David Reddy PhD, CEO of MMV - go-wcop.org€¦ · Miniportfolio GSK 2 projects GSK Miniportfolio...

35
Defeating Malaria Together David Reddy PhD, CEO of MMV Developing next-generation malaria medicines to address drug resistance and support malaria elimination efforts

Transcript of David Reddy PhD, CEO of MMV - go-wcop.org€¦ · Miniportfolio GSK 2 projects GSK Miniportfolio...

Page 1: David Reddy PhD, CEO of MMV - go-wcop.org€¦ · Miniportfolio GSK 2 projects GSK Miniportfolio Sanofi Orthologue Leads Heterocycles Univ. Campinas Tetraoxanes LSTM/Univ. Liverpool

Defeating Malaria Together

David Reddy PhD, CEO of MMV

Developing next-generation malaria

medicines to address drug resistance

and support malaria elimination efforts

Page 2: David Reddy PhD, CEO of MMV - go-wcop.org€¦ · Miniportfolio GSK 2 projects GSK Miniportfolio Sanofi Orthologue Leads Heterocycles Univ. Campinas Tetraoxanes LSTM/Univ. Liverpool

To reduce the burden of

malaria in disease-endemic

countries by discovering,

developing and facilitating

delivery of new, effective and

affordable antimalarial drugs

MMV is a Product Development Partnership (PDP)

Our mission is…

Page 3: David Reddy PhD, CEO of MMV - go-wcop.org€¦ · Miniportfolio GSK 2 projects GSK Miniportfolio Sanofi Orthologue Leads Heterocycles Univ. Campinas Tetraoxanes LSTM/Univ. Liverpool

COARTEMDISPERSIBLE

EURARTESIM PYRAMAX

ARTESUNINJECTED

SP-AQ AS-AQ* AS-MQ*

* Transferred from DNDi-led partnership portfolio to MMV-led partnership portfolio 20th May 2015

PYRAMAXGRANULES

MMV:Products launched through our partnerships

Page 4: David Reddy PhD, CEO of MMV - go-wcop.org€¦ · Miniportfolio GSK 2 projects GSK Miniportfolio Sanofi Orthologue Leads Heterocycles Univ. Campinas Tetraoxanes LSTM/Univ. Liverpool

Progress in the fight against malaria

2000-2015

GLOBAL

1.2 billioncases averted

6.2 milliondeaths averted*

60%reduction in malaria-related deaths

5.9 millionchildren’s lives saved*

* Difference between actual malaria deaths occurring between 2001 and 2015 versus projected deaths had incidence and mortality

rates remained unchanged since 2000.

Source: UNICEF and WHO. 2015. Achieving the malaria MDG Target. Reversing the incidence of malaria 2000-2015

Page 5: David Reddy PhD, CEO of MMV - go-wcop.org€¦ · Miniportfolio GSK 2 projects GSK Miniportfolio Sanofi Orthologue Leads Heterocycles Univ. Campinas Tetraoxanes LSTM/Univ. Liverpool

214 millioncases in 2015

91%deaths occur in

Sub-Saharan Africa

70%of deaths are children

<5 years of age

236 000 – 635 000deaths

Source: UNICEF and WHO. 2015. Achieving the malaria MDG Target. Reversing the incidence of malaria 2000-2015

Malaria remains a public health imperative

Page 6: David Reddy PhD, CEO of MMV - go-wcop.org€¦ · Miniportfolio GSK 2 projects GSK Miniportfolio Sanofi Orthologue Leads Heterocycles Univ. Campinas Tetraoxanes LSTM/Univ. Liverpool

Removal of control measures leads to resurgencethe cost of inaction: historical evidence

Source: Investing for a malaria-free world. Action and investment to defeat malaria 2016-2030 (AIM).

WHO Roll Back Malaria (RBM) Partnership 2015.

SUDAN

1975

1977

1979

1981

1983

1985

1987

1989

1991

1993

30%

20%

10%

0%

Program ends

INDIA

1961

1963

1965

1967

1969

1971

1973

1975

1977

1979

1981

1983

4%

8%

12%

0%

Funding withdrawnfollowed by

IRS shortages

THAILAND

1965

1967

1969

1971

1973

1975

1977

1979

1981

1983

1985

1987

8%

6%

4%

2%

0%

Attack phase ends

Page 7: David Reddy PhD, CEO of MMV - go-wcop.org€¦ · Miniportfolio GSK 2 projects GSK Miniportfolio Sanofi Orthologue Leads Heterocycles Univ. Campinas Tetraoxanes LSTM/Univ. Liverpool

WHO global technical strategy for malaria vision and objectives 2016-2030

2

Reduce malaria

case incidence

globally

compared with

2015

>40%

>75%

>90%

3

Eliminate

malaria from

countries

in which it was

transmitted

in 2015

>10 countries

>20 countries

>35 countries

4

Prevent

re-establishment

of malaria in all

countries that

are malaria-free

Re-establishment

prevented

1

Reduce malaria

mortality rates

globally

compared with

2015

>40%

>75%

>90%

2020

2025

2030

Source: Global Technical Strategy for Malaria 2016–2030. World Health Organization, June 2015

http://www.who.int/malaria/publications/atoz/9789241564991/en/

Page 8: David Reddy PhD, CEO of MMV - go-wcop.org€¦ · Miniportfolio GSK 2 projects GSK Miniportfolio Sanofi Orthologue Leads Heterocycles Univ. Campinas Tetraoxanes LSTM/Univ. Liverpool

Malaria elimination and eradication

We can accelerate the trajectory to malaria eradication by

targeting the human reservoir of infection

in asymptomatic persons combined with synchronous

transmission prevention

Target

the human

parasite

reservoir

Effective

transmission

preventionEradication

Adapted from Alan Magill’s BMGF Analytic Framework for Malaria Eradication

Page 9: David Reddy PhD, CEO of MMV - go-wcop.org€¦ · Miniportfolio GSK 2 projects GSK Miniportfolio Sanofi Orthologue Leads Heterocycles Univ. Campinas Tetraoxanes LSTM/Univ. Liverpool

Drugs targeting malaria in 20th Century

Chemotype and related series Biological target Number of molecules

4-aminoquinolines b-haematin 4 (CQ,AQ,PYRO, PIP)

Artemisinins Multiple including haem,

PI3K, ATP6

5 (ART, DHA, ARS,

artemether, arteether)

Amino-alcohols Cytosolic haem? 3 (QUIN, MEF, LUM)

Diaminopyrimidines & diamino-

triazines

DHFR 4 (PYR, trimethoprim, Cl-

and H-cycloguanil)

Anilines DHPS 2 (sulphadoxine,

sulphamethoxazole)

Antibiotics (macrolide, tetracyclines

and lincosamide)

Ribosome 4 (AZI, TET, DOXY, CLIN)

8-aminoquinolines Unknown. Mitochondrial

target?

2 (primaquine, tafenoquine)

Naphthoquinone Cytochrome bc1 1 (Atovaquone)

8 Clinically validated pathways/ chemistry-linked phenotypes

Page 10: David Reddy PhD, CEO of MMV - go-wcop.org€¦ · Miniportfolio GSK 2 projects GSK Miniportfolio Sanofi Orthologue Leads Heterocycles Univ. Campinas Tetraoxanes LSTM/Univ. Liverpool

CQ = chloroquine; SP = sulphadoxine-pyrimethamine; M15 = mefloquine 15 mg/kg body weight; M25 = mefloquine

25 mg/kg body weight; Q = quinine; QT = tetracycline; AM = amodiaquine; PQP = DHA-piperaquine

Anti-malaria drug resistanceDeclining cure rates in SE Asia (%)

In Cambodia a 5-10 fold increase in treatment failure rates

Slide courtesy of Professor Nick White; updated to include DHA-piperaquine day 42 efficacy data for Cambodia from WWARN

1975 1980 1985 1990 1995 2000 2005 2010 2015

100

80

60

40

20

CQ SP

Q

M25

AM

M15

QT

% t

reate

d p

atients

cure

dAM

PQP

Page 11: David Reddy PhD, CEO of MMV - go-wcop.org€¦ · Miniportfolio GSK 2 projects GSK Miniportfolio Sanofi Orthologue Leads Heterocycles Univ. Campinas Tetraoxanes LSTM/Univ. Liverpool

Start with the end in mindTarget Candidate Profiles for the molecules

SECsingle exposure chemoprotection

TCP1 TCP2 TCP3a TCP3b

Fast clearance of parasitaemia

Long-acting post treatment

prophylaxis

Radical cure

Transmission blocking

Long acting

Causal liver or slow onset asexual

Different MOA to SERCaP

TCP4

Alonso P et al., A research agenda for malaria eradication: drugs PLoS Med 8(1): e1000402

Target Candidate Profiles: Burrows JN et al., Malaria J. 12:187 (2013)

SERCaPsingle exposure

radical cure and prophylaxis

Page 12: David Reddy PhD, CEO of MMV - go-wcop.org€¦ · Miniportfolio GSK 2 projects GSK Miniportfolio Sanofi Orthologue Leads Heterocycles Univ. Campinas Tetraoxanes LSTM/Univ. Liverpool

A Liver-stage schizonts

B Blood-stage schizonts

C Gametocytes

D Micro- and Macro-gametes/zygotes

E Ookinetes

F Oocysts

G Sporozoites

Radical cure requires clearance

of all forms of the parasite

Page 13: David Reddy PhD, CEO of MMV - go-wcop.org€¦ · Miniportfolio GSK 2 projects GSK Miniportfolio Sanofi Orthologue Leads Heterocycles Univ. Campinas Tetraoxanes LSTM/Univ. Liverpool

A Liver-stage schizonts

B Blood-stage schizonts

C Gametocytes

D Micro- and Macro-gametes/zygotes

E Ookinetes

F Oocysts

G Sporozoites

Use of common assays across all projects

P. Cynomolgi hypnozoite assay

BPRC, Netherlands

P. vivax liver stages

Mahidol & USF-SMRU, Thailand;

NCBS, India; UCSD, Peru; BMGF

P. berghei liver stage assay

In vitro: UCSD, USA

In vivo: USF, USA

Blood stage activity

Swiss TPH, Switzerland; Syngene,

India; UCSD, USA & Eskitis, Australia

Parasite reduction rate

GSK Tres Cantos; STPH

in vivo huSCID model

GSK Tres Cantos; STPH

Target ID

BMGF Consortium/Cellzome

Gametocyte assay

BMGF; UCSD; Eskitis; GSK

Gamete formation assay

Imperial College UK

Resistance risk assessment

Columbia University, USA

Fields isolates:

Menzies, Australia, CSRS Côte

d’Ivoire, Tororo, Uganda

Membrane feed assay

TropIQ, Netherlands

GSK, Tres Cantos

Page 14: David Reddy PhD, CEO of MMV - go-wcop.org€¦ · Miniportfolio GSK 2 projects GSK Miniportfolio Sanofi Orthologue Leads Heterocycles Univ. Campinas Tetraoxanes LSTM/Univ. Liverpool

HTS Whole parasiteScreened >7 000 000 compounds

Hits to leads25,000 hits (EC50<1 uM)

Identify resistance

New candidatemolecules fordevelopment

Computational model built based on all data

Fastest screen to human trials in less

than four years

Chemistry: All available molecules

Identifies previously overlooked new targets

13in clinical or preclinical

development

Rottman M., et al, Science 325 1175–1180 (2010) | Verras A., et al, Manuscript in preparation

Meister S., et al Science 334 1372–1377 (2011) | Gamo FJ, et al., Nature 465 (7296): 305–310 (2010)

Guiguemde WA, et al., Nature 465, 311–315 (2010) | Wells TNC Science 329 1153–1154 (2010)

16candidatesdelivered

A transformation in drug discovery

In 2007, 95% of advisors preferred reductionism

Page 15: David Reddy PhD, CEO of MMV - go-wcop.org€¦ · Miniportfolio GSK 2 projects GSK Miniportfolio Sanofi Orthologue Leads Heterocycles Univ. Campinas Tetraoxanes LSTM/Univ. Liverpool

MMV candidates targeting malaria in 21st Century

Chemotype and related series Biological Target Number of molecules

Multiple diverse series New - ATP4 4 (KAE609, SJ733,

GSK030, PA92)

Triazolopyrimidine and others New – DHODH 2 (DSM265, DSM421)

Imidazolopiperazine CARL KAF156

Aminopyridine New - PI4K 1 (MMV048)

Quinoline amide New – EF2 1 (MMV121)

Triaminopyrimidine New - V-type H+ ATPase 1 (MMV243)

Quinolone New – bc1 Qi inhibitor 1 (ELQ-300)

Pathways to kill the parasite – doubled in 10 years

25 compounds now identified where no resistance has been generated

Page 16: David Reddy PhD, CEO of MMV - go-wcop.org€¦ · Miniportfolio GSK 2 projects GSK Miniportfolio Sanofi Orthologue Leads Heterocycles Univ. Campinas Tetraoxanes LSTM/Univ. Liverpool

2010 2011 2012 2013 2014 2015

KAE609Novartis

AN3661 ELQ-300DSM421

TakedaSJ733

St Jude/ Eisai

Genz-764DDD107498Merck KGaA

AZ412Partner

finalisation

GSK030GSK

P218BIOTEC

KAF156Novartis

DSM-265Takeda

21A092Drexel

MMV390048TIA

GSK692GSK

AN13762Anacor

candidates12 from phenotypic screens | 2 from target HTS | 2 from historical compounds

Delivered candidates cover all TCPs except

anti-relapse

Anti-relapse assays delivering; earliest candidate

in 2018?

Three projects terminated to date (toxicology/ CMC)

Exploring potential partnering

options early

Continued Parked Terminated

CONFIDENTIAL – MMV internal use only

16

New preclinical candidates 2010–2015

Page 17: David Reddy PhD, CEO of MMV - go-wcop.org€¦ · Miniportfolio GSK 2 projects GSK Miniportfolio Sanofi Orthologue Leads Heterocycles Univ. Campinas Tetraoxanes LSTM/Univ. Liverpool

Whole cellSt Jude/Rutgers/USF

Translational Product development Access

MiniportfolioNovartis

SJ733(St Jude/Eisai)

MMV048(UCT)

Rectal artesunate *Cipla/Strides/WHO-TDR

PreclinicalPatient

confirmatoryPost approval Human

volunteers

Patient exploratory

Regulatory review

1 projectNovartis

P218(Biotec Thailand)

DSM265UTSW/UW/Monash (Takeda)

TafenoquineGSK

MiniportfolioGSK

2 projectsGSK

MiniportfolioSanofi

Orthologue LeadsSanofi

HeterocyclesUniv. Campinas

TetraoxanesLSTM/Univ. Liverpool

DHODHUTSW/UW/Monash

HeterocyclesTakeda

ScreeningMerck KGaA

Pathogen BoxMMV

Other projects24 projects

HeterocyclesEisai

PA92 (Drexel/UW/GNF)

MMV253(AstraZeneca)

Artefenomel(OZ439)/FQSanofi

Cipargamin(KAE609)Novartis

KAF156Novartis

GSK030GSK

DSM421(UTSW/UW/Monash)

Dihydroartemisinin piperaquinePaediatricSigma-Tau

ResearchLead

optimizationLead

generation

DDD498Merck KGaA(Dundee)

HeterocyclesDaiichi-Sankyo

Diversity oriented SynthesisBroad/Eisai

GSK692GSK

AN13762Anacor

PantothenamidesTropIQ/RUMC/Pansynt

HeterocyclesUCT

HeterocyclesCelgene

Open SourceDrug DiscoveryUniv. Sydney

3

UCT943UCT

1. Brand name: Coartem® Dispersible; 2. Brand name: Artesun®; 3. Brand name: Eurartesim®; 4. Brand name: Pyramax® Tablets & Granules; 5. Brand name: ASAQ Winthrop; 6. Brand name: SPAQ-COTM;

Artesunate for Injection Guilin

Dihydroartemisinin-piperaquine Sigma-Tau

Pyronaridine-artesunateShin Poong

Artesunate-amodiaquineSanofi/DNDi

Artesunate-mefloquineCipla/DNDi/Farmanguinhos

Pyronaridine-artesunate PaediatricShin Poong

3

2

4

6

Artemether-lumefantrineDispersibleNovartis

Sulfadoxinepyrimethamine+amodiaquineGuilin

4

1

5

MMV-supported projects

Page 18: David Reddy PhD, CEO of MMV - go-wcop.org€¦ · Miniportfolio GSK 2 projects GSK Miniportfolio Sanofi Orthologue Leads Heterocycles Univ. Campinas Tetraoxanes LSTM/Univ. Liverpool

Predicted & (actual) human half lives,

and resistance

MoA Human dose human t1/2 Resistance Dd2 IC50 fold shift

OZ439 Unknown 800 (24-40) >9 No mutants

KAE609 ATP4 30 16 (40) 7 20

KAF156 Carl 800 (39) 8 100

AN3661 CPSF73 15 x 3 10-12 >9 ?

DSM265 DHOD 400 43 (100) 5.5 800

MMV048 PI4K 20-40 34 (125-237) 6 2

P218 DHFR 35-500 6-45 >9 No mutants

SJ733 ATP4 210-500 8-24 7 300

DDD498 EF2 750 43 6 4810

AZ412 ATP synthase 260/520 36 >9 ?

GSK030 ATP4 1000 11-40 8 632

DSM421 DHOD 215 83 ≤6

AN762 In progress <10/<50 14 6 8

GSK692 Unknown 250/490 34 >9 No mutants

MMV594 PI4K 100-1600 27

MMV943 PI4K 200-400 42

Page 19: David Reddy PhD, CEO of MMV - go-wcop.org€¦ · Miniportfolio GSK 2 projects GSK Miniportfolio Sanofi Orthologue Leads Heterocycles Univ. Campinas Tetraoxanes LSTM/Univ. Liverpool

19

Key translational platforms

Page 20: David Reddy PhD, CEO of MMV - go-wcop.org€¦ · Miniportfolio GSK 2 projects GSK Miniportfolio Sanofi Orthologue Leads Heterocycles Univ. Campinas Tetraoxanes LSTM/Univ. Liverpool

Measuring the MIC

1011 _

109 _

107_

105_

103_

101_

0 2 4 6 8 10 days

microscopic limit

PCR limit

Tota

l n

um

ber

of para

sites

[Concentration] > MIC

[Concentration] > MIC

[Concentration] > MIC

Page 21: David Reddy PhD, CEO of MMV - go-wcop.org€¦ · Miniportfolio GSK 2 projects GSK Miniportfolio Sanofi Orthologue Leads Heterocycles Univ. Campinas Tetraoxanes LSTM/Univ. Liverpool

Controlled human malaria infection (CHMI) modelCollaboration with QIMR-Berghofer

Page 22: David Reddy PhD, CEO of MMV - go-wcop.org€¦ · Miniportfolio GSK 2 projects GSK Miniportfolio Sanofi Orthologue Leads Heterocycles Univ. Campinas Tetraoxanes LSTM/Univ. Liverpool

Using the IBSM model

to de-risk and expedite malaria drug development

* IBSM (induced blood-stage malaria)

Page 23: David Reddy PhD, CEO of MMV - go-wcop.org€¦ · Miniportfolio GSK 2 projects GSK Miniportfolio Sanofi Orthologue Leads Heterocycles Univ. Campinas Tetraoxanes LSTM/Univ. Liverpool

TCP fit • TCP 1,2, 4

Product vision• Part of a single exposure radical cure

• Potential for chemoprophylaxis

MoA• Plasmodium dihydroorotate dehydrogenase

(DHODH) inhibitor

Key features • Novel mechanism of action

Challenges• Cost of goods for API, and formulation

• Reduced relative activity against P. vivax

Status

• Completed Phase IIa in patients with

P. falciparum or P. vivax malaria

• Completed Phase Ib blood-stage challenge

in combination with OZ439

Next

milestone

• Start sporozoite challenge studies in

Germany, 1Q 2016

• Start direct mosquito bite challenge study in

the USA

MMV Project

Director• Dr Thomas Rückle

DSM265NIH/Takeda

(Univ. of Texas

Southwestern/Univ. of

Washington/Monash Univ.)

Page 24: David Reddy PhD, CEO of MMV - go-wcop.org€¦ · Miniportfolio GSK 2 projects GSK Miniportfolio Sanofi Orthologue Leads Heterocycles Univ. Campinas Tetraoxanes LSTM/Univ. Liverpool

Activity of DSM265 against P. falciparum

in the HuSCID mouse model

HuSCID mouse

STPHI Basel

GSK Tres Cantos

Page 25: David Reddy PhD, CEO of MMV - go-wcop.org€¦ · Miniportfolio GSK 2 projects GSK Miniportfolio Sanofi Orthologue Leads Heterocycles Univ. Campinas Tetraoxanes LSTM/Univ. Liverpool

DSM265-13-01: FIM, pilot food & IBSM

challenge study (150 mg DSM265 cohort)

Parameter Value

Lag 12–15 hr

MPC (based on PD data and

PK simulation)

1.4 µg/mL

MPC (based on PK/PD from

clinical data)

0.95 µg/mL

(95% CI = 0.68–1.27)

PRR 2.2 (95% CI = 2.0–2.7)

Parasite clearance half-life 6.6 hours

(95% CI = 5.4–7.2)

Predicted human

efficacious dose

320 mg

QIMR-B: 7 subjects received DSM265 and 2 subjects received MQ

Day

1 2 3 4 50

106

102

104

103

105

S1056 MQ1

S1057 Redo

S1058

S1059

S1060

S1064

S1065

S1068 Redo

Average DSM

S1070 MQ2

Pa

rasite

s/m

L

Page 26: David Reddy PhD, CEO of MMV - go-wcop.org€¦ · Miniportfolio GSK 2 projects GSK Miniportfolio Sanofi Orthologue Leads Heterocycles Univ. Campinas Tetraoxanes LSTM/Univ. Liverpool

• Single centre, open-label, non-comparative study; site: ACSA, Iquitos, Peru

• Two arms: P. vivax and P. falciparum malaria

• Maximum of 3 cohorts per arm with 10 patients per cohort

• DSM265 administered as single dose

• Starting dose: 400 mg; Sequential adaptive design

• Study clinically complete, data base lock 02/2016

• 45 patients enrolled

DSM265 POC study for treatment

of uncomplicated malaria: study design

Page 27: David Reddy PhD, CEO of MMV - go-wcop.org€¦ · Miniportfolio GSK 2 projects GSK Miniportfolio Sanofi Orthologue Leads Heterocycles Univ. Campinas Tetraoxanes LSTM/Univ. Liverpool

P. falciparum 250 mg – Microscopy

P. falciparum 250 mg of DSM265 parasitaemia

F2002

F2003

F2004

F2005

F2008

F2009

F2010

F2007

F2006

F2001

Log p

ara

sites/µ

l

5

4

3

2

1

0

Constants

*non-drug SAE

Rescue

0 24 48 72 200 400 600 800

Never blood smear positive

Stopped based on PCR criteria

Page 28: David Reddy PhD, CEO of MMV - go-wcop.org€¦ · Miniportfolio GSK 2 projects GSK Miniportfolio Sanofi Orthologue Leads Heterocycles Univ. Campinas Tetraoxanes LSTM/Univ. Liverpool

P. falciparum 400 mg of DSM265 parasitaemia

Never blood smear positive

Stopped based on PCR criteria

F1002

F1003

F1004

F1005

F1008

F1009

F1010

F1007

F1006

F1001

Time (hours)

Log p

ara

sites/µ

l

P. falciparum 400 mg – Microscopy

5

4

3

2

1

0

0 24 48 72 200 400 600 800

Rescue

Page 29: David Reddy PhD, CEO of MMV - go-wcop.org€¦ · Miniportfolio GSK 2 projects GSK Miniportfolio Sanofi Orthologue Leads Heterocycles Univ. Campinas Tetraoxanes LSTM/Univ. Liverpool

Key checkpoints using predictive models

HuSCID mouse

STPHI Basel

GSK Tres Cantos

Human Challenge 150mg

QIMR-Berghofer 2012

Tübingen 2015

Patient PoC 400 mg

Peru 2015

Ethiopia 2017

Page 30: David Reddy PhD, CEO of MMV - go-wcop.org€¦ · Miniportfolio GSK 2 projects GSK Miniportfolio Sanofi Orthologue Leads Heterocycles Univ. Campinas Tetraoxanes LSTM/Univ. Liverpool

Partner selection matrix

Factor High Score (5) Low Score (1)

TPP - SERCaP TCP1, 2 and 3 Insufficient TCP1 & 2

Safety Different organ tox & manageable Same organ tox + SAEs

Dev stage Both drugs approved Both preclinical stage

PK- time > MPC Complete overlap > MPC for > 2wk Very short acting + very long acting

Total Dose (mg) <150mg >1200mg

BCS - formulation No challenges Two drugs with bad formulation

Prophylaxis - liver stage Both drugs 3-4wks > MPC Neither has >1 wk prophylaxis

Resistance None to either drug Widespread to 1 or 2 drugs

Food effect No food effect for both Both food effect + severe safety

issue

DDI between partners No predicted DDI Clinically concerning DDI

DDI with other conc-med No predicted DDI Clinically concerning DDI

MOAs Complementary Identical MOA + resistance mutation

IP flexibility Two drugs from same group Owner unwilling to partner

Wes van Voorhis, MD PhD, Stephan Chalon MD PhD

Page 31: David Reddy PhD, CEO of MMV - go-wcop.org€¦ · Miniportfolio GSK 2 projects GSK Miniportfolio Sanofi Orthologue Leads Heterocycles Univ. Campinas Tetraoxanes LSTM/Univ. Liverpool

Portfolio evaluation tool for prioritizing partner

drugs for a single-encounter radical cure (SERC)

Mefloq

PQP

FQ

KAF156

0

5

10

15

20

25

30

35

40

TCP1

+TCP2,

3

IP o

wne

r fle

xibi

lty

Proph

ylax

is

Differ

ent M

OA

Mat

ched

Tim

e > M

PC

Dev

Sta

ge

Safet

y/Diff O

rgan

tox

Diff e

limin

mec

h

Qua

ntity

of t

wo

need

ed

No

drug

xdru

g in

tera

ctio

ns

BCS/F

orm

ulat

ion

issu

es

No

food

effe

ct

Res

ista

nce

issu

es

Mefloq Pyronaridine PQP KAE609 FQ DSM265 KAF156 MMV048

Partner drugs for OZ439

March 2016

Page 32: David Reddy PhD, CEO of MMV - go-wcop.org€¦ · Miniportfolio GSK 2 projects GSK Miniportfolio Sanofi Orthologue Leads Heterocycles Univ. Campinas Tetraoxanes LSTM/Univ. Liverpool

SERCaP combination score: DSM265

Marketed Drugs Total Score

Piperaquine 79

Atovaq-Proguanil 65

Lumefantrine 64

Pyronaridine 63

Amodiaquine 58

Azithromycin 52

Mefloquine 50

NCEs Total Score

Phase 2 Candidates

OZ439 86

KAE609 85

Ferroquine 65

KAF156 59

Phase1 Candidates

MMV048 70

ACT840 64

Page 33: David Reddy PhD, CEO of MMV - go-wcop.org€¦ · Miniportfolio GSK 2 projects GSK Miniportfolio Sanofi Orthologue Leads Heterocycles Univ. Campinas Tetraoxanes LSTM/Univ. Liverpool

Pilot IBSM study with drug combination

DSM265/OZ439: study design and concept

• Single dose of each drug does not eliminate all parasites

• Low doses of OZ439 and DSM265 would allow observation of a

combination effect- Change of PRR

- Apparent MIC

- Proportion with recrudescence

- Time to recrudescence

- Presence of gametocytes

• 2 cohorts, 200/100 mg and 200/50 mg OZ439/DSM265

• Selection of drug combination for further studies

Page 34: David Reddy PhD, CEO of MMV - go-wcop.org€¦ · Miniportfolio GSK 2 projects GSK Miniportfolio Sanofi Orthologue Leads Heterocycles Univ. Campinas Tetraoxanes LSTM/Univ. Liverpool

Pilot IBSM study with drug combination

DSM265/OZ439: results

RecrudescenceCohort 1: 200/100 mg OZ439/DSM265: 4/8

Cohort 2: 200/50 mg OZ439/DSM265: 5/5

95% Confidence Interval =

Mean 1.96*SD

DSM265: 100 mg OZ439: 200 mg

DSM265: 150 mg

OZ439: 200 mg

DSM265: 50 mg OZ439: 200 mg

Time (hours)

-100 -50 0 50 100 150 200

0.1

1.0

10.0

100.0

1000.0

% P

ara

site

s r

ela

tive

to

ba

se

line

Page 35: David Reddy PhD, CEO of MMV - go-wcop.org€¦ · Miniportfolio GSK 2 projects GSK Miniportfolio Sanofi Orthologue Leads Heterocycles Univ. Campinas Tetraoxanes LSTM/Univ. Liverpool

MMV is grateful for the support of the following

committed donors

35