull GLP Tox
bull DMPK
bull Pre-formulation
studies
Next steps find the right partner
22
WHO guidance differentiated partner to protect against resistance
bull trusted friend or beautiful stranger
bull Can you afford to wait for the next best thing
Differentiated partner protects against resistance trusted friend or beautiful stranger can you afford to wait for the next best thing
Find the right
partner
httpsplusmathsorgcontentkissing-frog-mathematicians-guide-mating
Partner selection Matrix
23
Factor High Score (5) Low Score (1)
TPP - SERCap TCP1 2 and 3 Insufficient TCP1 amp 2
Safety Different organ tox amp manageable Same organ tox + SAEs
Dev Stage Both drugs approved Both preclinical stage
PK- time gt MPC Complete overlap gt MPC for gt 2wk Very short acting + very long acting
Total Dose (mg) lt150mg gt1200mg
BCS -Formulation No challenges Two drugs with bad formulation
Prophylaxis-Liver Stage Both drugs 3-4wks gt MPC Neither has gt1 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 Challon MD PhD
0
5
10
15
20
25
30
35
40
Mefloq Pyronaridine PQP KAE609 FQ DSM265 KAF156 MMV048
Partner selection matrix
24
Newer Newest
Two new combination phase II studies are ongoing
Options for clinical development
Phase IIb One day ndash three days Adults and children
Dose range to satisfy FDA combination rule
2017-18
Single Dose Phase III program
Confirm safety 2019-20
Single dose cohort safe
and gt95 efficacy
Multiple dose Phase III program
Confirm safety 2019-20
Three day cohort safe
and gt95 efficacy
Launch single dose cure
2021
Launch multiple dose
cure 2021
Phase III with three drug
combination 2021- 2
Drug interaction studies with third partner (at risk)
Eliminating the last parasite
Are medicines safe and well tolerated enough to use in subjects with
bull Repeated infection
bull asymptomatic infection
bull undiagnosed early pregnancies
bull in HIV patients (co-medication immunosuppresed)
bull malnutrition
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
A glass half full ndash How we are doing
Blood stage killers fast and long acting
610
Chemoprevention liver schizonticides
510
Transmission blocking safely sparing primaquine
410
Relapse Prevention 810
A glass half full ndash How we are doing
Blood stage killers fast and long acting safe and well tolerated for asymptomatics
310
Chemoprevention liver schizonticides once per month once per season
2510
Transmission blocking safely sparing primaquine
410
Relapse Prevention in G6PD- individuals
010
If you want to go fast go alone If you want to go far go together
Our partnerships are our greatest strength
32
Drugs for treatment and chemoprevention of malaria
Tim Wells Chief Scientific Officer MMV
Products with impact
Molecule
Lumefantrine 4 x 480 mg 2000 mg over 3 days
900 960
Artemether 4 x 80 mg 455
Ferroquine 3 x 200 mg 794
KAF156 1 x 800 mg 67
DSM265 1 x 400 mg 89
PCR corrected
IV Artesunate Univ Tuumlbingen
OZ439 MonashUNMCSTI
MK4815 (Merck)
2008
Translational Product development Access
3 projects Novartis
Preclinical Patient
confirmatory Post approval
Human volunteers
Patient exploratory
Regulatory review
2 projects GSK
5 projects BroadGenzyme
Immucillins Albert Einstein
Quinolones USF
4 projects Other screenings
3 projects Natural products
Research Lead
optimization Lead
generation
Heterocyclic Hit to Lead TDRPharmacopeia
DHFR BIOTECMonash
LSHTM
4 projects GSK
DHODH UTSWUWMonash
Aminoindoles BroadGenzyme
2 projects Novartis
Ozaonides MonashUNMCSTI
1
Artemether- lumefantrine Dispersible Novartis
Isoquine GSK
Pyronaridine-Artesunate Shin Poong
Tafenoquine GSK
DHA-Piperaquine Sigma-Tau
2 compounds GSK Pyridones
Artemisone UHKST
(+)-Meflonquine Treague
2 compounds Novartis
31 March 2016
Whole cell St JudeRutgersUSF
Translational Product development Access
Miniportfolio Novartis
SJ733 St JudeEisai
MMV048 UCT
Rectal Artesunate CiplaStridesWHO-TDR
Preclinical Patient
confirmatory Post approval Human
volunteers
Patient exploratory
Regulatory review
1 project Novartis
P218 (BIOTEC Thailand)
DSM265 UTSWUW Monash
Tafenoquine GSK
Miniportfolio GSK
2 projects GSK
Miniportfolio Sanofi
Orthologue Leads Sanofi
Heterocycles Univ Campinas
Tetraoxanes LSTMUniv Liverpool
DHODH UTSWUWMonash
Heterocycles Takeda
Screening Merck Serono
Pathogen Box MMV
Other projects 24 projects
Heterocycles Eisai
PA92 (DrexelUWGNF)
MMV253 (AstraZeneca)
OZ439FQ Sanofi
KAE609
Novartis
KAF156 Novartis
Artesunate for injection Guilin
Dihydroartemisinin- piperaquine Sigma-Tau
Pyronaridine- artesunate Shin Poong Univ of Iowa
Artesunate- amodiaquine Sanofi DNDi
Artesunate- mefloquine
CiplaDNDi Farmanguinhos
GSK030 GSK
DSM421
(UTSWUW Monash)
Pyronaridine- artesunate Paediatric Shin Poong Univ of Iowa
Sulfadoxine - pyrimethamine + amodiaquine Guilin
Dihydroartemisinin piperaquine Paediatric Sigma-Tau
Research Lead
optimization Lead
generation
3
1
2
4
5
6
DDD498 Merck Serono (Dundee)
Heterocycles Daiichi-Sankyo
Diversity oriented Synthesis BroadEisai
GSK692 GSK
AN13762 Anacor
Artemether- lumefantrine Dispersible Novartis
Pantothenamides TropIQRUMC Pansynt
Heterocycles UCT
Heterocycles Celgene
Open Source Drug Discovery Univ Sydney
4
3
2016
16 new candidates 2009-2016
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Building on an existing template
OZ03 OZ277 RBx11160
Reduce logP Improve solubility
OZ439
Decrease interaction with ferrous iron (single electron)
Vennerstrom JL et al Nature 2004430(7002)900ndash4 Charman SA et al PNAS 2011108(11)4400ndash5
Less potent on embryos and on granulocytes Active vs artesunate resistance
1
Molecular Design DHODH
DSM1 EC50 3D7 79 nM No oral efficacy
DSM191 EC50 3D7 220 nM ED90 Pf SCID 57 mgkg
DSM265 EC50 3D7 8 nM ED90 Pf SCID 81 mgkg
Coteron JM et al J Med Chem 201154(15)5540ndash61
bull Phase IIa completed December 2015
2
Optimising phenotypic hits 3
New targets from parasite screening
Chemotype and related series
New Biological Target
Molecules
Multiple diverse series
ATP4 Na channel KAE609 SJ733 GSK030 PA92
Imidazolopiperazine CARL KAF156
Triazolopyrimidine DHODH DSM265 (DSM421)
Aminopyridine PI4K MMV048 (UCT943)
Quinoline eEF2 DDD498
Triaminopyrimidine V-type H+ ATPase AZ412
Target Identification Consortium 50 compounds from Malaria Box 10-15 new targets Collection of lsquoirresistable scaffoldsrsquo
New Chemotypes by calculation
14
Sequence alignments Homology modelsdocking
Prioritization of new chemistry Validating models to drive
compound design
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Standard Phase II data Response in patients for first 36h
log10PRR(48h) P falciparum 276 -362 log10PRR(48h) P vivax 392-480
16
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
20000
-1 4 9 14 19 24 29
200 mg
400 mg
800 mg
1200 mg
Time h
pa
rasite
s m
l
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
-1 4 9 14 19 24 29
200 mg
400 mg
800 mg
1200 mg
P falciparum P vivax
pa
rasite
s m
l
Time h
Measuring the MIC clinically
17
1011 _
109 _
107_
105_
103_
101_
0 2 4 6 8 10 days
microscopic
limit
PCR limit
Tota
l num
ber
of para
sites
[Concentration] gt MIC
[Concentration] gt MIC
[Concentration] gt MIC
119875119905 = 119875119905
0
119866 minus 1198630 119862119905119867(119862119905
119867 + 11986811986250119867 119889119905
Early data in CHMI models saves time and money
18
Thai Patients (100 mg) Australian Volunteers (100-500mg)
1 month per cohort 1 centre All year round
6 months 4 centres seasonal
19
Human volunteer challenge ndash early readout that the drug works
150 mg DSM265 predicts Human Effective Dose as
400 mg
Day
1 2 3 4 5 0
106
102
104
103
105
S1056 MQ1 S1057 Redo S1058 S1059 S1060 S1064 S1065 S1068 Redo Average DSM S1070 MQ2
Para
site
sm
L
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Candidate selection
Pre- clinical
Transition to human
Phase I
Phase III
Phase IIa
End of Phase IIa
Phase IIb
Candidate Profiling
DDI Phase I
Initiate Phase III
New Chemical
Entity
SRA filing
Discovery and
Candidate Profiling
bull in vitro and in vivo
activity
bull DMPK
bull Solid state
characterization
bull SaltForm screen Phase IIb (adult and
pediatric pts)
bull Safety tolerability
bull Dose finding
bull Contribution of each
agent to the efficacy of
the combination (FDA
rule)
bull Efficacy (ACPR Day 28
and 42)
Discovery
Phase I (hv) and Phase
IIa (adult pts)
bull Single agent
- Safety
- PK
- Parasite clearance and
time to recrudescence
(up to Day 28)
bull Combination
- Safety
- Drug-Drug interactions
- PKPD modeling
Development for combination medicine
21
Preclinical
formulation
Phase III (adult and
pediatric pts)
bull Safety tolerabiliyt
bull Confirm efficacy of
fixed dose
combination (ACPR
Day 28 42 and 63)
Single agent
Combination (with Pharma Partner)
Phase I and Phase IIa
formulation
Phase IIb loose
combination or dose
scalable formulation
Phase III FDC market
formulation
Preclinical
bull GLP Tox
bull DMPK
bull Pre-formulation
studies
Next steps find the right partner
22
WHO guidance differentiated partner to protect against resistance
bull trusted friend or beautiful stranger
bull Can you afford to wait for the next best thing
Differentiated partner protects against resistance trusted friend or beautiful stranger can you afford to wait for the next best thing
Find the right
partner
httpsplusmathsorgcontentkissing-frog-mathematicians-guide-mating
Partner selection Matrix
23
Factor High Score (5) Low Score (1)
TPP - SERCap TCP1 2 and 3 Insufficient TCP1 amp 2
Safety Different organ tox amp manageable Same organ tox + SAEs
Dev Stage Both drugs approved Both preclinical stage
PK- time gt MPC Complete overlap gt MPC for gt 2wk Very short acting + very long acting
Total Dose (mg) lt150mg gt1200mg
BCS -Formulation No challenges Two drugs with bad formulation
Prophylaxis-Liver Stage Both drugs 3-4wks gt MPC Neither has gt1 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 Challon MD PhD
0
5
10
15
20
25
30
35
40
Mefloq Pyronaridine PQP KAE609 FQ DSM265 KAF156 MMV048
Partner selection matrix
24
Newer Newest
Two new combination phase II studies are ongoing
Options for clinical development
Phase IIb One day ndash three days Adults and children
Dose range to satisfy FDA combination rule
2017-18
Single Dose Phase III program
Confirm safety 2019-20
Single dose cohort safe
and gt95 efficacy
Multiple dose Phase III program
Confirm safety 2019-20
Three day cohort safe
and gt95 efficacy
Launch single dose cure
2021
Launch multiple dose
cure 2021
Phase III with three drug
combination 2021- 2
Drug interaction studies with third partner (at risk)
Eliminating the last parasite
Are medicines safe and well tolerated enough to use in subjects with
bull Repeated infection
bull asymptomatic infection
bull undiagnosed early pregnancies
bull in HIV patients (co-medication immunosuppresed)
bull malnutrition
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
A glass half full ndash How we are doing
Blood stage killers fast and long acting
610
Chemoprevention liver schizonticides
510
Transmission blocking safely sparing primaquine
410
Relapse Prevention 810
A glass half full ndash How we are doing
Blood stage killers fast and long acting safe and well tolerated for asymptomatics
310
Chemoprevention liver schizonticides once per month once per season
2510
Transmission blocking safely sparing primaquine
410
Relapse Prevention in G6PD- individuals
010
If you want to go fast go alone If you want to go far go together
Our partnerships are our greatest strength
32
Drugs for treatment and chemoprevention of malaria
Tim Wells Chief Scientific Officer MMV
Products with impact
Molecule
Lumefantrine 4 x 480 mg 2000 mg over 3 days
900 960
Artemether 4 x 80 mg 455
Ferroquine 3 x 200 mg 794
KAF156 1 x 800 mg 67
DSM265 1 x 400 mg 89
PCR corrected
31 March 2016
Whole cell St JudeRutgersUSF
Translational Product development Access
Miniportfolio Novartis
SJ733 St JudeEisai
MMV048 UCT
Rectal Artesunate CiplaStridesWHO-TDR
Preclinical Patient
confirmatory Post approval Human
volunteers
Patient exploratory
Regulatory review
1 project Novartis
P218 (BIOTEC Thailand)
DSM265 UTSWUW Monash
Tafenoquine GSK
Miniportfolio GSK
2 projects GSK
Miniportfolio Sanofi
Orthologue Leads Sanofi
Heterocycles Univ Campinas
Tetraoxanes LSTMUniv Liverpool
DHODH UTSWUWMonash
Heterocycles Takeda
Screening Merck Serono
Pathogen Box MMV
Other projects 24 projects
Heterocycles Eisai
PA92 (DrexelUWGNF)
MMV253 (AstraZeneca)
OZ439FQ Sanofi
KAE609
Novartis
KAF156 Novartis
Artesunate for injection Guilin
Dihydroartemisinin- piperaquine Sigma-Tau
Pyronaridine- artesunate Shin Poong Univ of Iowa
Artesunate- amodiaquine Sanofi DNDi
Artesunate- mefloquine
CiplaDNDi Farmanguinhos
GSK030 GSK
DSM421
(UTSWUW Monash)
Pyronaridine- artesunate Paediatric Shin Poong Univ of Iowa
Sulfadoxine - pyrimethamine + amodiaquine Guilin
Dihydroartemisinin piperaquine Paediatric Sigma-Tau
Research Lead
optimization Lead
generation
3
1
2
4
5
6
DDD498 Merck Serono (Dundee)
Heterocycles Daiichi-Sankyo
Diversity oriented Synthesis BroadEisai
GSK692 GSK
AN13762 Anacor
Artemether- lumefantrine Dispersible Novartis
Pantothenamides TropIQRUMC Pansynt
Heterocycles UCT
Heterocycles Celgene
Open Source Drug Discovery Univ Sydney
4
3
2016
16 new candidates 2009-2016
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Building on an existing template
OZ03 OZ277 RBx11160
Reduce logP Improve solubility
OZ439
Decrease interaction with ferrous iron (single electron)
Vennerstrom JL et al Nature 2004430(7002)900ndash4 Charman SA et al PNAS 2011108(11)4400ndash5
Less potent on embryos and on granulocytes Active vs artesunate resistance
1
Molecular Design DHODH
DSM1 EC50 3D7 79 nM No oral efficacy
DSM191 EC50 3D7 220 nM ED90 Pf SCID 57 mgkg
DSM265 EC50 3D7 8 nM ED90 Pf SCID 81 mgkg
Coteron JM et al J Med Chem 201154(15)5540ndash61
bull Phase IIa completed December 2015
2
Optimising phenotypic hits 3
New targets from parasite screening
Chemotype and related series
New Biological Target
Molecules
Multiple diverse series
ATP4 Na channel KAE609 SJ733 GSK030 PA92
Imidazolopiperazine CARL KAF156
Triazolopyrimidine DHODH DSM265 (DSM421)
Aminopyridine PI4K MMV048 (UCT943)
Quinoline eEF2 DDD498
Triaminopyrimidine V-type H+ ATPase AZ412
Target Identification Consortium 50 compounds from Malaria Box 10-15 new targets Collection of lsquoirresistable scaffoldsrsquo
New Chemotypes by calculation
14
Sequence alignments Homology modelsdocking
Prioritization of new chemistry Validating models to drive
compound design
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Standard Phase II data Response in patients for first 36h
log10PRR(48h) P falciparum 276 -362 log10PRR(48h) P vivax 392-480
16
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
20000
-1 4 9 14 19 24 29
200 mg
400 mg
800 mg
1200 mg
Time h
pa
rasite
s m
l
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
-1 4 9 14 19 24 29
200 mg
400 mg
800 mg
1200 mg
P falciparum P vivax
pa
rasite
s m
l
Time h
Measuring the MIC clinically
17
1011 _
109 _
107_
105_
103_
101_
0 2 4 6 8 10 days
microscopic
limit
PCR limit
Tota
l num
ber
of para
sites
[Concentration] gt MIC
[Concentration] gt MIC
[Concentration] gt MIC
119875119905 = 119875119905
0
119866 minus 1198630 119862119905119867(119862119905
119867 + 11986811986250119867 119889119905
Early data in CHMI models saves time and money
18
Thai Patients (100 mg) Australian Volunteers (100-500mg)
1 month per cohort 1 centre All year round
6 months 4 centres seasonal
19
Human volunteer challenge ndash early readout that the drug works
150 mg DSM265 predicts Human Effective Dose as
400 mg
Day
1 2 3 4 5 0
106
102
104
103
105
S1056 MQ1 S1057 Redo S1058 S1059 S1060 S1064 S1065 S1068 Redo Average DSM S1070 MQ2
Para
site
sm
L
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Candidate selection
Pre- clinical
Transition to human
Phase I
Phase III
Phase IIa
End of Phase IIa
Phase IIb
Candidate Profiling
DDI Phase I
Initiate Phase III
New Chemical
Entity
SRA filing
Discovery and
Candidate Profiling
bull in vitro and in vivo
activity
bull DMPK
bull Solid state
characterization
bull SaltForm screen Phase IIb (adult and
pediatric pts)
bull Safety tolerability
bull Dose finding
bull Contribution of each
agent to the efficacy of
the combination (FDA
rule)
bull Efficacy (ACPR Day 28
and 42)
Discovery
Phase I (hv) and Phase
IIa (adult pts)
bull Single agent
- Safety
- PK
- Parasite clearance and
time to recrudescence
(up to Day 28)
bull Combination
- Safety
- Drug-Drug interactions
- PKPD modeling
Development for combination medicine
21
Preclinical
formulation
Phase III (adult and
pediatric pts)
bull Safety tolerabiliyt
bull Confirm efficacy of
fixed dose
combination (ACPR
Day 28 42 and 63)
Single agent
Combination (with Pharma Partner)
Phase I and Phase IIa
formulation
Phase IIb loose
combination or dose
scalable formulation
Phase III FDC market
formulation
Preclinical
bull GLP Tox
bull DMPK
bull Pre-formulation
studies
Next steps find the right partner
22
WHO guidance differentiated partner to protect against resistance
bull trusted friend or beautiful stranger
bull Can you afford to wait for the next best thing
Differentiated partner protects against resistance trusted friend or beautiful stranger can you afford to wait for the next best thing
Find the right
partner
httpsplusmathsorgcontentkissing-frog-mathematicians-guide-mating
Partner selection Matrix
23
Factor High Score (5) Low Score (1)
TPP - SERCap TCP1 2 and 3 Insufficient TCP1 amp 2
Safety Different organ tox amp manageable Same organ tox + SAEs
Dev Stage Both drugs approved Both preclinical stage
PK- time gt MPC Complete overlap gt MPC for gt 2wk Very short acting + very long acting
Total Dose (mg) lt150mg gt1200mg
BCS -Formulation No challenges Two drugs with bad formulation
Prophylaxis-Liver Stage Both drugs 3-4wks gt MPC Neither has gt1 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 Challon MD PhD
0
5
10
15
20
25
30
35
40
Mefloq Pyronaridine PQP KAE609 FQ DSM265 KAF156 MMV048
Partner selection matrix
24
Newer Newest
Two new combination phase II studies are ongoing
Options for clinical development
Phase IIb One day ndash three days Adults and children
Dose range to satisfy FDA combination rule
2017-18
Single Dose Phase III program
Confirm safety 2019-20
Single dose cohort safe
and gt95 efficacy
Multiple dose Phase III program
Confirm safety 2019-20
Three day cohort safe
and gt95 efficacy
Launch single dose cure
2021
Launch multiple dose
cure 2021
Phase III with three drug
combination 2021- 2
Drug interaction studies with third partner (at risk)
Eliminating the last parasite
Are medicines safe and well tolerated enough to use in subjects with
bull Repeated infection
bull asymptomatic infection
bull undiagnosed early pregnancies
bull in HIV patients (co-medication immunosuppresed)
bull malnutrition
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
A glass half full ndash How we are doing
Blood stage killers fast and long acting
610
Chemoprevention liver schizonticides
510
Transmission blocking safely sparing primaquine
410
Relapse Prevention 810
A glass half full ndash How we are doing
Blood stage killers fast and long acting safe and well tolerated for asymptomatics
310
Chemoprevention liver schizonticides once per month once per season
2510
Transmission blocking safely sparing primaquine
410
Relapse Prevention in G6PD- individuals
010
If you want to go fast go alone If you want to go far go together
Our partnerships are our greatest strength
32
Drugs for treatment and chemoprevention of malaria
Tim Wells Chief Scientific Officer MMV
Products with impact
Molecule
Lumefantrine 4 x 480 mg 2000 mg over 3 days
900 960
Artemether 4 x 80 mg 455
Ferroquine 3 x 200 mg 794
KAF156 1 x 800 mg 67
DSM265 1 x 400 mg 89
PCR corrected
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Building on an existing template
OZ03 OZ277 RBx11160
Reduce logP Improve solubility
OZ439
Decrease interaction with ferrous iron (single electron)
Vennerstrom JL et al Nature 2004430(7002)900ndash4 Charman SA et al PNAS 2011108(11)4400ndash5
Less potent on embryos and on granulocytes Active vs artesunate resistance
1
Molecular Design DHODH
DSM1 EC50 3D7 79 nM No oral efficacy
DSM191 EC50 3D7 220 nM ED90 Pf SCID 57 mgkg
DSM265 EC50 3D7 8 nM ED90 Pf SCID 81 mgkg
Coteron JM et al J Med Chem 201154(15)5540ndash61
bull Phase IIa completed December 2015
2
Optimising phenotypic hits 3
New targets from parasite screening
Chemotype and related series
New Biological Target
Molecules
Multiple diverse series
ATP4 Na channel KAE609 SJ733 GSK030 PA92
Imidazolopiperazine CARL KAF156
Triazolopyrimidine DHODH DSM265 (DSM421)
Aminopyridine PI4K MMV048 (UCT943)
Quinoline eEF2 DDD498
Triaminopyrimidine V-type H+ ATPase AZ412
Target Identification Consortium 50 compounds from Malaria Box 10-15 new targets Collection of lsquoirresistable scaffoldsrsquo
New Chemotypes by calculation
14
Sequence alignments Homology modelsdocking
Prioritization of new chemistry Validating models to drive
compound design
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Standard Phase II data Response in patients for first 36h
log10PRR(48h) P falciparum 276 -362 log10PRR(48h) P vivax 392-480
16
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
20000
-1 4 9 14 19 24 29
200 mg
400 mg
800 mg
1200 mg
Time h
pa
rasite
s m
l
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
-1 4 9 14 19 24 29
200 mg
400 mg
800 mg
1200 mg
P falciparum P vivax
pa
rasite
s m
l
Time h
Measuring the MIC clinically
17
1011 _
109 _
107_
105_
103_
101_
0 2 4 6 8 10 days
microscopic
limit
PCR limit
Tota
l num
ber
of para
sites
[Concentration] gt MIC
[Concentration] gt MIC
[Concentration] gt MIC
119875119905 = 119875119905
0
119866 minus 1198630 119862119905119867(119862119905
119867 + 11986811986250119867 119889119905
Early data in CHMI models saves time and money
18
Thai Patients (100 mg) Australian Volunteers (100-500mg)
1 month per cohort 1 centre All year round
6 months 4 centres seasonal
19
Human volunteer challenge ndash early readout that the drug works
150 mg DSM265 predicts Human Effective Dose as
400 mg
Day
1 2 3 4 5 0
106
102
104
103
105
S1056 MQ1 S1057 Redo S1058 S1059 S1060 S1064 S1065 S1068 Redo Average DSM S1070 MQ2
Para
site
sm
L
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Candidate selection
Pre- clinical
Transition to human
Phase I
Phase III
Phase IIa
End of Phase IIa
Phase IIb
Candidate Profiling
DDI Phase I
Initiate Phase III
New Chemical
Entity
SRA filing
Discovery and
Candidate Profiling
bull in vitro and in vivo
activity
bull DMPK
bull Solid state
characterization
bull SaltForm screen Phase IIb (adult and
pediatric pts)
bull Safety tolerability
bull Dose finding
bull Contribution of each
agent to the efficacy of
the combination (FDA
rule)
bull Efficacy (ACPR Day 28
and 42)
Discovery
Phase I (hv) and Phase
IIa (adult pts)
bull Single agent
- Safety
- PK
- Parasite clearance and
time to recrudescence
(up to Day 28)
bull Combination
- Safety
- Drug-Drug interactions
- PKPD modeling
Development for combination medicine
21
Preclinical
formulation
Phase III (adult and
pediatric pts)
bull Safety tolerabiliyt
bull Confirm efficacy of
fixed dose
combination (ACPR
Day 28 42 and 63)
Single agent
Combination (with Pharma Partner)
Phase I and Phase IIa
formulation
Phase IIb loose
combination or dose
scalable formulation
Phase III FDC market
formulation
Preclinical
bull GLP Tox
bull DMPK
bull Pre-formulation
studies
Next steps find the right partner
22
WHO guidance differentiated partner to protect against resistance
bull trusted friend or beautiful stranger
bull Can you afford to wait for the next best thing
Differentiated partner protects against resistance trusted friend or beautiful stranger can you afford to wait for the next best thing
Find the right
partner
httpsplusmathsorgcontentkissing-frog-mathematicians-guide-mating
Partner selection Matrix
23
Factor High Score (5) Low Score (1)
TPP - SERCap TCP1 2 and 3 Insufficient TCP1 amp 2
Safety Different organ tox amp manageable Same organ tox + SAEs
Dev Stage Both drugs approved Both preclinical stage
PK- time gt MPC Complete overlap gt MPC for gt 2wk Very short acting + very long acting
Total Dose (mg) lt150mg gt1200mg
BCS -Formulation No challenges Two drugs with bad formulation
Prophylaxis-Liver Stage Both drugs 3-4wks gt MPC Neither has gt1 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 Challon MD PhD
0
5
10
15
20
25
30
35
40
Mefloq Pyronaridine PQP KAE609 FQ DSM265 KAF156 MMV048
Partner selection matrix
24
Newer Newest
Two new combination phase II studies are ongoing
Options for clinical development
Phase IIb One day ndash three days Adults and children
Dose range to satisfy FDA combination rule
2017-18
Single Dose Phase III program
Confirm safety 2019-20
Single dose cohort safe
and gt95 efficacy
Multiple dose Phase III program
Confirm safety 2019-20
Three day cohort safe
and gt95 efficacy
Launch single dose cure
2021
Launch multiple dose
cure 2021
Phase III with three drug
combination 2021- 2
Drug interaction studies with third partner (at risk)
Eliminating the last parasite
Are medicines safe and well tolerated enough to use in subjects with
bull Repeated infection
bull asymptomatic infection
bull undiagnosed early pregnancies
bull in HIV patients (co-medication immunosuppresed)
bull malnutrition
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
A glass half full ndash How we are doing
Blood stage killers fast and long acting
610
Chemoprevention liver schizonticides
510
Transmission blocking safely sparing primaquine
410
Relapse Prevention 810
A glass half full ndash How we are doing
Blood stage killers fast and long acting safe and well tolerated for asymptomatics
310
Chemoprevention liver schizonticides once per month once per season
2510
Transmission blocking safely sparing primaquine
410
Relapse Prevention in G6PD- individuals
010
If you want to go fast go alone If you want to go far go together
Our partnerships are our greatest strength
32
Drugs for treatment and chemoprevention of malaria
Tim Wells Chief Scientific Officer MMV
Products with impact
Molecule
Lumefantrine 4 x 480 mg 2000 mg over 3 days
900 960
Artemether 4 x 80 mg 455
Ferroquine 3 x 200 mg 794
KAF156 1 x 800 mg 67
DSM265 1 x 400 mg 89
PCR corrected
Building on an existing template
OZ03 OZ277 RBx11160
Reduce logP Improve solubility
OZ439
Decrease interaction with ferrous iron (single electron)
Vennerstrom JL et al Nature 2004430(7002)900ndash4 Charman SA et al PNAS 2011108(11)4400ndash5
Less potent on embryos and on granulocytes Active vs artesunate resistance
1
Molecular Design DHODH
DSM1 EC50 3D7 79 nM No oral efficacy
DSM191 EC50 3D7 220 nM ED90 Pf SCID 57 mgkg
DSM265 EC50 3D7 8 nM ED90 Pf SCID 81 mgkg
Coteron JM et al J Med Chem 201154(15)5540ndash61
bull Phase IIa completed December 2015
2
Optimising phenotypic hits 3
New targets from parasite screening
Chemotype and related series
New Biological Target
Molecules
Multiple diverse series
ATP4 Na channel KAE609 SJ733 GSK030 PA92
Imidazolopiperazine CARL KAF156
Triazolopyrimidine DHODH DSM265 (DSM421)
Aminopyridine PI4K MMV048 (UCT943)
Quinoline eEF2 DDD498
Triaminopyrimidine V-type H+ ATPase AZ412
Target Identification Consortium 50 compounds from Malaria Box 10-15 new targets Collection of lsquoirresistable scaffoldsrsquo
New Chemotypes by calculation
14
Sequence alignments Homology modelsdocking
Prioritization of new chemistry Validating models to drive
compound design
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Standard Phase II data Response in patients for first 36h
log10PRR(48h) P falciparum 276 -362 log10PRR(48h) P vivax 392-480
16
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
20000
-1 4 9 14 19 24 29
200 mg
400 mg
800 mg
1200 mg
Time h
pa
rasite
s m
l
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
-1 4 9 14 19 24 29
200 mg
400 mg
800 mg
1200 mg
P falciparum P vivax
pa
rasite
s m
l
Time h
Measuring the MIC clinically
17
1011 _
109 _
107_
105_
103_
101_
0 2 4 6 8 10 days
microscopic
limit
PCR limit
Tota
l num
ber
of para
sites
[Concentration] gt MIC
[Concentration] gt MIC
[Concentration] gt MIC
119875119905 = 119875119905
0
119866 minus 1198630 119862119905119867(119862119905
119867 + 11986811986250119867 119889119905
Early data in CHMI models saves time and money
18
Thai Patients (100 mg) Australian Volunteers (100-500mg)
1 month per cohort 1 centre All year round
6 months 4 centres seasonal
19
Human volunteer challenge ndash early readout that the drug works
150 mg DSM265 predicts Human Effective Dose as
400 mg
Day
1 2 3 4 5 0
106
102
104
103
105
S1056 MQ1 S1057 Redo S1058 S1059 S1060 S1064 S1065 S1068 Redo Average DSM S1070 MQ2
Para
site
sm
L
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Candidate selection
Pre- clinical
Transition to human
Phase I
Phase III
Phase IIa
End of Phase IIa
Phase IIb
Candidate Profiling
DDI Phase I
Initiate Phase III
New Chemical
Entity
SRA filing
Discovery and
Candidate Profiling
bull in vitro and in vivo
activity
bull DMPK
bull Solid state
characterization
bull SaltForm screen Phase IIb (adult and
pediatric pts)
bull Safety tolerability
bull Dose finding
bull Contribution of each
agent to the efficacy of
the combination (FDA
rule)
bull Efficacy (ACPR Day 28
and 42)
Discovery
Phase I (hv) and Phase
IIa (adult pts)
bull Single agent
- Safety
- PK
- Parasite clearance and
time to recrudescence
(up to Day 28)
bull Combination
- Safety
- Drug-Drug interactions
- PKPD modeling
Development for combination medicine
21
Preclinical
formulation
Phase III (adult and
pediatric pts)
bull Safety tolerabiliyt
bull Confirm efficacy of
fixed dose
combination (ACPR
Day 28 42 and 63)
Single agent
Combination (with Pharma Partner)
Phase I and Phase IIa
formulation
Phase IIb loose
combination or dose
scalable formulation
Phase III FDC market
formulation
Preclinical
bull GLP Tox
bull DMPK
bull Pre-formulation
studies
Next steps find the right partner
22
WHO guidance differentiated partner to protect against resistance
bull trusted friend or beautiful stranger
bull Can you afford to wait for the next best thing
Differentiated partner protects against resistance trusted friend or beautiful stranger can you afford to wait for the next best thing
Find the right
partner
httpsplusmathsorgcontentkissing-frog-mathematicians-guide-mating
Partner selection Matrix
23
Factor High Score (5) Low Score (1)
TPP - SERCap TCP1 2 and 3 Insufficient TCP1 amp 2
Safety Different organ tox amp manageable Same organ tox + SAEs
Dev Stage Both drugs approved Both preclinical stage
PK- time gt MPC Complete overlap gt MPC for gt 2wk Very short acting + very long acting
Total Dose (mg) lt150mg gt1200mg
BCS -Formulation No challenges Two drugs with bad formulation
Prophylaxis-Liver Stage Both drugs 3-4wks gt MPC Neither has gt1 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 Challon MD PhD
0
5
10
15
20
25
30
35
40
Mefloq Pyronaridine PQP KAE609 FQ DSM265 KAF156 MMV048
Partner selection matrix
24
Newer Newest
Two new combination phase II studies are ongoing
Options for clinical development
Phase IIb One day ndash three days Adults and children
Dose range to satisfy FDA combination rule
2017-18
Single Dose Phase III program
Confirm safety 2019-20
Single dose cohort safe
and gt95 efficacy
Multiple dose Phase III program
Confirm safety 2019-20
Three day cohort safe
and gt95 efficacy
Launch single dose cure
2021
Launch multiple dose
cure 2021
Phase III with three drug
combination 2021- 2
Drug interaction studies with third partner (at risk)
Eliminating the last parasite
Are medicines safe and well tolerated enough to use in subjects with
bull Repeated infection
bull asymptomatic infection
bull undiagnosed early pregnancies
bull in HIV patients (co-medication immunosuppresed)
bull malnutrition
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
A glass half full ndash How we are doing
Blood stage killers fast and long acting
610
Chemoprevention liver schizonticides
510
Transmission blocking safely sparing primaquine
410
Relapse Prevention 810
A glass half full ndash How we are doing
Blood stage killers fast and long acting safe and well tolerated for asymptomatics
310
Chemoprevention liver schizonticides once per month once per season
2510
Transmission blocking safely sparing primaquine
410
Relapse Prevention in G6PD- individuals
010
If you want to go fast go alone If you want to go far go together
Our partnerships are our greatest strength
32
Drugs for treatment and chemoprevention of malaria
Tim Wells Chief Scientific Officer MMV
Products with impact
Molecule
Lumefantrine 4 x 480 mg 2000 mg over 3 days
900 960
Artemether 4 x 80 mg 455
Ferroquine 3 x 200 mg 794
KAF156 1 x 800 mg 67
DSM265 1 x 400 mg 89
PCR corrected
Molecular Design DHODH
DSM1 EC50 3D7 79 nM No oral efficacy
DSM191 EC50 3D7 220 nM ED90 Pf SCID 57 mgkg
DSM265 EC50 3D7 8 nM ED90 Pf SCID 81 mgkg
Coteron JM et al J Med Chem 201154(15)5540ndash61
bull Phase IIa completed December 2015
2
Optimising phenotypic hits 3
New targets from parasite screening
Chemotype and related series
New Biological Target
Molecules
Multiple diverse series
ATP4 Na channel KAE609 SJ733 GSK030 PA92
Imidazolopiperazine CARL KAF156
Triazolopyrimidine DHODH DSM265 (DSM421)
Aminopyridine PI4K MMV048 (UCT943)
Quinoline eEF2 DDD498
Triaminopyrimidine V-type H+ ATPase AZ412
Target Identification Consortium 50 compounds from Malaria Box 10-15 new targets Collection of lsquoirresistable scaffoldsrsquo
New Chemotypes by calculation
14
Sequence alignments Homology modelsdocking
Prioritization of new chemistry Validating models to drive
compound design
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Standard Phase II data Response in patients for first 36h
log10PRR(48h) P falciparum 276 -362 log10PRR(48h) P vivax 392-480
16
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
20000
-1 4 9 14 19 24 29
200 mg
400 mg
800 mg
1200 mg
Time h
pa
rasite
s m
l
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
-1 4 9 14 19 24 29
200 mg
400 mg
800 mg
1200 mg
P falciparum P vivax
pa
rasite
s m
l
Time h
Measuring the MIC clinically
17
1011 _
109 _
107_
105_
103_
101_
0 2 4 6 8 10 days
microscopic
limit
PCR limit
Tota
l num
ber
of para
sites
[Concentration] gt MIC
[Concentration] gt MIC
[Concentration] gt MIC
119875119905 = 119875119905
0
119866 minus 1198630 119862119905119867(119862119905
119867 + 11986811986250119867 119889119905
Early data in CHMI models saves time and money
18
Thai Patients (100 mg) Australian Volunteers (100-500mg)
1 month per cohort 1 centre All year round
6 months 4 centres seasonal
19
Human volunteer challenge ndash early readout that the drug works
150 mg DSM265 predicts Human Effective Dose as
400 mg
Day
1 2 3 4 5 0
106
102
104
103
105
S1056 MQ1 S1057 Redo S1058 S1059 S1060 S1064 S1065 S1068 Redo Average DSM S1070 MQ2
Para
site
sm
L
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Candidate selection
Pre- clinical
Transition to human
Phase I
Phase III
Phase IIa
End of Phase IIa
Phase IIb
Candidate Profiling
DDI Phase I
Initiate Phase III
New Chemical
Entity
SRA filing
Discovery and
Candidate Profiling
bull in vitro and in vivo
activity
bull DMPK
bull Solid state
characterization
bull SaltForm screen Phase IIb (adult and
pediatric pts)
bull Safety tolerability
bull Dose finding
bull Contribution of each
agent to the efficacy of
the combination (FDA
rule)
bull Efficacy (ACPR Day 28
and 42)
Discovery
Phase I (hv) and Phase
IIa (adult pts)
bull Single agent
- Safety
- PK
- Parasite clearance and
time to recrudescence
(up to Day 28)
bull Combination
- Safety
- Drug-Drug interactions
- PKPD modeling
Development for combination medicine
21
Preclinical
formulation
Phase III (adult and
pediatric pts)
bull Safety tolerabiliyt
bull Confirm efficacy of
fixed dose
combination (ACPR
Day 28 42 and 63)
Single agent
Combination (with Pharma Partner)
Phase I and Phase IIa
formulation
Phase IIb loose
combination or dose
scalable formulation
Phase III FDC market
formulation
Preclinical
bull GLP Tox
bull DMPK
bull Pre-formulation
studies
Next steps find the right partner
22
WHO guidance differentiated partner to protect against resistance
bull trusted friend or beautiful stranger
bull Can you afford to wait for the next best thing
Differentiated partner protects against resistance trusted friend or beautiful stranger can you afford to wait for the next best thing
Find the right
partner
httpsplusmathsorgcontentkissing-frog-mathematicians-guide-mating
Partner selection Matrix
23
Factor High Score (5) Low Score (1)
TPP - SERCap TCP1 2 and 3 Insufficient TCP1 amp 2
Safety Different organ tox amp manageable Same organ tox + SAEs
Dev Stage Both drugs approved Both preclinical stage
PK- time gt MPC Complete overlap gt MPC for gt 2wk Very short acting + very long acting
Total Dose (mg) lt150mg gt1200mg
BCS -Formulation No challenges Two drugs with bad formulation
Prophylaxis-Liver Stage Both drugs 3-4wks gt MPC Neither has gt1 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 Challon MD PhD
0
5
10
15
20
25
30
35
40
Mefloq Pyronaridine PQP KAE609 FQ DSM265 KAF156 MMV048
Partner selection matrix
24
Newer Newest
Two new combination phase II studies are ongoing
Options for clinical development
Phase IIb One day ndash three days Adults and children
Dose range to satisfy FDA combination rule
2017-18
Single Dose Phase III program
Confirm safety 2019-20
Single dose cohort safe
and gt95 efficacy
Multiple dose Phase III program
Confirm safety 2019-20
Three day cohort safe
and gt95 efficacy
Launch single dose cure
2021
Launch multiple dose
cure 2021
Phase III with three drug
combination 2021- 2
Drug interaction studies with third partner (at risk)
Eliminating the last parasite
Are medicines safe and well tolerated enough to use in subjects with
bull Repeated infection
bull asymptomatic infection
bull undiagnosed early pregnancies
bull in HIV patients (co-medication immunosuppresed)
bull malnutrition
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
A glass half full ndash How we are doing
Blood stage killers fast and long acting
610
Chemoprevention liver schizonticides
510
Transmission blocking safely sparing primaquine
410
Relapse Prevention 810
A glass half full ndash How we are doing
Blood stage killers fast and long acting safe and well tolerated for asymptomatics
310
Chemoprevention liver schizonticides once per month once per season
2510
Transmission blocking safely sparing primaquine
410
Relapse Prevention in G6PD- individuals
010
If you want to go fast go alone If you want to go far go together
Our partnerships are our greatest strength
32
Drugs for treatment and chemoprevention of malaria
Tim Wells Chief Scientific Officer MMV
Products with impact
Molecule
Lumefantrine 4 x 480 mg 2000 mg over 3 days
900 960
Artemether 4 x 80 mg 455
Ferroquine 3 x 200 mg 794
KAF156 1 x 800 mg 67
DSM265 1 x 400 mg 89
PCR corrected
Optimising phenotypic hits 3
New targets from parasite screening
Chemotype and related series
New Biological Target
Molecules
Multiple diverse series
ATP4 Na channel KAE609 SJ733 GSK030 PA92
Imidazolopiperazine CARL KAF156
Triazolopyrimidine DHODH DSM265 (DSM421)
Aminopyridine PI4K MMV048 (UCT943)
Quinoline eEF2 DDD498
Triaminopyrimidine V-type H+ ATPase AZ412
Target Identification Consortium 50 compounds from Malaria Box 10-15 new targets Collection of lsquoirresistable scaffoldsrsquo
New Chemotypes by calculation
14
Sequence alignments Homology modelsdocking
Prioritization of new chemistry Validating models to drive
compound design
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Standard Phase II data Response in patients for first 36h
log10PRR(48h) P falciparum 276 -362 log10PRR(48h) P vivax 392-480
16
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
20000
-1 4 9 14 19 24 29
200 mg
400 mg
800 mg
1200 mg
Time h
pa
rasite
s m
l
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
-1 4 9 14 19 24 29
200 mg
400 mg
800 mg
1200 mg
P falciparum P vivax
pa
rasite
s m
l
Time h
Measuring the MIC clinically
17
1011 _
109 _
107_
105_
103_
101_
0 2 4 6 8 10 days
microscopic
limit
PCR limit
Tota
l num
ber
of para
sites
[Concentration] gt MIC
[Concentration] gt MIC
[Concentration] gt MIC
119875119905 = 119875119905
0
119866 minus 1198630 119862119905119867(119862119905
119867 + 11986811986250119867 119889119905
Early data in CHMI models saves time and money
18
Thai Patients (100 mg) Australian Volunteers (100-500mg)
1 month per cohort 1 centre All year round
6 months 4 centres seasonal
19
Human volunteer challenge ndash early readout that the drug works
150 mg DSM265 predicts Human Effective Dose as
400 mg
Day
1 2 3 4 5 0
106
102
104
103
105
S1056 MQ1 S1057 Redo S1058 S1059 S1060 S1064 S1065 S1068 Redo Average DSM S1070 MQ2
Para
site
sm
L
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Candidate selection
Pre- clinical
Transition to human
Phase I
Phase III
Phase IIa
End of Phase IIa
Phase IIb
Candidate Profiling
DDI Phase I
Initiate Phase III
New Chemical
Entity
SRA filing
Discovery and
Candidate Profiling
bull in vitro and in vivo
activity
bull DMPK
bull Solid state
characterization
bull SaltForm screen Phase IIb (adult and
pediatric pts)
bull Safety tolerability
bull Dose finding
bull Contribution of each
agent to the efficacy of
the combination (FDA
rule)
bull Efficacy (ACPR Day 28
and 42)
Discovery
Phase I (hv) and Phase
IIa (adult pts)
bull Single agent
- Safety
- PK
- Parasite clearance and
time to recrudescence
(up to Day 28)
bull Combination
- Safety
- Drug-Drug interactions
- PKPD modeling
Development for combination medicine
21
Preclinical
formulation
Phase III (adult and
pediatric pts)
bull Safety tolerabiliyt
bull Confirm efficacy of
fixed dose
combination (ACPR
Day 28 42 and 63)
Single agent
Combination (with Pharma Partner)
Phase I and Phase IIa
formulation
Phase IIb loose
combination or dose
scalable formulation
Phase III FDC market
formulation
Preclinical
bull GLP Tox
bull DMPK
bull Pre-formulation
studies
Next steps find the right partner
22
WHO guidance differentiated partner to protect against resistance
bull trusted friend or beautiful stranger
bull Can you afford to wait for the next best thing
Differentiated partner protects against resistance trusted friend or beautiful stranger can you afford to wait for the next best thing
Find the right
partner
httpsplusmathsorgcontentkissing-frog-mathematicians-guide-mating
Partner selection Matrix
23
Factor High Score (5) Low Score (1)
TPP - SERCap TCP1 2 and 3 Insufficient TCP1 amp 2
Safety Different organ tox amp manageable Same organ tox + SAEs
Dev Stage Both drugs approved Both preclinical stage
PK- time gt MPC Complete overlap gt MPC for gt 2wk Very short acting + very long acting
Total Dose (mg) lt150mg gt1200mg
BCS -Formulation No challenges Two drugs with bad formulation
Prophylaxis-Liver Stage Both drugs 3-4wks gt MPC Neither has gt1 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 Challon MD PhD
0
5
10
15
20
25
30
35
40
Mefloq Pyronaridine PQP KAE609 FQ DSM265 KAF156 MMV048
Partner selection matrix
24
Newer Newest
Two new combination phase II studies are ongoing
Options for clinical development
Phase IIb One day ndash three days Adults and children
Dose range to satisfy FDA combination rule
2017-18
Single Dose Phase III program
Confirm safety 2019-20
Single dose cohort safe
and gt95 efficacy
Multiple dose Phase III program
Confirm safety 2019-20
Three day cohort safe
and gt95 efficacy
Launch single dose cure
2021
Launch multiple dose
cure 2021
Phase III with three drug
combination 2021- 2
Drug interaction studies with third partner (at risk)
Eliminating the last parasite
Are medicines safe and well tolerated enough to use in subjects with
bull Repeated infection
bull asymptomatic infection
bull undiagnosed early pregnancies
bull in HIV patients (co-medication immunosuppresed)
bull malnutrition
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
A glass half full ndash How we are doing
Blood stage killers fast and long acting
610
Chemoprevention liver schizonticides
510
Transmission blocking safely sparing primaquine
410
Relapse Prevention 810
A glass half full ndash How we are doing
Blood stage killers fast and long acting safe and well tolerated for asymptomatics
310
Chemoprevention liver schizonticides once per month once per season
2510
Transmission blocking safely sparing primaquine
410
Relapse Prevention in G6PD- individuals
010
If you want to go fast go alone If you want to go far go together
Our partnerships are our greatest strength
32
Drugs for treatment and chemoprevention of malaria
Tim Wells Chief Scientific Officer MMV
Products with impact
Molecule
Lumefantrine 4 x 480 mg 2000 mg over 3 days
900 960
Artemether 4 x 80 mg 455
Ferroquine 3 x 200 mg 794
KAF156 1 x 800 mg 67
DSM265 1 x 400 mg 89
PCR corrected
New targets from parasite screening
Chemotype and related series
New Biological Target
Molecules
Multiple diverse series
ATP4 Na channel KAE609 SJ733 GSK030 PA92
Imidazolopiperazine CARL KAF156
Triazolopyrimidine DHODH DSM265 (DSM421)
Aminopyridine PI4K MMV048 (UCT943)
Quinoline eEF2 DDD498
Triaminopyrimidine V-type H+ ATPase AZ412
Target Identification Consortium 50 compounds from Malaria Box 10-15 new targets Collection of lsquoirresistable scaffoldsrsquo
New Chemotypes by calculation
14
Sequence alignments Homology modelsdocking
Prioritization of new chemistry Validating models to drive
compound design
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Standard Phase II data Response in patients for first 36h
log10PRR(48h) P falciparum 276 -362 log10PRR(48h) P vivax 392-480
16
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
20000
-1 4 9 14 19 24 29
200 mg
400 mg
800 mg
1200 mg
Time h
pa
rasite
s m
l
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
-1 4 9 14 19 24 29
200 mg
400 mg
800 mg
1200 mg
P falciparum P vivax
pa
rasite
s m
l
Time h
Measuring the MIC clinically
17
1011 _
109 _
107_
105_
103_
101_
0 2 4 6 8 10 days
microscopic
limit
PCR limit
Tota
l num
ber
of para
sites
[Concentration] gt MIC
[Concentration] gt MIC
[Concentration] gt MIC
119875119905 = 119875119905
0
119866 minus 1198630 119862119905119867(119862119905
119867 + 11986811986250119867 119889119905
Early data in CHMI models saves time and money
18
Thai Patients (100 mg) Australian Volunteers (100-500mg)
1 month per cohort 1 centre All year round
6 months 4 centres seasonal
19
Human volunteer challenge ndash early readout that the drug works
150 mg DSM265 predicts Human Effective Dose as
400 mg
Day
1 2 3 4 5 0
106
102
104
103
105
S1056 MQ1 S1057 Redo S1058 S1059 S1060 S1064 S1065 S1068 Redo Average DSM S1070 MQ2
Para
site
sm
L
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Candidate selection
Pre- clinical
Transition to human
Phase I
Phase III
Phase IIa
End of Phase IIa
Phase IIb
Candidate Profiling
DDI Phase I
Initiate Phase III
New Chemical
Entity
SRA filing
Discovery and
Candidate Profiling
bull in vitro and in vivo
activity
bull DMPK
bull Solid state
characterization
bull SaltForm screen Phase IIb (adult and
pediatric pts)
bull Safety tolerability
bull Dose finding
bull Contribution of each
agent to the efficacy of
the combination (FDA
rule)
bull Efficacy (ACPR Day 28
and 42)
Discovery
Phase I (hv) and Phase
IIa (adult pts)
bull Single agent
- Safety
- PK
- Parasite clearance and
time to recrudescence
(up to Day 28)
bull Combination
- Safety
- Drug-Drug interactions
- PKPD modeling
Development for combination medicine
21
Preclinical
formulation
Phase III (adult and
pediatric pts)
bull Safety tolerabiliyt
bull Confirm efficacy of
fixed dose
combination (ACPR
Day 28 42 and 63)
Single agent
Combination (with Pharma Partner)
Phase I and Phase IIa
formulation
Phase IIb loose
combination or dose
scalable formulation
Phase III FDC market
formulation
Preclinical
bull GLP Tox
bull DMPK
bull Pre-formulation
studies
Next steps find the right partner
22
WHO guidance differentiated partner to protect against resistance
bull trusted friend or beautiful stranger
bull Can you afford to wait for the next best thing
Differentiated partner protects against resistance trusted friend or beautiful stranger can you afford to wait for the next best thing
Find the right
partner
httpsplusmathsorgcontentkissing-frog-mathematicians-guide-mating
Partner selection Matrix
23
Factor High Score (5) Low Score (1)
TPP - SERCap TCP1 2 and 3 Insufficient TCP1 amp 2
Safety Different organ tox amp manageable Same organ tox + SAEs
Dev Stage Both drugs approved Both preclinical stage
PK- time gt MPC Complete overlap gt MPC for gt 2wk Very short acting + very long acting
Total Dose (mg) lt150mg gt1200mg
BCS -Formulation No challenges Two drugs with bad formulation
Prophylaxis-Liver Stage Both drugs 3-4wks gt MPC Neither has gt1 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 Challon MD PhD
0
5
10
15
20
25
30
35
40
Mefloq Pyronaridine PQP KAE609 FQ DSM265 KAF156 MMV048
Partner selection matrix
24
Newer Newest
Two new combination phase II studies are ongoing
Options for clinical development
Phase IIb One day ndash three days Adults and children
Dose range to satisfy FDA combination rule
2017-18
Single Dose Phase III program
Confirm safety 2019-20
Single dose cohort safe
and gt95 efficacy
Multiple dose Phase III program
Confirm safety 2019-20
Three day cohort safe
and gt95 efficacy
Launch single dose cure
2021
Launch multiple dose
cure 2021
Phase III with three drug
combination 2021- 2
Drug interaction studies with third partner (at risk)
Eliminating the last parasite
Are medicines safe and well tolerated enough to use in subjects with
bull Repeated infection
bull asymptomatic infection
bull undiagnosed early pregnancies
bull in HIV patients (co-medication immunosuppresed)
bull malnutrition
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
A glass half full ndash How we are doing
Blood stage killers fast and long acting
610
Chemoprevention liver schizonticides
510
Transmission blocking safely sparing primaquine
410
Relapse Prevention 810
A glass half full ndash How we are doing
Blood stage killers fast and long acting safe and well tolerated for asymptomatics
310
Chemoprevention liver schizonticides once per month once per season
2510
Transmission blocking safely sparing primaquine
410
Relapse Prevention in G6PD- individuals
010
If you want to go fast go alone If you want to go far go together
Our partnerships are our greatest strength
32
Drugs for treatment and chemoprevention of malaria
Tim Wells Chief Scientific Officer MMV
Products with impact
Molecule
Lumefantrine 4 x 480 mg 2000 mg over 3 days
900 960
Artemether 4 x 80 mg 455
Ferroquine 3 x 200 mg 794
KAF156 1 x 800 mg 67
DSM265 1 x 400 mg 89
PCR corrected
New Chemotypes by calculation
14
Sequence alignments Homology modelsdocking
Prioritization of new chemistry Validating models to drive
compound design
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Standard Phase II data Response in patients for first 36h
log10PRR(48h) P falciparum 276 -362 log10PRR(48h) P vivax 392-480
16
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
20000
-1 4 9 14 19 24 29
200 mg
400 mg
800 mg
1200 mg
Time h
pa
rasite
s m
l
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
-1 4 9 14 19 24 29
200 mg
400 mg
800 mg
1200 mg
P falciparum P vivax
pa
rasite
s m
l
Time h
Measuring the MIC clinically
17
1011 _
109 _
107_
105_
103_
101_
0 2 4 6 8 10 days
microscopic
limit
PCR limit
Tota
l num
ber
of para
sites
[Concentration] gt MIC
[Concentration] gt MIC
[Concentration] gt MIC
119875119905 = 119875119905
0
119866 minus 1198630 119862119905119867(119862119905
119867 + 11986811986250119867 119889119905
Early data in CHMI models saves time and money
18
Thai Patients (100 mg) Australian Volunteers (100-500mg)
1 month per cohort 1 centre All year round
6 months 4 centres seasonal
19
Human volunteer challenge ndash early readout that the drug works
150 mg DSM265 predicts Human Effective Dose as
400 mg
Day
1 2 3 4 5 0
106
102
104
103
105
S1056 MQ1 S1057 Redo S1058 S1059 S1060 S1064 S1065 S1068 Redo Average DSM S1070 MQ2
Para
site
sm
L
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Candidate selection
Pre- clinical
Transition to human
Phase I
Phase III
Phase IIa
End of Phase IIa
Phase IIb
Candidate Profiling
DDI Phase I
Initiate Phase III
New Chemical
Entity
SRA filing
Discovery and
Candidate Profiling
bull in vitro and in vivo
activity
bull DMPK
bull Solid state
characterization
bull SaltForm screen Phase IIb (adult and
pediatric pts)
bull Safety tolerability
bull Dose finding
bull Contribution of each
agent to the efficacy of
the combination (FDA
rule)
bull Efficacy (ACPR Day 28
and 42)
Discovery
Phase I (hv) and Phase
IIa (adult pts)
bull Single agent
- Safety
- PK
- Parasite clearance and
time to recrudescence
(up to Day 28)
bull Combination
- Safety
- Drug-Drug interactions
- PKPD modeling
Development for combination medicine
21
Preclinical
formulation
Phase III (adult and
pediatric pts)
bull Safety tolerabiliyt
bull Confirm efficacy of
fixed dose
combination (ACPR
Day 28 42 and 63)
Single agent
Combination (with Pharma Partner)
Phase I and Phase IIa
formulation
Phase IIb loose
combination or dose
scalable formulation
Phase III FDC market
formulation
Preclinical
bull GLP Tox
bull DMPK
bull Pre-formulation
studies
Next steps find the right partner
22
WHO guidance differentiated partner to protect against resistance
bull trusted friend or beautiful stranger
bull Can you afford to wait for the next best thing
Differentiated partner protects against resistance trusted friend or beautiful stranger can you afford to wait for the next best thing
Find the right
partner
httpsplusmathsorgcontentkissing-frog-mathematicians-guide-mating
Partner selection Matrix
23
Factor High Score (5) Low Score (1)
TPP - SERCap TCP1 2 and 3 Insufficient TCP1 amp 2
Safety Different organ tox amp manageable Same organ tox + SAEs
Dev Stage Both drugs approved Both preclinical stage
PK- time gt MPC Complete overlap gt MPC for gt 2wk Very short acting + very long acting
Total Dose (mg) lt150mg gt1200mg
BCS -Formulation No challenges Two drugs with bad formulation
Prophylaxis-Liver Stage Both drugs 3-4wks gt MPC Neither has gt1 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 Challon MD PhD
0
5
10
15
20
25
30
35
40
Mefloq Pyronaridine PQP KAE609 FQ DSM265 KAF156 MMV048
Partner selection matrix
24
Newer Newest
Two new combination phase II studies are ongoing
Options for clinical development
Phase IIb One day ndash three days Adults and children
Dose range to satisfy FDA combination rule
2017-18
Single Dose Phase III program
Confirm safety 2019-20
Single dose cohort safe
and gt95 efficacy
Multiple dose Phase III program
Confirm safety 2019-20
Three day cohort safe
and gt95 efficacy
Launch single dose cure
2021
Launch multiple dose
cure 2021
Phase III with three drug
combination 2021- 2
Drug interaction studies with third partner (at risk)
Eliminating the last parasite
Are medicines safe and well tolerated enough to use in subjects with
bull Repeated infection
bull asymptomatic infection
bull undiagnosed early pregnancies
bull in HIV patients (co-medication immunosuppresed)
bull malnutrition
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
A glass half full ndash How we are doing
Blood stage killers fast and long acting
610
Chemoprevention liver schizonticides
510
Transmission blocking safely sparing primaquine
410
Relapse Prevention 810
A glass half full ndash How we are doing
Blood stage killers fast and long acting safe and well tolerated for asymptomatics
310
Chemoprevention liver schizonticides once per month once per season
2510
Transmission blocking safely sparing primaquine
410
Relapse Prevention in G6PD- individuals
010
If you want to go fast go alone If you want to go far go together
Our partnerships are our greatest strength
32
Drugs for treatment and chemoprevention of malaria
Tim Wells Chief Scientific Officer MMV
Products with impact
Molecule
Lumefantrine 4 x 480 mg 2000 mg over 3 days
900 960
Artemether 4 x 80 mg 455
Ferroquine 3 x 200 mg 794
KAF156 1 x 800 mg 67
DSM265 1 x 400 mg 89
PCR corrected
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Standard Phase II data Response in patients for first 36h
log10PRR(48h) P falciparum 276 -362 log10PRR(48h) P vivax 392-480
16
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
20000
-1 4 9 14 19 24 29
200 mg
400 mg
800 mg
1200 mg
Time h
pa
rasite
s m
l
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
-1 4 9 14 19 24 29
200 mg
400 mg
800 mg
1200 mg
P falciparum P vivax
pa
rasite
s m
l
Time h
Measuring the MIC clinically
17
1011 _
109 _
107_
105_
103_
101_
0 2 4 6 8 10 days
microscopic
limit
PCR limit
Tota
l num
ber
of para
sites
[Concentration] gt MIC
[Concentration] gt MIC
[Concentration] gt MIC
119875119905 = 119875119905
0
119866 minus 1198630 119862119905119867(119862119905
119867 + 11986811986250119867 119889119905
Early data in CHMI models saves time and money
18
Thai Patients (100 mg) Australian Volunteers (100-500mg)
1 month per cohort 1 centre All year round
6 months 4 centres seasonal
19
Human volunteer challenge ndash early readout that the drug works
150 mg DSM265 predicts Human Effective Dose as
400 mg
Day
1 2 3 4 5 0
106
102
104
103
105
S1056 MQ1 S1057 Redo S1058 S1059 S1060 S1064 S1065 S1068 Redo Average DSM S1070 MQ2
Para
site
sm
L
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Candidate selection
Pre- clinical
Transition to human
Phase I
Phase III
Phase IIa
End of Phase IIa
Phase IIb
Candidate Profiling
DDI Phase I
Initiate Phase III
New Chemical
Entity
SRA filing
Discovery and
Candidate Profiling
bull in vitro and in vivo
activity
bull DMPK
bull Solid state
characterization
bull SaltForm screen Phase IIb (adult and
pediatric pts)
bull Safety tolerability
bull Dose finding
bull Contribution of each
agent to the efficacy of
the combination (FDA
rule)
bull Efficacy (ACPR Day 28
and 42)
Discovery
Phase I (hv) and Phase
IIa (adult pts)
bull Single agent
- Safety
- PK
- Parasite clearance and
time to recrudescence
(up to Day 28)
bull Combination
- Safety
- Drug-Drug interactions
- PKPD modeling
Development for combination medicine
21
Preclinical
formulation
Phase III (adult and
pediatric pts)
bull Safety tolerabiliyt
bull Confirm efficacy of
fixed dose
combination (ACPR
Day 28 42 and 63)
Single agent
Combination (with Pharma Partner)
Phase I and Phase IIa
formulation
Phase IIb loose
combination or dose
scalable formulation
Phase III FDC market
formulation
Preclinical
bull GLP Tox
bull DMPK
bull Pre-formulation
studies
Next steps find the right partner
22
WHO guidance differentiated partner to protect against resistance
bull trusted friend or beautiful stranger
bull Can you afford to wait for the next best thing
Differentiated partner protects against resistance trusted friend or beautiful stranger can you afford to wait for the next best thing
Find the right
partner
httpsplusmathsorgcontentkissing-frog-mathematicians-guide-mating
Partner selection Matrix
23
Factor High Score (5) Low Score (1)
TPP - SERCap TCP1 2 and 3 Insufficient TCP1 amp 2
Safety Different organ tox amp manageable Same organ tox + SAEs
Dev Stage Both drugs approved Both preclinical stage
PK- time gt MPC Complete overlap gt MPC for gt 2wk Very short acting + very long acting
Total Dose (mg) lt150mg gt1200mg
BCS -Formulation No challenges Two drugs with bad formulation
Prophylaxis-Liver Stage Both drugs 3-4wks gt MPC Neither has gt1 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 Challon MD PhD
0
5
10
15
20
25
30
35
40
Mefloq Pyronaridine PQP KAE609 FQ DSM265 KAF156 MMV048
Partner selection matrix
24
Newer Newest
Two new combination phase II studies are ongoing
Options for clinical development
Phase IIb One day ndash three days Adults and children
Dose range to satisfy FDA combination rule
2017-18
Single Dose Phase III program
Confirm safety 2019-20
Single dose cohort safe
and gt95 efficacy
Multiple dose Phase III program
Confirm safety 2019-20
Three day cohort safe
and gt95 efficacy
Launch single dose cure
2021
Launch multiple dose
cure 2021
Phase III with three drug
combination 2021- 2
Drug interaction studies with third partner (at risk)
Eliminating the last parasite
Are medicines safe and well tolerated enough to use in subjects with
bull Repeated infection
bull asymptomatic infection
bull undiagnosed early pregnancies
bull in HIV patients (co-medication immunosuppresed)
bull malnutrition
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
A glass half full ndash How we are doing
Blood stage killers fast and long acting
610
Chemoprevention liver schizonticides
510
Transmission blocking safely sparing primaquine
410
Relapse Prevention 810
A glass half full ndash How we are doing
Blood stage killers fast and long acting safe and well tolerated for asymptomatics
310
Chemoprevention liver schizonticides once per month once per season
2510
Transmission blocking safely sparing primaquine
410
Relapse Prevention in G6PD- individuals
010
If you want to go fast go alone If you want to go far go together
Our partnerships are our greatest strength
32
Drugs for treatment and chemoprevention of malaria
Tim Wells Chief Scientific Officer MMV
Products with impact
Molecule
Lumefantrine 4 x 480 mg 2000 mg over 3 days
900 960
Artemether 4 x 80 mg 455
Ferroquine 3 x 200 mg 794
KAF156 1 x 800 mg 67
DSM265 1 x 400 mg 89
PCR corrected
Standard Phase II data Response in patients for first 36h
log10PRR(48h) P falciparum 276 -362 log10PRR(48h) P vivax 392-480
16
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
20000
-1 4 9 14 19 24 29
200 mg
400 mg
800 mg
1200 mg
Time h
pa
rasite
s m
l
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
-1 4 9 14 19 24 29
200 mg
400 mg
800 mg
1200 mg
P falciparum P vivax
pa
rasite
s m
l
Time h
Measuring the MIC clinically
17
1011 _
109 _
107_
105_
103_
101_
0 2 4 6 8 10 days
microscopic
limit
PCR limit
Tota
l num
ber
of para
sites
[Concentration] gt MIC
[Concentration] gt MIC
[Concentration] gt MIC
119875119905 = 119875119905
0
119866 minus 1198630 119862119905119867(119862119905
119867 + 11986811986250119867 119889119905
Early data in CHMI models saves time and money
18
Thai Patients (100 mg) Australian Volunteers (100-500mg)
1 month per cohort 1 centre All year round
6 months 4 centres seasonal
19
Human volunteer challenge ndash early readout that the drug works
150 mg DSM265 predicts Human Effective Dose as
400 mg
Day
1 2 3 4 5 0
106
102
104
103
105
S1056 MQ1 S1057 Redo S1058 S1059 S1060 S1064 S1065 S1068 Redo Average DSM S1070 MQ2
Para
site
sm
L
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Candidate selection
Pre- clinical
Transition to human
Phase I
Phase III
Phase IIa
End of Phase IIa
Phase IIb
Candidate Profiling
DDI Phase I
Initiate Phase III
New Chemical
Entity
SRA filing
Discovery and
Candidate Profiling
bull in vitro and in vivo
activity
bull DMPK
bull Solid state
characterization
bull SaltForm screen Phase IIb (adult and
pediatric pts)
bull Safety tolerability
bull Dose finding
bull Contribution of each
agent to the efficacy of
the combination (FDA
rule)
bull Efficacy (ACPR Day 28
and 42)
Discovery
Phase I (hv) and Phase
IIa (adult pts)
bull Single agent
- Safety
- PK
- Parasite clearance and
time to recrudescence
(up to Day 28)
bull Combination
- Safety
- Drug-Drug interactions
- PKPD modeling
Development for combination medicine
21
Preclinical
formulation
Phase III (adult and
pediatric pts)
bull Safety tolerabiliyt
bull Confirm efficacy of
fixed dose
combination (ACPR
Day 28 42 and 63)
Single agent
Combination (with Pharma Partner)
Phase I and Phase IIa
formulation
Phase IIb loose
combination or dose
scalable formulation
Phase III FDC market
formulation
Preclinical
bull GLP Tox
bull DMPK
bull Pre-formulation
studies
Next steps find the right partner
22
WHO guidance differentiated partner to protect against resistance
bull trusted friend or beautiful stranger
bull Can you afford to wait for the next best thing
Differentiated partner protects against resistance trusted friend or beautiful stranger can you afford to wait for the next best thing
Find the right
partner
httpsplusmathsorgcontentkissing-frog-mathematicians-guide-mating
Partner selection Matrix
23
Factor High Score (5) Low Score (1)
TPP - SERCap TCP1 2 and 3 Insufficient TCP1 amp 2
Safety Different organ tox amp manageable Same organ tox + SAEs
Dev Stage Both drugs approved Both preclinical stage
PK- time gt MPC Complete overlap gt MPC for gt 2wk Very short acting + very long acting
Total Dose (mg) lt150mg gt1200mg
BCS -Formulation No challenges Two drugs with bad formulation
Prophylaxis-Liver Stage Both drugs 3-4wks gt MPC Neither has gt1 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 Challon MD PhD
0
5
10
15
20
25
30
35
40
Mefloq Pyronaridine PQP KAE609 FQ DSM265 KAF156 MMV048
Partner selection matrix
24
Newer Newest
Two new combination phase II studies are ongoing
Options for clinical development
Phase IIb One day ndash three days Adults and children
Dose range to satisfy FDA combination rule
2017-18
Single Dose Phase III program
Confirm safety 2019-20
Single dose cohort safe
and gt95 efficacy
Multiple dose Phase III program
Confirm safety 2019-20
Three day cohort safe
and gt95 efficacy
Launch single dose cure
2021
Launch multiple dose
cure 2021
Phase III with three drug
combination 2021- 2
Drug interaction studies with third partner (at risk)
Eliminating the last parasite
Are medicines safe and well tolerated enough to use in subjects with
bull Repeated infection
bull asymptomatic infection
bull undiagnosed early pregnancies
bull in HIV patients (co-medication immunosuppresed)
bull malnutrition
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
A glass half full ndash How we are doing
Blood stage killers fast and long acting
610
Chemoprevention liver schizonticides
510
Transmission blocking safely sparing primaquine
410
Relapse Prevention 810
A glass half full ndash How we are doing
Blood stage killers fast and long acting safe and well tolerated for asymptomatics
310
Chemoprevention liver schizonticides once per month once per season
2510
Transmission blocking safely sparing primaquine
410
Relapse Prevention in G6PD- individuals
010
If you want to go fast go alone If you want to go far go together
Our partnerships are our greatest strength
32
Drugs for treatment and chemoprevention of malaria
Tim Wells Chief Scientific Officer MMV
Products with impact
Molecule
Lumefantrine 4 x 480 mg 2000 mg over 3 days
900 960
Artemether 4 x 80 mg 455
Ferroquine 3 x 200 mg 794
KAF156 1 x 800 mg 67
DSM265 1 x 400 mg 89
PCR corrected
Measuring the MIC clinically
17
1011 _
109 _
107_
105_
103_
101_
0 2 4 6 8 10 days
microscopic
limit
PCR limit
Tota
l num
ber
of para
sites
[Concentration] gt MIC
[Concentration] gt MIC
[Concentration] gt MIC
119875119905 = 119875119905
0
119866 minus 1198630 119862119905119867(119862119905
119867 + 11986811986250119867 119889119905
Early data in CHMI models saves time and money
18
Thai Patients (100 mg) Australian Volunteers (100-500mg)
1 month per cohort 1 centre All year round
6 months 4 centres seasonal
19
Human volunteer challenge ndash early readout that the drug works
150 mg DSM265 predicts Human Effective Dose as
400 mg
Day
1 2 3 4 5 0
106
102
104
103
105
S1056 MQ1 S1057 Redo S1058 S1059 S1060 S1064 S1065 S1068 Redo Average DSM S1070 MQ2
Para
site
sm
L
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Candidate selection
Pre- clinical
Transition to human
Phase I
Phase III
Phase IIa
End of Phase IIa
Phase IIb
Candidate Profiling
DDI Phase I
Initiate Phase III
New Chemical
Entity
SRA filing
Discovery and
Candidate Profiling
bull in vitro and in vivo
activity
bull DMPK
bull Solid state
characterization
bull SaltForm screen Phase IIb (adult and
pediatric pts)
bull Safety tolerability
bull Dose finding
bull Contribution of each
agent to the efficacy of
the combination (FDA
rule)
bull Efficacy (ACPR Day 28
and 42)
Discovery
Phase I (hv) and Phase
IIa (adult pts)
bull Single agent
- Safety
- PK
- Parasite clearance and
time to recrudescence
(up to Day 28)
bull Combination
- Safety
- Drug-Drug interactions
- PKPD modeling
Development for combination medicine
21
Preclinical
formulation
Phase III (adult and
pediatric pts)
bull Safety tolerabiliyt
bull Confirm efficacy of
fixed dose
combination (ACPR
Day 28 42 and 63)
Single agent
Combination (with Pharma Partner)
Phase I and Phase IIa
formulation
Phase IIb loose
combination or dose
scalable formulation
Phase III FDC market
formulation
Preclinical
bull GLP Tox
bull DMPK
bull Pre-formulation
studies
Next steps find the right partner
22
WHO guidance differentiated partner to protect against resistance
bull trusted friend or beautiful stranger
bull Can you afford to wait for the next best thing
Differentiated partner protects against resistance trusted friend or beautiful stranger can you afford to wait for the next best thing
Find the right
partner
httpsplusmathsorgcontentkissing-frog-mathematicians-guide-mating
Partner selection Matrix
23
Factor High Score (5) Low Score (1)
TPP - SERCap TCP1 2 and 3 Insufficient TCP1 amp 2
Safety Different organ tox amp manageable Same organ tox + SAEs
Dev Stage Both drugs approved Both preclinical stage
PK- time gt MPC Complete overlap gt MPC for gt 2wk Very short acting + very long acting
Total Dose (mg) lt150mg gt1200mg
BCS -Formulation No challenges Two drugs with bad formulation
Prophylaxis-Liver Stage Both drugs 3-4wks gt MPC Neither has gt1 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 Challon MD PhD
0
5
10
15
20
25
30
35
40
Mefloq Pyronaridine PQP KAE609 FQ DSM265 KAF156 MMV048
Partner selection matrix
24
Newer Newest
Two new combination phase II studies are ongoing
Options for clinical development
Phase IIb One day ndash three days Adults and children
Dose range to satisfy FDA combination rule
2017-18
Single Dose Phase III program
Confirm safety 2019-20
Single dose cohort safe
and gt95 efficacy
Multiple dose Phase III program
Confirm safety 2019-20
Three day cohort safe
and gt95 efficacy
Launch single dose cure
2021
Launch multiple dose
cure 2021
Phase III with three drug
combination 2021- 2
Drug interaction studies with third partner (at risk)
Eliminating the last parasite
Are medicines safe and well tolerated enough to use in subjects with
bull Repeated infection
bull asymptomatic infection
bull undiagnosed early pregnancies
bull in HIV patients (co-medication immunosuppresed)
bull malnutrition
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
A glass half full ndash How we are doing
Blood stage killers fast and long acting
610
Chemoprevention liver schizonticides
510
Transmission blocking safely sparing primaquine
410
Relapse Prevention 810
A glass half full ndash How we are doing
Blood stage killers fast and long acting safe and well tolerated for asymptomatics
310
Chemoprevention liver schizonticides once per month once per season
2510
Transmission blocking safely sparing primaquine
410
Relapse Prevention in G6PD- individuals
010
If you want to go fast go alone If you want to go far go together
Our partnerships are our greatest strength
32
Drugs for treatment and chemoprevention of malaria
Tim Wells Chief Scientific Officer MMV
Products with impact
Molecule
Lumefantrine 4 x 480 mg 2000 mg over 3 days
900 960
Artemether 4 x 80 mg 455
Ferroquine 3 x 200 mg 794
KAF156 1 x 800 mg 67
DSM265 1 x 400 mg 89
PCR corrected
Early data in CHMI models saves time and money
18
Thai Patients (100 mg) Australian Volunteers (100-500mg)
1 month per cohort 1 centre All year round
6 months 4 centres seasonal
19
Human volunteer challenge ndash early readout that the drug works
150 mg DSM265 predicts Human Effective Dose as
400 mg
Day
1 2 3 4 5 0
106
102
104
103
105
S1056 MQ1 S1057 Redo S1058 S1059 S1060 S1064 S1065 S1068 Redo Average DSM S1070 MQ2
Para
site
sm
L
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Candidate selection
Pre- clinical
Transition to human
Phase I
Phase III
Phase IIa
End of Phase IIa
Phase IIb
Candidate Profiling
DDI Phase I
Initiate Phase III
New Chemical
Entity
SRA filing
Discovery and
Candidate Profiling
bull in vitro and in vivo
activity
bull DMPK
bull Solid state
characterization
bull SaltForm screen Phase IIb (adult and
pediatric pts)
bull Safety tolerability
bull Dose finding
bull Contribution of each
agent to the efficacy of
the combination (FDA
rule)
bull Efficacy (ACPR Day 28
and 42)
Discovery
Phase I (hv) and Phase
IIa (adult pts)
bull Single agent
- Safety
- PK
- Parasite clearance and
time to recrudescence
(up to Day 28)
bull Combination
- Safety
- Drug-Drug interactions
- PKPD modeling
Development for combination medicine
21
Preclinical
formulation
Phase III (adult and
pediatric pts)
bull Safety tolerabiliyt
bull Confirm efficacy of
fixed dose
combination (ACPR
Day 28 42 and 63)
Single agent
Combination (with Pharma Partner)
Phase I and Phase IIa
formulation
Phase IIb loose
combination or dose
scalable formulation
Phase III FDC market
formulation
Preclinical
bull GLP Tox
bull DMPK
bull Pre-formulation
studies
Next steps find the right partner
22
WHO guidance differentiated partner to protect against resistance
bull trusted friend or beautiful stranger
bull Can you afford to wait for the next best thing
Differentiated partner protects against resistance trusted friend or beautiful stranger can you afford to wait for the next best thing
Find the right
partner
httpsplusmathsorgcontentkissing-frog-mathematicians-guide-mating
Partner selection Matrix
23
Factor High Score (5) Low Score (1)
TPP - SERCap TCP1 2 and 3 Insufficient TCP1 amp 2
Safety Different organ tox amp manageable Same organ tox + SAEs
Dev Stage Both drugs approved Both preclinical stage
PK- time gt MPC Complete overlap gt MPC for gt 2wk Very short acting + very long acting
Total Dose (mg) lt150mg gt1200mg
BCS -Formulation No challenges Two drugs with bad formulation
Prophylaxis-Liver Stage Both drugs 3-4wks gt MPC Neither has gt1 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 Challon MD PhD
0
5
10
15
20
25
30
35
40
Mefloq Pyronaridine PQP KAE609 FQ DSM265 KAF156 MMV048
Partner selection matrix
24
Newer Newest
Two new combination phase II studies are ongoing
Options for clinical development
Phase IIb One day ndash three days Adults and children
Dose range to satisfy FDA combination rule
2017-18
Single Dose Phase III program
Confirm safety 2019-20
Single dose cohort safe
and gt95 efficacy
Multiple dose Phase III program
Confirm safety 2019-20
Three day cohort safe
and gt95 efficacy
Launch single dose cure
2021
Launch multiple dose
cure 2021
Phase III with three drug
combination 2021- 2
Drug interaction studies with third partner (at risk)
Eliminating the last parasite
Are medicines safe and well tolerated enough to use in subjects with
bull Repeated infection
bull asymptomatic infection
bull undiagnosed early pregnancies
bull in HIV patients (co-medication immunosuppresed)
bull malnutrition
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
A glass half full ndash How we are doing
Blood stage killers fast and long acting
610
Chemoprevention liver schizonticides
510
Transmission blocking safely sparing primaquine
410
Relapse Prevention 810
A glass half full ndash How we are doing
Blood stage killers fast and long acting safe and well tolerated for asymptomatics
310
Chemoprevention liver schizonticides once per month once per season
2510
Transmission blocking safely sparing primaquine
410
Relapse Prevention in G6PD- individuals
010
If you want to go fast go alone If you want to go far go together
Our partnerships are our greatest strength
32
Drugs for treatment and chemoprevention of malaria
Tim Wells Chief Scientific Officer MMV
Products with impact
Molecule
Lumefantrine 4 x 480 mg 2000 mg over 3 days
900 960
Artemether 4 x 80 mg 455
Ferroquine 3 x 200 mg 794
KAF156 1 x 800 mg 67
DSM265 1 x 400 mg 89
PCR corrected
19
Human volunteer challenge ndash early readout that the drug works
150 mg DSM265 predicts Human Effective Dose as
400 mg
Day
1 2 3 4 5 0
106
102
104
103
105
S1056 MQ1 S1057 Redo S1058 S1059 S1060 S1064 S1065 S1068 Redo Average DSM S1070 MQ2
Para
site
sm
L
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Candidate selection
Pre- clinical
Transition to human
Phase I
Phase III
Phase IIa
End of Phase IIa
Phase IIb
Candidate Profiling
DDI Phase I
Initiate Phase III
New Chemical
Entity
SRA filing
Discovery and
Candidate Profiling
bull in vitro and in vivo
activity
bull DMPK
bull Solid state
characterization
bull SaltForm screen Phase IIb (adult and
pediatric pts)
bull Safety tolerability
bull Dose finding
bull Contribution of each
agent to the efficacy of
the combination (FDA
rule)
bull Efficacy (ACPR Day 28
and 42)
Discovery
Phase I (hv) and Phase
IIa (adult pts)
bull Single agent
- Safety
- PK
- Parasite clearance and
time to recrudescence
(up to Day 28)
bull Combination
- Safety
- Drug-Drug interactions
- PKPD modeling
Development for combination medicine
21
Preclinical
formulation
Phase III (adult and
pediatric pts)
bull Safety tolerabiliyt
bull Confirm efficacy of
fixed dose
combination (ACPR
Day 28 42 and 63)
Single agent
Combination (with Pharma Partner)
Phase I and Phase IIa
formulation
Phase IIb loose
combination or dose
scalable formulation
Phase III FDC market
formulation
Preclinical
bull GLP Tox
bull DMPK
bull Pre-formulation
studies
Next steps find the right partner
22
WHO guidance differentiated partner to protect against resistance
bull trusted friend or beautiful stranger
bull Can you afford to wait for the next best thing
Differentiated partner protects against resistance trusted friend or beautiful stranger can you afford to wait for the next best thing
Find the right
partner
httpsplusmathsorgcontentkissing-frog-mathematicians-guide-mating
Partner selection Matrix
23
Factor High Score (5) Low Score (1)
TPP - SERCap TCP1 2 and 3 Insufficient TCP1 amp 2
Safety Different organ tox amp manageable Same organ tox + SAEs
Dev Stage Both drugs approved Both preclinical stage
PK- time gt MPC Complete overlap gt MPC for gt 2wk Very short acting + very long acting
Total Dose (mg) lt150mg gt1200mg
BCS -Formulation No challenges Two drugs with bad formulation
Prophylaxis-Liver Stage Both drugs 3-4wks gt MPC Neither has gt1 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 Challon MD PhD
0
5
10
15
20
25
30
35
40
Mefloq Pyronaridine PQP KAE609 FQ DSM265 KAF156 MMV048
Partner selection matrix
24
Newer Newest
Two new combination phase II studies are ongoing
Options for clinical development
Phase IIb One day ndash three days Adults and children
Dose range to satisfy FDA combination rule
2017-18
Single Dose Phase III program
Confirm safety 2019-20
Single dose cohort safe
and gt95 efficacy
Multiple dose Phase III program
Confirm safety 2019-20
Three day cohort safe
and gt95 efficacy
Launch single dose cure
2021
Launch multiple dose
cure 2021
Phase III with three drug
combination 2021- 2
Drug interaction studies with third partner (at risk)
Eliminating the last parasite
Are medicines safe and well tolerated enough to use in subjects with
bull Repeated infection
bull asymptomatic infection
bull undiagnosed early pregnancies
bull in HIV patients (co-medication immunosuppresed)
bull malnutrition
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
A glass half full ndash How we are doing
Blood stage killers fast and long acting
610
Chemoprevention liver schizonticides
510
Transmission blocking safely sparing primaquine
410
Relapse Prevention 810
A glass half full ndash How we are doing
Blood stage killers fast and long acting safe and well tolerated for asymptomatics
310
Chemoprevention liver schizonticides once per month once per season
2510
Transmission blocking safely sparing primaquine
410
Relapse Prevention in G6PD- individuals
010
If you want to go fast go alone If you want to go far go together
Our partnerships are our greatest strength
32
Drugs for treatment and chemoprevention of malaria
Tim Wells Chief Scientific Officer MMV
Products with impact
Molecule
Lumefantrine 4 x 480 mg 2000 mg over 3 days
900 960
Artemether 4 x 80 mg 455
Ferroquine 3 x 200 mg 794
KAF156 1 x 800 mg 67
DSM265 1 x 400 mg 89
PCR corrected
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
Candidate selection
Pre- clinical
Transition to human
Phase I
Phase III
Phase IIa
End of Phase IIa
Phase IIb
Candidate Profiling
DDI Phase I
Initiate Phase III
New Chemical
Entity
SRA filing
Discovery and
Candidate Profiling
bull in vitro and in vivo
activity
bull DMPK
bull Solid state
characterization
bull SaltForm screen Phase IIb (adult and
pediatric pts)
bull Safety tolerability
bull Dose finding
bull Contribution of each
agent to the efficacy of
the combination (FDA
rule)
bull Efficacy (ACPR Day 28
and 42)
Discovery
Phase I (hv) and Phase
IIa (adult pts)
bull Single agent
- Safety
- PK
- Parasite clearance and
time to recrudescence
(up to Day 28)
bull Combination
- Safety
- Drug-Drug interactions
- PKPD modeling
Development for combination medicine
21
Preclinical
formulation
Phase III (adult and
pediatric pts)
bull Safety tolerabiliyt
bull Confirm efficacy of
fixed dose
combination (ACPR
Day 28 42 and 63)
Single agent
Combination (with Pharma Partner)
Phase I and Phase IIa
formulation
Phase IIb loose
combination or dose
scalable formulation
Phase III FDC market
formulation
Preclinical
bull GLP Tox
bull DMPK
bull Pre-formulation
studies
Next steps find the right partner
22
WHO guidance differentiated partner to protect against resistance
bull trusted friend or beautiful stranger
bull Can you afford to wait for the next best thing
Differentiated partner protects against resistance trusted friend or beautiful stranger can you afford to wait for the next best thing
Find the right
partner
httpsplusmathsorgcontentkissing-frog-mathematicians-guide-mating
Partner selection Matrix
23
Factor High Score (5) Low Score (1)
TPP - SERCap TCP1 2 and 3 Insufficient TCP1 amp 2
Safety Different organ tox amp manageable Same organ tox + SAEs
Dev Stage Both drugs approved Both preclinical stage
PK- time gt MPC Complete overlap gt MPC for gt 2wk Very short acting + very long acting
Total Dose (mg) lt150mg gt1200mg
BCS -Formulation No challenges Two drugs with bad formulation
Prophylaxis-Liver Stage Both drugs 3-4wks gt MPC Neither has gt1 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 Challon MD PhD
0
5
10
15
20
25
30
35
40
Mefloq Pyronaridine PQP KAE609 FQ DSM265 KAF156 MMV048
Partner selection matrix
24
Newer Newest
Two new combination phase II studies are ongoing
Options for clinical development
Phase IIb One day ndash three days Adults and children
Dose range to satisfy FDA combination rule
2017-18
Single Dose Phase III program
Confirm safety 2019-20
Single dose cohort safe
and gt95 efficacy
Multiple dose Phase III program
Confirm safety 2019-20
Three day cohort safe
and gt95 efficacy
Launch single dose cure
2021
Launch multiple dose
cure 2021
Phase III with three drug
combination 2021- 2
Drug interaction studies with third partner (at risk)
Eliminating the last parasite
Are medicines safe and well tolerated enough to use in subjects with
bull Repeated infection
bull asymptomatic infection
bull undiagnosed early pregnancies
bull in HIV patients (co-medication immunosuppresed)
bull malnutrition
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
A glass half full ndash How we are doing
Blood stage killers fast and long acting
610
Chemoprevention liver schizonticides
510
Transmission blocking safely sparing primaquine
410
Relapse Prevention 810
A glass half full ndash How we are doing
Blood stage killers fast and long acting safe and well tolerated for asymptomatics
310
Chemoprevention liver schizonticides once per month once per season
2510
Transmission blocking safely sparing primaquine
410
Relapse Prevention in G6PD- individuals
010
If you want to go fast go alone If you want to go far go together
Our partnerships are our greatest strength
32
Drugs for treatment and chemoprevention of malaria
Tim Wells Chief Scientific Officer MMV
Products with impact
Molecule
Lumefantrine 4 x 480 mg 2000 mg over 3 days
900 960
Artemether 4 x 80 mg 455
Ferroquine 3 x 200 mg 794
KAF156 1 x 800 mg 67
DSM265 1 x 400 mg 89
PCR corrected
Candidate selection
Pre- clinical
Transition to human
Phase I
Phase III
Phase IIa
End of Phase IIa
Phase IIb
Candidate Profiling
DDI Phase I
Initiate Phase III
New Chemical
Entity
SRA filing
Discovery and
Candidate Profiling
bull in vitro and in vivo
activity
bull DMPK
bull Solid state
characterization
bull SaltForm screen Phase IIb (adult and
pediatric pts)
bull Safety tolerability
bull Dose finding
bull Contribution of each
agent to the efficacy of
the combination (FDA
rule)
bull Efficacy (ACPR Day 28
and 42)
Discovery
Phase I (hv) and Phase
IIa (adult pts)
bull Single agent
- Safety
- PK
- Parasite clearance and
time to recrudescence
(up to Day 28)
bull Combination
- Safety
- Drug-Drug interactions
- PKPD modeling
Development for combination medicine
21
Preclinical
formulation
Phase III (adult and
pediatric pts)
bull Safety tolerabiliyt
bull Confirm efficacy of
fixed dose
combination (ACPR
Day 28 42 and 63)
Single agent
Combination (with Pharma Partner)
Phase I and Phase IIa
formulation
Phase IIb loose
combination or dose
scalable formulation
Phase III FDC market
formulation
Preclinical
bull GLP Tox
bull DMPK
bull Pre-formulation
studies
Next steps find the right partner
22
WHO guidance differentiated partner to protect against resistance
bull trusted friend or beautiful stranger
bull Can you afford to wait for the next best thing
Differentiated partner protects against resistance trusted friend or beautiful stranger can you afford to wait for the next best thing
Find the right
partner
httpsplusmathsorgcontentkissing-frog-mathematicians-guide-mating
Partner selection Matrix
23
Factor High Score (5) Low Score (1)
TPP - SERCap TCP1 2 and 3 Insufficient TCP1 amp 2
Safety Different organ tox amp manageable Same organ tox + SAEs
Dev Stage Both drugs approved Both preclinical stage
PK- time gt MPC Complete overlap gt MPC for gt 2wk Very short acting + very long acting
Total Dose (mg) lt150mg gt1200mg
BCS -Formulation No challenges Two drugs with bad formulation
Prophylaxis-Liver Stage Both drugs 3-4wks gt MPC Neither has gt1 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 Challon MD PhD
0
5
10
15
20
25
30
35
40
Mefloq Pyronaridine PQP KAE609 FQ DSM265 KAF156 MMV048
Partner selection matrix
24
Newer Newest
Two new combination phase II studies are ongoing
Options for clinical development
Phase IIb One day ndash three days Adults and children
Dose range to satisfy FDA combination rule
2017-18
Single Dose Phase III program
Confirm safety 2019-20
Single dose cohort safe
and gt95 efficacy
Multiple dose Phase III program
Confirm safety 2019-20
Three day cohort safe
and gt95 efficacy
Launch single dose cure
2021
Launch multiple dose
cure 2021
Phase III with three drug
combination 2021- 2
Drug interaction studies with third partner (at risk)
Eliminating the last parasite
Are medicines safe and well tolerated enough to use in subjects with
bull Repeated infection
bull asymptomatic infection
bull undiagnosed early pregnancies
bull in HIV patients (co-medication immunosuppresed)
bull malnutrition
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
A glass half full ndash How we are doing
Blood stage killers fast and long acting
610
Chemoprevention liver schizonticides
510
Transmission blocking safely sparing primaquine
410
Relapse Prevention 810
A glass half full ndash How we are doing
Blood stage killers fast and long acting safe and well tolerated for asymptomatics
310
Chemoprevention liver schizonticides once per month once per season
2510
Transmission blocking safely sparing primaquine
410
Relapse Prevention in G6PD- individuals
010
If you want to go fast go alone If you want to go far go together
Our partnerships are our greatest strength
32
Drugs for treatment and chemoprevention of malaria
Tim Wells Chief Scientific Officer MMV
Products with impact
Molecule
Lumefantrine 4 x 480 mg 2000 mg over 3 days
900 960
Artemether 4 x 80 mg 455
Ferroquine 3 x 200 mg 794
KAF156 1 x 800 mg 67
DSM265 1 x 400 mg 89
PCR corrected
Next steps find the right partner
22
WHO guidance differentiated partner to protect against resistance
bull trusted friend or beautiful stranger
bull Can you afford to wait for the next best thing
Differentiated partner protects against resistance trusted friend or beautiful stranger can you afford to wait for the next best thing
Find the right
partner
httpsplusmathsorgcontentkissing-frog-mathematicians-guide-mating
Partner selection Matrix
23
Factor High Score (5) Low Score (1)
TPP - SERCap TCP1 2 and 3 Insufficient TCP1 amp 2
Safety Different organ tox amp manageable Same organ tox + SAEs
Dev Stage Both drugs approved Both preclinical stage
PK- time gt MPC Complete overlap gt MPC for gt 2wk Very short acting + very long acting
Total Dose (mg) lt150mg gt1200mg
BCS -Formulation No challenges Two drugs with bad formulation
Prophylaxis-Liver Stage Both drugs 3-4wks gt MPC Neither has gt1 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 Challon MD PhD
0
5
10
15
20
25
30
35
40
Mefloq Pyronaridine PQP KAE609 FQ DSM265 KAF156 MMV048
Partner selection matrix
24
Newer Newest
Two new combination phase II studies are ongoing
Options for clinical development
Phase IIb One day ndash three days Adults and children
Dose range to satisfy FDA combination rule
2017-18
Single Dose Phase III program
Confirm safety 2019-20
Single dose cohort safe
and gt95 efficacy
Multiple dose Phase III program
Confirm safety 2019-20
Three day cohort safe
and gt95 efficacy
Launch single dose cure
2021
Launch multiple dose
cure 2021
Phase III with three drug
combination 2021- 2
Drug interaction studies with third partner (at risk)
Eliminating the last parasite
Are medicines safe and well tolerated enough to use in subjects with
bull Repeated infection
bull asymptomatic infection
bull undiagnosed early pregnancies
bull in HIV patients (co-medication immunosuppresed)
bull malnutrition
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
A glass half full ndash How we are doing
Blood stage killers fast and long acting
610
Chemoprevention liver schizonticides
510
Transmission blocking safely sparing primaquine
410
Relapse Prevention 810
A glass half full ndash How we are doing
Blood stage killers fast and long acting safe and well tolerated for asymptomatics
310
Chemoprevention liver schizonticides once per month once per season
2510
Transmission blocking safely sparing primaquine
410
Relapse Prevention in G6PD- individuals
010
If you want to go fast go alone If you want to go far go together
Our partnerships are our greatest strength
32
Drugs for treatment and chemoprevention of malaria
Tim Wells Chief Scientific Officer MMV
Products with impact
Molecule
Lumefantrine 4 x 480 mg 2000 mg over 3 days
900 960
Artemether 4 x 80 mg 455
Ferroquine 3 x 200 mg 794
KAF156 1 x 800 mg 67
DSM265 1 x 400 mg 89
PCR corrected
Partner selection Matrix
23
Factor High Score (5) Low Score (1)
TPP - SERCap TCP1 2 and 3 Insufficient TCP1 amp 2
Safety Different organ tox amp manageable Same organ tox + SAEs
Dev Stage Both drugs approved Both preclinical stage
PK- time gt MPC Complete overlap gt MPC for gt 2wk Very short acting + very long acting
Total Dose (mg) lt150mg gt1200mg
BCS -Formulation No challenges Two drugs with bad formulation
Prophylaxis-Liver Stage Both drugs 3-4wks gt MPC Neither has gt1 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 Challon MD PhD
0
5
10
15
20
25
30
35
40
Mefloq Pyronaridine PQP KAE609 FQ DSM265 KAF156 MMV048
Partner selection matrix
24
Newer Newest
Two new combination phase II studies are ongoing
Options for clinical development
Phase IIb One day ndash three days Adults and children
Dose range to satisfy FDA combination rule
2017-18
Single Dose Phase III program
Confirm safety 2019-20
Single dose cohort safe
and gt95 efficacy
Multiple dose Phase III program
Confirm safety 2019-20
Three day cohort safe
and gt95 efficacy
Launch single dose cure
2021
Launch multiple dose
cure 2021
Phase III with three drug
combination 2021- 2
Drug interaction studies with third partner (at risk)
Eliminating the last parasite
Are medicines safe and well tolerated enough to use in subjects with
bull Repeated infection
bull asymptomatic infection
bull undiagnosed early pregnancies
bull in HIV patients (co-medication immunosuppresed)
bull malnutrition
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
A glass half full ndash How we are doing
Blood stage killers fast and long acting
610
Chemoprevention liver schizonticides
510
Transmission blocking safely sparing primaquine
410
Relapse Prevention 810
A glass half full ndash How we are doing
Blood stage killers fast and long acting safe and well tolerated for asymptomatics
310
Chemoprevention liver schizonticides once per month once per season
2510
Transmission blocking safely sparing primaquine
410
Relapse Prevention in G6PD- individuals
010
If you want to go fast go alone If you want to go far go together
Our partnerships are our greatest strength
32
Drugs for treatment and chemoprevention of malaria
Tim Wells Chief Scientific Officer MMV
Products with impact
Molecule
Lumefantrine 4 x 480 mg 2000 mg over 3 days
900 960
Artemether 4 x 80 mg 455
Ferroquine 3 x 200 mg 794
KAF156 1 x 800 mg 67
DSM265 1 x 400 mg 89
PCR corrected
0
5
10
15
20
25
30
35
40
Mefloq Pyronaridine PQP KAE609 FQ DSM265 KAF156 MMV048
Partner selection matrix
24
Newer Newest
Two new combination phase II studies are ongoing
Options for clinical development
Phase IIb One day ndash three days Adults and children
Dose range to satisfy FDA combination rule
2017-18
Single Dose Phase III program
Confirm safety 2019-20
Single dose cohort safe
and gt95 efficacy
Multiple dose Phase III program
Confirm safety 2019-20
Three day cohort safe
and gt95 efficacy
Launch single dose cure
2021
Launch multiple dose
cure 2021
Phase III with three drug
combination 2021- 2
Drug interaction studies with third partner (at risk)
Eliminating the last parasite
Are medicines safe and well tolerated enough to use in subjects with
bull Repeated infection
bull asymptomatic infection
bull undiagnosed early pregnancies
bull in HIV patients (co-medication immunosuppresed)
bull malnutrition
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
A glass half full ndash How we are doing
Blood stage killers fast and long acting
610
Chemoprevention liver schizonticides
510
Transmission blocking safely sparing primaquine
410
Relapse Prevention 810
A glass half full ndash How we are doing
Blood stage killers fast and long acting safe and well tolerated for asymptomatics
310
Chemoprevention liver schizonticides once per month once per season
2510
Transmission blocking safely sparing primaquine
410
Relapse Prevention in G6PD- individuals
010
If you want to go fast go alone If you want to go far go together
Our partnerships are our greatest strength
32
Drugs for treatment and chemoprevention of malaria
Tim Wells Chief Scientific Officer MMV
Products with impact
Molecule
Lumefantrine 4 x 480 mg 2000 mg over 3 days
900 960
Artemether 4 x 80 mg 455
Ferroquine 3 x 200 mg 794
KAF156 1 x 800 mg 67
DSM265 1 x 400 mg 89
PCR corrected
Newer Newest
Two new combination phase II studies are ongoing
Options for clinical development
Phase IIb One day ndash three days Adults and children
Dose range to satisfy FDA combination rule
2017-18
Single Dose Phase III program
Confirm safety 2019-20
Single dose cohort safe
and gt95 efficacy
Multiple dose Phase III program
Confirm safety 2019-20
Three day cohort safe
and gt95 efficacy
Launch single dose cure
2021
Launch multiple dose
cure 2021
Phase III with three drug
combination 2021- 2
Drug interaction studies with third partner (at risk)
Eliminating the last parasite
Are medicines safe and well tolerated enough to use in subjects with
bull Repeated infection
bull asymptomatic infection
bull undiagnosed early pregnancies
bull in HIV patients (co-medication immunosuppresed)
bull malnutrition
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
A glass half full ndash How we are doing
Blood stage killers fast and long acting
610
Chemoprevention liver schizonticides
510
Transmission blocking safely sparing primaquine
410
Relapse Prevention 810
A glass half full ndash How we are doing
Blood stage killers fast and long acting safe and well tolerated for asymptomatics
310
Chemoprevention liver schizonticides once per month once per season
2510
Transmission blocking safely sparing primaquine
410
Relapse Prevention in G6PD- individuals
010
If you want to go fast go alone If you want to go far go together
Our partnerships are our greatest strength
32
Drugs for treatment and chemoprevention of malaria
Tim Wells Chief Scientific Officer MMV
Products with impact
Molecule
Lumefantrine 4 x 480 mg 2000 mg over 3 days
900 960
Artemether 4 x 80 mg 455
Ferroquine 3 x 200 mg 794
KAF156 1 x 800 mg 67
DSM265 1 x 400 mg 89
PCR corrected
Options for clinical development
Phase IIb One day ndash three days Adults and children
Dose range to satisfy FDA combination rule
2017-18
Single Dose Phase III program
Confirm safety 2019-20
Single dose cohort safe
and gt95 efficacy
Multiple dose Phase III program
Confirm safety 2019-20
Three day cohort safe
and gt95 efficacy
Launch single dose cure
2021
Launch multiple dose
cure 2021
Phase III with three drug
combination 2021- 2
Drug interaction studies with third partner (at risk)
Eliminating the last parasite
Are medicines safe and well tolerated enough to use in subjects with
bull Repeated infection
bull asymptomatic infection
bull undiagnosed early pregnancies
bull in HIV patients (co-medication immunosuppresed)
bull malnutrition
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
A glass half full ndash How we are doing
Blood stage killers fast and long acting
610
Chemoprevention liver schizonticides
510
Transmission blocking safely sparing primaquine
410
Relapse Prevention 810
A glass half full ndash How we are doing
Blood stage killers fast and long acting safe and well tolerated for asymptomatics
310
Chemoprevention liver schizonticides once per month once per season
2510
Transmission blocking safely sparing primaquine
410
Relapse Prevention in G6PD- individuals
010
If you want to go fast go alone If you want to go far go together
Our partnerships are our greatest strength
32
Drugs for treatment and chemoprevention of malaria
Tim Wells Chief Scientific Officer MMV
Products with impact
Molecule
Lumefantrine 4 x 480 mg 2000 mg over 3 days
900 960
Artemether 4 x 80 mg 455
Ferroquine 3 x 200 mg 794
KAF156 1 x 800 mg 67
DSM265 1 x 400 mg 89
PCR corrected
Eliminating the last parasite
Are medicines safe and well tolerated enough to use in subjects with
bull Repeated infection
bull asymptomatic infection
bull undiagnosed early pregnancies
bull in HIV patients (co-medication immunosuppresed)
bull malnutrition
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
A glass half full ndash How we are doing
Blood stage killers fast and long acting
610
Chemoprevention liver schizonticides
510
Transmission blocking safely sparing primaquine
410
Relapse Prevention 810
A glass half full ndash How we are doing
Blood stage killers fast and long acting safe and well tolerated for asymptomatics
310
Chemoprevention liver schizonticides once per month once per season
2510
Transmission blocking safely sparing primaquine
410
Relapse Prevention in G6PD- individuals
010
If you want to go fast go alone If you want to go far go together
Our partnerships are our greatest strength
32
Drugs for treatment and chemoprevention of malaria
Tim Wells Chief Scientific Officer MMV
Products with impact
Molecule
Lumefantrine 4 x 480 mg 2000 mg over 3 days
900 960
Artemether 4 x 80 mg 455
Ferroquine 3 x 200 mg 794
KAF156 1 x 800 mg 67
DSM265 1 x 400 mg 89
PCR corrected
SETTING
THE GOALS
MEASURING
SUCCESS
FINDING THE
MOLECULES
WINNING
COMBINATIONS
A glass half full ndash How we are doing
Blood stage killers fast and long acting
610
Chemoprevention liver schizonticides
510
Transmission blocking safely sparing primaquine
410
Relapse Prevention 810
A glass half full ndash How we are doing
Blood stage killers fast and long acting safe and well tolerated for asymptomatics
310
Chemoprevention liver schizonticides once per month once per season
2510
Transmission blocking safely sparing primaquine
410
Relapse Prevention in G6PD- individuals
010
If you want to go fast go alone If you want to go far go together
Our partnerships are our greatest strength
32
Drugs for treatment and chemoprevention of malaria
Tim Wells Chief Scientific Officer MMV
Products with impact
Molecule
Lumefantrine 4 x 480 mg 2000 mg over 3 days
900 960
Artemether 4 x 80 mg 455
Ferroquine 3 x 200 mg 794
KAF156 1 x 800 mg 67
DSM265 1 x 400 mg 89
PCR corrected
A glass half full ndash How we are doing
Blood stage killers fast and long acting
610
Chemoprevention liver schizonticides
510
Transmission blocking safely sparing primaquine
410
Relapse Prevention 810
A glass half full ndash How we are doing
Blood stage killers fast and long acting safe and well tolerated for asymptomatics
310
Chemoprevention liver schizonticides once per month once per season
2510
Transmission blocking safely sparing primaquine
410
Relapse Prevention in G6PD- individuals
010
If you want to go fast go alone If you want to go far go together
Our partnerships are our greatest strength
32
Drugs for treatment and chemoprevention of malaria
Tim Wells Chief Scientific Officer MMV
Products with impact
Molecule
Lumefantrine 4 x 480 mg 2000 mg over 3 days
900 960
Artemether 4 x 80 mg 455
Ferroquine 3 x 200 mg 794
KAF156 1 x 800 mg 67
DSM265 1 x 400 mg 89
PCR corrected
A glass half full ndash How we are doing
Blood stage killers fast and long acting safe and well tolerated for asymptomatics
310
Chemoprevention liver schizonticides once per month once per season
2510
Transmission blocking safely sparing primaquine
410
Relapse Prevention in G6PD- individuals
010
If you want to go fast go alone If you want to go far go together
Our partnerships are our greatest strength
32
Drugs for treatment and chemoprevention of malaria
Tim Wells Chief Scientific Officer MMV
Products with impact
Molecule
Lumefantrine 4 x 480 mg 2000 mg over 3 days
900 960
Artemether 4 x 80 mg 455
Ferroquine 3 x 200 mg 794
KAF156 1 x 800 mg 67
DSM265 1 x 400 mg 89
PCR corrected
If you want to go fast go alone If you want to go far go together
Our partnerships are our greatest strength
32
Drugs for treatment and chemoprevention of malaria
Tim Wells Chief Scientific Officer MMV
Products with impact
Molecule
Lumefantrine 4 x 480 mg 2000 mg over 3 days
900 960
Artemether 4 x 80 mg 455
Ferroquine 3 x 200 mg 794
KAF156 1 x 800 mg 67
DSM265 1 x 400 mg 89
PCR corrected
Our partnerships are our greatest strength
32
Drugs for treatment and chemoprevention of malaria
Tim Wells Chief Scientific Officer MMV
Products with impact
Molecule
Lumefantrine 4 x 480 mg 2000 mg over 3 days
900 960
Artemether 4 x 80 mg 455
Ferroquine 3 x 200 mg 794
KAF156 1 x 800 mg 67
DSM265 1 x 400 mg 89
PCR corrected
Drugs for treatment and chemoprevention of malaria
Tim Wells Chief Scientific Officer MMV
Products with impact
Molecule
Lumefantrine 4 x 480 mg 2000 mg over 3 days
900 960
Artemether 4 x 80 mg 455
Ferroquine 3 x 200 mg 794
KAF156 1 x 800 mg 67
DSM265 1 x 400 mg 89
PCR corrected
Products with impact
Molecule
Lumefantrine 4 x 480 mg 2000 mg over 3 days
900 960
Artemether 4 x 80 mg 455
Ferroquine 3 x 200 mg 794
KAF156 1 x 800 mg 67
DSM265 1 x 400 mg 89
PCR corrected
Molecule
Lumefantrine 4 x 480 mg 2000 mg over 3 days
900 960
Artemether 4 x 80 mg 455
Ferroquine 3 x 200 mg 794
KAF156 1 x 800 mg 67
DSM265 1 x 400 mg 89
PCR corrected