MMV Annual_Report_2015, My Interview

ANNUAL

REPORT

2015

Medicines for Malaria

Venture (MMV) is recognized as a leading

product development partnership in the field of antimalarial drug research

and development. It was established as a foundation in 1999

in Switzerland.

MMV’s mission is to reduce the burden of malaria in disease-endemic countries by

discovering, developing and delivering new,

effective and affordable antimalarial drugs.

MMV’s vision is a world in which these

innovative medicines will cure and protect the vulnerable and under-

served populations at risk of malaria, and help

to ultimately eradicate this terrible disease.

© June 2016 Medicines for Malaria VentureAll rights are reserved by Medicines for Malaria Venture. The document may be freely reviewed and abstracted, with a clear and appropriate acknowledgement of source, but is not for sale or for use in conjunction with commercial purposes.

Requests for permission to reproduce or translate the document, in part or in full, should be addressed to the administration of Medicines for Malaria Venture, where information on any translation or reprints is centralized.

MMV Disclaimer This document contains certain forward-looking statements that may be identified by words such as ‘believes’, ‘expects’, ‘anticipates’, ‘projects’, ‘intends’, ‘should’, ‘seeks’, ‘estimates’, ‘future’ or similar expressions, or by discussion of, among

other things, vision, strategy, goals, plans, or intentions. It contains hypothetical future product target profiles, development timelines and approval/launch dates, positioning statements, claims and actions for which the relevant data may still

have to be established. Stated or implied strategies and action items may be implemented only upon receipt of approvals including, but not limited to, local institutional review board approvals, local regulatory approvals, and following local laws

and regulations. Thus, actual results, performances or events may differ from those expressed or implied by such statements. We ask you not to rely unduly on these statements. Such forward-looking statements reflect the current views of

Medicines for Malaria Venture (MMV) and its partner(s) regarding future events, and involve known and unknown risks and uncertainties.

MMV accepts no liability for the information presented here, nor for the consequences of any actions taken on the basis of this information. Furthermore, MMV accepts no liability for the decisions made by its pharmaceutical partner(s), the

impact of any of their decisions, their earnings and their financial status.

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ContentsTooling up to bring malaria down

Message from the Chairman and CEO 4

Key achievements 6

MMV strategic overview 8

MMV-supported projects 9

Working with regulators to advance access to quality medicines

Message from Wendy Sanhai and Wiweka Kaszubska 10

Developing next-generation medicines

Addressing resistance and improving compliance 12

Aiming to stop relapsing malaria with a single-dose treatment 22 Advancing the science of eradication

MMV’s drug discovery engine 25

Opening up malaria drug discovery 26

Open access initiatives to catalyse drug discovery 27

New models to discover new molecules against the relapse 28

MMV Project of the Year 2015: GSK692 30

Getting better medicines to more people

Developing treatment options for children 32

Facilitating sustainable uptake of injectable artesunate 34

Buying time to save lives with rectal artesunate 36

Aiming for elimination 37

Protecting children at their most vulnerable 38

Improving malaria chemoprevention and treatment during pregnancy 39

Financial view 40

Behind the scenes 56

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1 | Tooling-up to bring malaria down

4

1

Dr David Reddy

CEO

Mr Per Wold-Olsen

Chairman of the Board

Message from the Chairman and CEO

Fired by our mission, in 2015 MMV

tooled up to drive the develop-

ment of new medicines and increase

access to antimalarials for vulnerable

populations – contributing to the global

effort to bring the burden of malaria

down to zero.

The year also marked a key milestone

for the entire malaria community – the

transition from the MDGs to the SDGs.

MMV is proud to have played its part

in the achievement of malaria-related

Millennium Development Goal (MDG)

6.C – to halt and begin to reverse

the incidence of malaria by 2015.

The intensified scale-up of control

measures like bed nets, insecticides

and medicines saved the lives of more

than 6 million people from malaria since

2000, including 5.9 million children

under 5 years of age.1

Yet malaria continues to kill and

debilitate, keeping people entrenched

in poverty and threatening the lives of

young children. More than 300,000

children died from malaria in 2015

alone. The newly adopted Sustainable

Development Goals (SDGs) for 2030

recognize the critical need to pull people

out of poverty into universal health and

prosperity. Stopping scourges like

malaria is one of the cornerstones to

achieving this.

With this end in mind, key global players

recommitted to malaria eradication with

the publication of several far-sighted

reports. The World Health Organization

launched The Global Technical Strategy

for Malaria 2016–2030,2 and the Roll

Back Malaria Partnership launched

Action and Investment to defeat Malaria

2016–2030 (AIM) – for a malaria-

free world.3 Both reports target a

fall of 90% in malaria incidence and

mortality rates by 2030. A plan to

pave the way for malaria elimination

by 2040, From Aspiration to Action,4

was also launched in a joint initiative by

the United Nations Secretary-General’s

Special Envoy for Health in Agenda

2030 and for Malaria, Ray Chambers,

together with the Bill & Melinda Gates

Foundation. In addition, India recently

published its National Framework for

Malaria Elimination.5 Each of these

reports emphasize the need for universal

coverage of core interventions like bed

nets, insecticide sprays, diagnostics

and medicines for all populations at risk.

Increasing the range of high-quality

medicines available to treat these

populations is vital and we are delighted

to report that in 2015 MMV brought

forward another new, high-quality

medicine through registration, bringing

MMV and partners’ total contribution

to six. Child-friendly Pyramax® granules

(pyronaridine-artesunate) (page 32-33)

developed with Shin Poong Pharma -

ceutical received positive scientific

opinion under Article 58 from the

European Medicines Agency and joined

MMV’s first co-developed medicine,

Coartem® Dispersible (artemether-

lumefantrine), as the second stringently

approved paediatric artemisinin-

based combination therapy (ACT).

While much work remains to maximize

the impact of this and other quality

medicines in saving lives, the number

of MMV-supported treatments delivered

continues to rise. For example, in 2015

Coartem Dispersible, co-developed with

Novartis, reached the landmark of 300

million treatments delivered since its

launch.

Looking to the ultimate eradication

of malaria, the strategic reports also

highlight the critical need to develop

new transformational tools, such as

single-dose cures and medicines

to tackle resistance. MMV and its

partners continue to tool up for the

challenge. Of 65 drug development

projects, eight have progressed to

Tooling up to bring malaria down

Mahatma Gandhi

A small body of

determined spirits fired

by an unquenchable faith

in their mission can alter

the course of history.”

“

5

clinical development targeting unmet

needs, including medicines for children,

pregnant women, and people suffering

from relapsing or drug-resistant malaria.

We are developing a new business

plan for the next 5 years and prioritizing

research and delivery activities for the

eradication agenda. Our portfolio of

projects is evolving like never before.

If we are to help the global health

community meet the SDGs by 2030, we

have no time to lose. We are rigorously

testing promising compounds, both

singly and in combination, to ensure

they are fit to progress through the

pipeline. To accelerate the process,

we have begun parallel programmes;

notably artefenomel (OZ439) (page 16)

which, in partnership with Sanofi, was

trialled in combination with piperaquine

(PQP) and also with ferroquine (FQ).

Early indicators showed that the

artefenomel+PQP combination was

unlikely to meet the rigorous criteria for

a single exposure radical cure. While

this setback serves as a reminder that

drug development is complex, risky

and uncertain, MMV was able to rapidly

progress the parallel programme of

artefenomel+FQ while deploying efforts

to other high-potential prospects. These

include DSM265 (page 17), a new

molecule with promise as a single-dose

cure or prophylaxis, which succeeded in

demonstrating initial proof of efficacy as

an antimalarial.

Meanwhile, our partnership network

continues to expand with several new

partners joining the MMV fold: Mitsubishi

Tanabe Pharma, Daiichi Sankyo, OP Bio

Factory Co. and Sumitomo Dainippon

Pharma from Japan and Merck

Serono from Germany. As our network

increases, so does the quantity and

quality of the molecules in our portfolio

alongside the tools and platforms to test

and refine them.

To stay at the cutting edge, we constantly

challenge the status quo. For example,

over the years MMV and partners have

been pioneering more open ways of

working, from publishing screening data

in the public domain in 2010 to launching

the open access Malaria Box, and more

recently the Pathogen Box (page 27).

These two collections of carefully

selected active compounds distributed

for free have proved to be a hit. By

responding to the need for researchers

to access physical compounds, the

projects are helping to catalyse new

drug discovery programmes around the

world. In recognition of this work, MMV

was proud to receive the Tim Berners-

Lee Open Data Innovation Award for the

Malaria Box thanks to a nomination from

the UK Department for International

Development.

Through open research initiatives like

these, as well as sharing our expertise

and resources, MMV’s impact is

stretching beyond the malaria field.

During the Ebola outbreak in West

Africa in 2014–2015, MMV and partners

temporarily stopped a clinical trial in

Guinea yet continued to fund resources

and support the staff thus enabling

them to focus on tackling the outbreak.

Today, the trial’s Principal Investigator is

the focal point for Ebola in Guinea, in

part thanks to the good clinical practice

training he received as part of this

involvement.

As we reflect on 2015, both in terms of

MMV’s progress and that of the wider

malaria community, it’s clear we have

much to celebrate, yet much remains to

be done for the global malaria community

to reach the very ambitious targets it has

set itself. Haunted by the tragedy of

the failed global malaria eradication

campaign in the 1950s and 1960s, in

part caused by waning commitment for

the last-mile push, concerns about the

risk of declining global focus on malaria

remain real until our ultimate goal is

achieved.

MMV’s achievements in 2015 would

not have been possible without the

determination of the team, as well

as the commitment of our donors,

partners and Board of Directors. We are

immensely grateful for this support and

a special debt of gratitude is owed to

Ray Chambers. Ray stepped down after

4 years as Chairman of MMV’s Board of

Directors in 2015, entrusting the role to

Vice Chair, Per Wold-Olsen. Fortunately

for us, thanks to his ongoing role as UN

Special Envoy for Health in Agenda 2030

and for Malaria, MMV will continue to

benefit from his leadership as will the rest

of the malaria community.

The American scholar Warren G Bennis

once said: “Leadership is the capacity to

translate vision into reality.” MMV’s vision

to develop innovative medicines for

vulnerable populations at risk of malaria

is a reality thanks to Ray’s leadership.

Today we are poised to deliver the next-

generation medicines to help change the

course of history and bring malaria cases

down to zero.

1 World Health Organization. World Malaria Report 2015 (2015): http://www.who.int/malaria/publications/world-malaria-report-2015/report/en/

2 World Health Organization. Global Technical Strategy for Malaria 2016–2030, (2015): http://www.who.int/malaria/areas/global_technical_strategy/en/

3 The Roll Back Malaria Partnership. Action and Investment to defeat Malaria 2016–2030 (AIM) – for a malaria-free world (2015): http://www.rollbackmalaria.org/about/about-rbm/aim-2016-2030

4 From Aspiration to Action – What will it take to end malaria? UN Secretary-General’s Special Envoy for Health in Agenda 2030 and for Malaria, Bill & Melinda Gates Foundation (2015): http://endmalaria2040.org/

5 Government of India. National Framework for Elimination of Malaria (2016): http://www.searo.who.int/india/publications/national_framework_malaria_elimination_india_2016_2030.pdf?ua=1


6

health-care workers across 1,650 health-care facilities in six

African countries trained to administer injectable artesunate

for severe malaria, via Clinton Health Access Initiative and the

Malaria Consortium in the MMV-led Improving Severe Malaria

Outcomes (ISMO) Project funded by UNITAID

18,000

300 million

medicine for children approved; Pyramax® granules

(pyronaridine-artesunate), co-developed with Shin Poong,

received positive scientific opinion from the European

Medicines Agency via its Article 58 procedure

treatments of Coartem® Dispersible (artemether-lumefantrine) for children,

co-developed with Novartis, delivered

to over 50 countries

New

compounds active against

neglected diseases (the

Pathogen Box) available

for free to boost drug

research

9new medicines in clinical

development prioritizing

eradication and treatment

for vulnerable populations

including children and

pregnant women

ACTs (artesunate-

amodiaquine & artesunate-

mefloquine), developed by

DNDi and partners

transitioned to MMV’s

portfolio

2MMV wins Open Data

Innovation Award for work

on the Malaria Box

1st

400

Key

achie

ve

7

children across the Sahel region benefit from

Seasonal Malaria Chemoprevention using

sulfadoxine-pyrimethamine+amodiaquine,

supplied by MMV’s partner Guilin Pharma

3 million

of investment impact thanks to direct

and in-kind support from partners

USD 1 = USD 3.5

2dossiers for rectal

artesunate suppositories

submitted for WHO

prequalification

by Cipla and Strides

drug candidates brought

forward from discovery

research since 2010

17

doses of Eurartesim® (dihydroartemisinin-piperaquine),

co-developed with Sigma-Tau, distributed in

two ground-breaking mass drug administration

pilots in Zambia and Mozambique

>200,000

2 0 1 5

ments vials of Artesun® (Guilin Pharma’s injectable artesunate)

delivered to treat children with severe malaria, saving

an estimated additional 300,000–350,000

lives compared to quinine treatment

52.9 million


8

MMV strategic overview – from malaria control to eradication

To save lives from malaria today

and tomorrow, MMV focuses on

two broad areas: maximizing the use

of current medicines and developing

next-generation medicines to support

elimination and eventual eradication.

Maximizing the impact of current

medicines both for treatment and

protection of vulnerable populations

involves developing formulations for

children and gathering data on the

tolerability of medicines in pregnant

women – the two most at-risk groups.

In addition, we are working with partners

studying the use of currently available

medicines co-developed by MMV

for Mass Drug Administration (MDA)

programmes (page 37). This strategy

has been shown to accelerate the

trajectory to elimination and eradication

by targeting the human reservoir of

malaria infection and thereby reducing

transmission.1

In line with the World Health Organization

(WHO)’s Global Technical Strategy

for Malaria 2016–2030,2 and From

Aspiration to Action3 from the UN and

the Bill & Melinda Gates Foundation,

we are focused on developing future

transformational medicines to get us

from malaria control to eradication.

Given the long-term nature of research

& development (R&D) it is important

to know the characteristics of these

medicines, as described by their Target

Product Profiles (TPPs).

The TPPs of medicines needed for

malaria eradication fall into two broad

categories: treatment and protection.

The ideal medicine for treatment would

be a Single Encounter Radical Cure and

Prophylaxis (SERCaP), effective against

resistant strains of malaria that will

help improve compliance and provide

prophylaxis for at least one month after

treatment; and for protection, a Single

Exposure Chemoprotection (SEC)1

(see Table 1) for vulnerable populations.

Ideally, both medicines would be

suitable for MDA.

Delivering a single exposure medicine

places an extraordinary demand on

a molecule in terms of the required

pharmacokinetics, potency, absolute

dose, safety, tolerability and formulation;

consequently, a trade-off must be

navigated between single- and

multiple-dose therapies, particularly

when multiple-dose regimens show

activity against current resistant

strains. Although 3 days is the longest

acceptable regimen, our goal remains

the development of a single exposure

medicine.

The development of either SERCaP or

SEC will require the combination of at

least two active molecules; MMV has

defined five Target Candidate Profiles

(TCPs) for them corresponding to the

different clinical attributes needed for

the TPPs (see key features column of

Table 1).

To identify these active molecules,

develop future medicines and support

the use of current medicines, MMV is

working extensively with its growing

network of partners that today number

over 400. In 2015, the network was

augmented by the addition of four

new Japanese drug discovery partners

through the Global Health Innovation

and Technology Fund (GHIT Fund)

and Merck Serono, with whom we are

progressing a promising antimalarial

compound, DDD498 (page 20), through

preclinical development.

1 World Health Organization. Guidelines for the treatment of malaria. Third edition. (2015): http://apps.who.int/iris/ bitstream/10665/162441/ 1/9789241549127_ eng.pdf

2 World Health Organization. Global Technical Strategy for Malaria 2016–2030, (2015): http://www.who.int/malaria/areas/global_ technical_strategy/en/

3 From Aspiration to Action – What will it take to end malaria? UN Secretary- General’s Special Envoy for Health in Agenda 2030 and for Malaria, the Bill & Melinda Gates Foundation (2015): http://endmalaria2040.org/

Liver schizonts

TPP and attributes Key features TCP and lifecycle stage

Chemoprevention

The SERCaP (Single Exposure Radical Cure

and Prophylaxis)

D Single dose

D Single exposure

D Radical cure

D Targeting all lifecycle stages

D Treating all five species to infect humans

D High barrier to resistance

The SEC (Single Exposure Chemoprotection)

D Single exposure

D Suitable for mass administration at frequent intervals

D Chemoprevention for all five species to infect humans

D Orthogonal mechanism of action

Treatm

ent

Pre

venti

on

Asexual blood-stage activity

Fast clearance

Long duration of action/post treatment prophylaxis

Liver-stage activity/relapse prevention

Transmission reduction(gametocytocidal or sporontocidal)

Blood stage

Blood stage

Schizonts/Hypnozoites

Gametocytes

Table 1: Attributes of Target Product Profiles and Target Candidate Profiles for eradication

9

MMV-supported projects – 4th quarter 2015

ESAC Expert Scientific Advisory Committee

GSB Global Safety Board

MMV Board of Directors/Executive Committee/Financial Audit Committee

APMACAccess and Product ManagementAdvisory Committee

APAC Authorization for Phase III/Advancement Committee

Access andProduct

Management

GO

VE

RN

AN

CE

Research Translational Product developmentLead

optimizationPreclinical Human

volunteersPatient

exploratoryPatient

confirmatoryRegulatory

reviewPost

approval

Access

Miniportfolio Novartis

1 project Novartis

Miniportfolio GSK

Miniportfolio Sanofi

2 projectsGSK

OrthologueleadsSanofi

TetraoxanesLiverpool School of Trop Med/Univ. Liverpool

DHODHUniv. of Texas Southwestern/Univ. Washington/Monash Univ.

HeterocyclesUniv. Cape Town

HeterocyclesCelgene

HeterocyclesUniv. Campinas

Heterocycles Daiichi-Sankyo

Heterocycles Takeda

Heterocycles Eisai

ScreeningMerck Serono

Whole cellSt Jude/Rutgers Univ./Univ. of South Florida

DiversityorientedsynthesisBroad/Eisai

Other projects 24 projects

P218 (Biotec

Thailand)

MMV048Univ. Cape Town/ Technology Innovation Agency

DSM265(Univ. of TexasSouthwestern/Monash Univ.//Univ. ofWashington)/Takeda

Artemether- lumefantrinedispersible Novartis

Artesunate for injection Guilin

Dihydro-artemisinin- piperaquine Sigma-Tau

Pyronaridine-artesunateShin Poong

Artesunate- amodiaquine

Sanofi/DNDi

Open Source Drug DiscoveryUniv. Sydney

OZ439/PQPSanofi

Leadgeneration

Rectal artesunate Cipla/Strides/WHO-TDR

Pathogen BoxMMV

Artesunate- mefloquine

Cipla/DNDi

Tafenoquine GSK

Dihydro-artemisinin-piperaquinepaediatric Sigma-Tau

Pyronaridine-artesunatepaediatricShin Poong

KAE609 Novartis

KAF156Novartis

SP+AQ(sulfadoxine-pyrimethamine + amodiaquine)Guilin

DDD498Merck Serono/ (Univ. Dundee)

PA92(Drexel Univ./ Univ. Washington/ Genomics Institute of the Novartis Research Foundation)

MMV253(AstraZeneca)

GSK030GSK

SJ733St Jude/Eisai

DSM421(Univ. of Texas Southwestern/Monash Univ./Univ. of Washington)

GSK692GSK

AN13762Anacor

OZ439/FQSanofi

3 day treatment products – TPP1

› Artemether-lumefantrine dispersible (Coartem® Dispersible), generic by Ajanta

› Dihydroartemisinin-piperaquine (Eurartesim®)

› Dihydroartemisinin-piperaquine paediatric (Eurartesim®)

› Pyronaridine-artesunate (Pyramax®)

› Pyronaridine-artesunate paediatric (Pyramax®)

› Artesunate-amodiaquine (CoarsucamTM, ASAQ/Winthrop®) FDC generics by Ajanta,

Ipca, Guilin and co-blistered generics by Strides & Cipla

› Artesunate-mefloquine, co-blistered generic by Acino/Mepha

New compounds to contribute to SERCaP or MERCaP

(Multiple exposure radical cure prophylaxies) – TPP1

Seasonal malaria chemoprevention

› Sulfadoxine-pyrimethamine + amodiaquine (SP+AQ)

Severe malaria

› Rectal artesunate

› Artesunate for injection (Artesun®)

Relapse prevention

› Tafenoquine

The malaria community has defined two Target Product Profiles (TPPs) for medicines to make

eradication achievable: TPP1: a treatment combination that is ideally a Single Exposure Radical

cure and Prophylaxis (SERCaP) and TPP2: Single Exposure Chemoprotection (SEC).

Target Product Profiles

Brought into portfolio after approval. Collaboration with DNDi

Pending review or approval by WHO Prequalification, or by regulatory bodies

who are ICH members or observers

See Table 1 for descriptions of Target Candidate Profiles illustrated by the icons.

2 | Message of Wendy Sanhai and Wiweka Kaszubska

10

Dr Wendy Sanhai

MMV Board Member;

Associate Professor

(adj), School of Medicine,

Duke University, USA

Dr Wiweka Kaszubska

Vice President, Head of

Product Development,

MMV

2 Working with regulators to advance access to quality medicines

Quality is critical to MMV’s mandate.

We strongly believe that everyone,

rich or poor, deserves the most effective

and best tolerated treatments possible

when they are sick. Thus, we are

dedicated to developing innovative

medicines of the highest quality to

address the unmet medical needs of

vulnerable people at risk of malaria.

The best way to ensure quality is by

meeting the rigorous guidelines of

stringent regulatory authorities (SRAs),1

for example, those of the US Food

and Drug Administration (FDA), the

European Medicines Agency (EMA),

Swissmedic or the World Health

Organization (WHO)’s prequalification

programme. SRA approval or opinion

indicates a new medicine has met the

highest levels of safety and effective-

ness in the specific patient populations

in which it was studied. These interna-

tionally recognized approvals also

enable medicines to be procured and

distributed by international funding

bodies, such as the Global Fund to

Fight AIDS, Tuberculosis and Malaria.

The SRA assessment process of a new

drug application (NDA) often takes about

a year. To make the process as smooth

as possible, MMV engages proactively

with regulators early in the drug

development process. Ahead of dossier

submission, we ensure compliance

with the clinical data requirements and

incorporate regulatory guidance into

the design of our protocols and trials.

This decreases the risk of the dossier

failing to meet the SRA’s standard and

makes the process more efficient. In

addition, this collaborative relationship

with regulators, as well as with our

development partners, allows MMV to

leverage drug development experience

and know-how towards the ultimate

goal of benefiting patients.

SRAs are keenly aware of the need for

expedited development of drugs for

neglected tropical diseases and malaria.

In 2012, under its Food and Drug

Administration Safety and Innovation

Act,2 the FDA started the newest of

four expedited review and development

mechanisms for drug development:3

Breakthrough Therapy Designation.4

MMV/GlaxoSmithKline (GSK) received

this designation in 2013 for tafenoquine

(pages 22-23). Consequently, we have

had a number of consultations with the

FDA during the phase IIb and III studies

for tafenoquine and expect that the

application will undergo an expedited

review. The benefit of regular, real-time

feedback translates to shorter drug

development timelines which ultimately,

for patients, means earlier access to life-

saving therapies. To prepare the ground,

MMV has also begun working closely

with regulators in malaria-endemic

countries to make the drug available as

quickly as possible.

To make the process

as smooth as possible,

MMV engages

proactively with

regulators early in the

drug development

process.”

“

11

The EMA is also engaged in activities

to support approval of medicines

for neglected diseases. Since 2004,

in cooperation with WHO, the EMA

has been undertaking regulatory

assessments and providing scientific

opinion on products not intended for

use in Europe through the Article 58

procedure. Pyramax® (pyronaridine-

artesunate), developed by MMV and

Shin Poong, was the first antimalarial to

be granted a positive scientific opinion

by the EMA under Article 58 in 2012

(pages 32-33). In 2015, we were

invited by the EMA to review whether

other drugs in development might be

appropriate for the Article 58 procedure.

We took the opportunity to provide

insights gleaned from discussions with

endemic country regulators on how

Article 58 could be used to expedite

regional approvals.

Beyond the regulatory engagement

on individual drug development

programmes, MMV is representing the

wider global health community and

putting the challenges of antimalarial

drug development even higher on the

FDA’s radar screen. In 2015, we held

an MMV pipeline overview meeting at

the FDA where some of the challenges

were outlined. MMV also proposed a

scientific workshop – bringing together

global experts to discuss challenges

in antimalarial drug development.

The FDA will be hosting this event on

30 June 2016 to identify and bridge

clinical and scientific gaps in antimalarial

drug development, and inform future

regulatory decisions.

MMV also works closely with partners

to ensure their medicines meet the

criteria for inclusion in the WHO list of

prequalified medicines. We consider

WHO prequalification the seal of approval

for medicines already listed on the WHO

treatment guidelines. Recently, after

working with WHO-TDR 5 on transferring

comparative reference data, MMV has

supported two pharma partners in

their pursuit of prequalification of rectal

artesunate suppositories as a pre-

referral intervention for severe malaria

(page 36).

MMV’s goal is crystal clear: to develop

high-quality antimalarials and ensure

their timely access to vulnerable

populations. By interacting with

regulatory bodies at each stage of

development, and meeting their rigorous

standards, we are working to realize this

goal for malaria patients all around the

world.

1 A regulatory body which is: (a) a member of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) as specified on www.ich.org; or (b) an ICH observer, being the European Free Trade Association (EFTA), as represented by Swissmedic and Health Canada (as may be updated from time to time); or (c) a regulatory authority associated with an ICH member through a legally-binding, mutual recognition agreement currently including Australia, Iceland, Liechtenstein and Norway (http://apps.who.int/prequal/)

2 The Food and Drug Administration Safety and Innovation Act, Public Law 112–144, 112th Congress (2012): https://www.gpo.gov/fdsys/pkg/PLAW-112publ144/pdf/PLAW-112publ144.pdf

3 The FDA’s Four Expedited Review Pathways for Drugs: http://www.fda.gov/forpatients/approvals/fast/ucm20041766.htm

4 The FDA’s Breakthrough Therapy Designation: http://www.fda.gov/ForPatients/Approvals/Fast/ucm405397.htm

5 WHO-TDR: World Health Organization Special Programme for Research and Training in Tropical Diseases.

MMV’s goal is crystal

clear: to develop high-

quality antimalarials

and ensure their timely

access to vulnerable

populations.”

“

3 | Developing next-generation medicines

12

Addressing resistance and improving compliance

3 Developing next-generation medicines

To stem the emergence of drug resistance and reduce its impact, the World Health Organization (WHO)

recommends the use of a combination of two drugs that act in different ways. Recent reports from south-

east Asia and along India’s borders1 of parasite strains resistant to both artemisinin and partner drugs, such as

mefloquine and piperaquine, are thus of great concern.2 Populations of drug-resistant parasites can lead to an overall

reduction in efficacy and treatment failure.3 In the worst case this could lead to an epidemic of drug-resistant malaria.

Without new and effective treatment at hand, we may then start to see a rise in the malaria burden and mortality.

Current artemisinin-based combination therapy (ACT) must be taken once or twice daily over a period of 3 days. Several

studies suggest that patients often do not complete the full course of treatment, which can lead to incomplete cure and

the appearance of drug-resistant pathogens.4

MMV and partners have prioritized the development of new therapies (see Table 2) aiming to solve the challenges of drug

resistance and treatment adherence by identifying molecules with novel mechanisms of action and activity against all-

known resistant parasite strains. The new molecules either kill the parasite quickly, stay in the blood long enough to ensure

complete parasite clearance, and/or can protect against subsequent re-infection. These compounds could form part of a

Single Exposure Radical Cure (SERC) – a single-dose combination expected to ensure better compliance.

The longer-term aim is to develop a Single Exposure Radical Cure and Prophylaxis (SERCaP) that would provide some

form of additional chemoprotection and be suitable for use in mass drug administration programmes. A Multiple Exposure

Radical Cure (MERC)/MERCaP that demonstrates efficacy against key resistant strains may also be considered.

To bring you the latest on these projects, we spoke to key individuals representing MMV and its partners for their unique

insights into the development of next-generation antimalarial medicines for the treatment and prevention of uncomplicated

malaria.

Artemisinin resistance in south-east Asia is increasing

and has the potential to spread to other malaria-endemic

regions. Recently, parasite strains with resistance to the

artemisinin partner drugs have also been reported, which

could lead to loss of treatment efficacy unless alternative

compounds are identified.

In addition, current treatments must be taken over 3 days

and studies suggest that patient adherence is low. This

can lead to incomplete cure and the spread of resistant

pathogen strains.

MMV is identifying new, fast-acting compounds active

against all-known resistant parasite strains. Ultimately,

these compounds will form part of a Single Exposure

Radical Cure and Prophylaxis (SERCaP) treatment to

increase patient compliance, potentially support mass

drug administration campaigns for elimination and

combat the threat of drug resistance.

ISSUE ACTION BY MMV AND PARTNERS

1 Tun KM et al. “Spread of artemisinin-resistant Plasmodium falciparum in Myanmar: a cross-sectional survey of the K13 molecular marker.” Lancet Infect Dis. 15;415-21 (2015).

2 Yeka A et al. “Efficacy and safety of fixed dose artesunate-amodiaquine vs. artemether-lumefantrine for repeated treatment of uncomplicated malaria in Ugandan children.” PLoS One. 1;9(12);e113311 (2014).

3 Phyo AP et al. “Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study.” Lancet. 379:1960-6 (2012).

4 Bruxvoort K et al. “How patients take malaria treatment: a systematic review of the literature on adherence to antimalarial drugs.” PLoS One. 9(1):e84555 (2014).

13

Tafeno-

quine

Arte-

fenomel

(OZ439)

KAE609 KAF156 DSM265 MMV048 SJ733 P218 DDD498

Target

indication

Single-dose

treatment for

relapsing

P. vivax

malaria

Part of a

single expo-

sure radical

cure

Part of a

single expo-

sure radical

cure

Part of a

single expo-

sure radical

cure

Part of a

single expo-

sure radical

cure

Part of a

single expo-

sure radical

cure

Part of a

single expo-

sure radical

cure

Potential for

seasonal

malaria

chemopro-

tection

Part of a

single expo-

sure treat-

ment of un-

complicated

malaria

Partner GSK Sanofi

(Monash

Univ./Univ.

of Nebraska/

Swiss TPH)

Novartis

(Swiss TPH)

Novartis

(Swiss TPH)

NIH/Takeda

(Univ. of

Texas South-

western/

Univ. of

Washington/

Monash

Univ.)

UCT/TIA St Jude/Eisai

(Rutgers/

NIH)

(BIOTEC

Thailand)

Merck (Univ.

of Dundee,

UK)

Stage of

development

Patient con-

firmatory

(phase III)

Patient ex-

ploratory

(phase IIb)

Patient ex-

ploratory

(phase IIa)

Patient ex-

ploratory

(phase IIb)

Patient ex-

ploratory

(phase IIa)

Human

volunteers

Preclinical Preclinical Preclinical

MMV Project

Leader

Dr Wiweka

Kaszubska

Dr Marc

Adamy

Dr Marc

Adamy

Dr Marc

Adamy

Dr Thomas

Rückle

Dr Cristina

Donini

Dr Lidiya

Bebrevska

Dr Emilie

Rossignol

Dr Lidiya

Bebrevska

Fast

parasite

clearance

Long

duration of

action

Potential

to block

transmission

Potential

to prevent

relapse

Potential

for chemo-

protection

Table 2: Activity of MMV-supported molecules in development, 2015

14

Mom Neth, from Oslev village in

Cambodia, is 20 years old and a recently

qualified VMW or Volunteer Malaria

Worker. Each day she goes to the

homes of people suspected of having

malaria. She conducts blood tests and, if

needed, administers medicines. She also

educates people about malaria and how

to use bed nets properly.

Her job is critical in this part of Cambodia,

close to the Thai border. The area has

been the epicentre of malaria drug

resistance on more than one occasion;

first to chloroquine during the first global

malaria eradication campaign in the

1950s and 1960s and, more recently,

to artemisinin and its partner drugs – the

current standard of care.

Malaria has a big impact on the commu-

nity in Oslev village – patients fall ill time and

again as the parasite develops resistance

to each medicine used to treat it.

“When someone gets malaria, they can’t

earn any money to support their family,”

Mom explains. Today, some patients in the

village are taking longer to get better after

artemisinin-based combination therapy

(ACT) than they used to. “After 3 days of

treatment, some patients still feel weak

and continue to have fevers,” Mom

continues.

It is clear that the malaria parasite is

growing resistant to the drugs being

used against it. As some ACTs are taking

longer to cure Mom’s patients she often

needs to give them alternative ACTs.

Mom and other health-care workers in

the region are concerned that the day

may soon come when all ACTs stop

working altogether and they will have

nothing left to treat their patients. We

have to be prepared for that day, with

treatments developed from new chemical

compounds that are effective against

resistant strains and easier to take. It’s the

only way to ensure Mom’s patients and

others suffering from malaria around the

world can continue to be cured from this

deadly disease.

Mom’s story

CAMBODIA

…the day may

soon come

when all ACTs

stop working

altogether…”

“

+

15

Working with partners in

Cambodia and the USA, MMV

is profiling the activity of new and in-

development molecules against drug-

resistant parasites. This information is

helping to determine which molecules

to prioritize in the development of next-

generation medicines active against all

resistant parasites.

Dr Didier Ménard and Dr Benoit

Witkowski from the Malaria Molecular

Epidemiology Unit, Institut Pasteur in

Cambodia have developed an in vitro

assay to enable testing of molecules

against the most multidrug-resistant

parasite strains we know of today

(resistant to artemisinin and partner

drugs). The assay closely emulates the

conditions the parasite experiences

in patients, and the parasite strains

come from recent clinical isolates from

Cambodian patients. This makes the

assay as representative of a real-world

situation as possible. So far, the team

have analysed around 15 compounds

from MMV’s portfolio.

Prof. David Fidock, Columbia University

Medical Center, New York, is defining

the resistance liabilities of MMV-

supported antimalarials using in vitro

culture and drug pressure methods.

These experiments provide insights into

the minimum number of parasites and

time required for resistance to emerge

as well as the degree of resistance.

Since 2011, the Fidock group have

determined the resistance profile of 44

compounds from MMV’s portfolio.

In the future, once a sufficient number of

these compounds have been trialled in

patients, we will also be able to build

a data set, which can then be used

to help extrapolate, based on in

vitro findings, how new compounds

will fare in the field. This will enable

stronger decision-making around which

compounds to develop to counter drug

resistance.

Determining activity of new compounds against resistant parasites

This molecule belongs to a novel class of antimalarial molecules, the imidazolopiperazines. It has recently completed phase IIa studies in

patients in Thailand where it was shown to be highly effective, with rapid clearance of both P. falciparum and P. vivax parasites. Over the

next year, Novartis will start a phase IIb study of KAF156 drug combinations in adults and children, with scientific and financial support from MMV.

The study will explore both the potential for a single-dose cure, and the potential for a multiday regimen to address the multidrug resistance that

has emerged in south-east Asia.

KAF156 is the result of a Wellcome Trust, MMV and Singapore Economic Development Board-supported joint research programme with the

Genomics Institute of the Novartis Research Foundation, the Novartis Institute for Tropical Diseases, the Netherlands Primate Research Centre

and the Swiss Tropical and Public Health Institute.

KAF156


16

What is exciting about

artefenomel as a future

antimalarial?

Usually antimalarial combinations are

developed in adults and then later,

potentially, in children. Artefenomel is

the first antimalarial to be developed

for children and adult populations in

parallel, with the goal of accelerating

access to the main target population,

African children below 5 years of age. If

we can develop a suitable artefenomel

plus partner drug formulation and if

it is confirmed efficacious against all

P. falciparum infections (including those

resistant to the major antimalarial drugs

currently used in the field) it could be

a new ‘gold standard’, that is more

convenient to take and therefore easier

to adhere to. Although an ambitious

goal, I am confident we will be able to

improve on the current 3-day treatment

regimens, with the aim of developing

the combination as a single-dose cure.

In 2015, artefenomel

was in phase IIb trials in

combination with partner

drugs, piperaquine (PQP)

and ferroquine (FQ). What

have we learnt so far and

what are the next steps?

The artefenomel+PQP trial is now

complete – 448 patients from

eight countries participated in the

trial which took 17 months from

first patient dosed to top-

line results. This was

the first-ever Single

Exposure Radical

C u r e ( S E R C )

p r o g r a m m e

we have

conducted

for malaria and provided a wealth

of information. The upper dose of

piperaquine tested was selected based

on its safety profile; however, it did not

reach a satisfactory efficacy level as part

of the combination with artefenomel.

Importantly, we were able to determine

that a dose of 800 mg artefenomel was

well tolerated.

We are now focusing our efforts on the

development of the artefenomel+FQ

combination and have transferred key

methodological learnings from the

artefenomel+PQP trial. These learnings

relate to the selected drug doses

that may be tested in young children,

the importance of Directly Observed

Treatment, and how to optimize patient

recruitment. The artefenomel+FQ

phase IIb trial started in July 2015 and

we expect the results in 2018. As part

of the clinical programme, we will also

be looking at artefenomel’s activity in

patients infected with emerging drug-

resistant strains of the parasite.

Meanwhile, we are investigating

alternative partner drugs that, in

combination with artefenomel, could

meet the requirements of the SERC

Target Product Profile.

Artefenomel, a novel trioxolane, is a lead candidate for inclusion in a new antimalarial combination with a simpler dosing regimen, specifically

formulated for children. Achieving an equivalent efficacy and safety profile in fewer doses than current 3-day ACT regimens is a major

challenge. In partnership with Sanofi, MMV is aiming to overcome that challenge and is conducting a phase IIb trial of artefenomel in combination

with ferroquine.

Q.

Q.Dr Marc Adamy

Artefenomel

Project Leader

at MMV

Dr Marc Adamy describes the potential of this compound, its current status and future plans.

Maurosia and Jemima’s story

Artefenomel (OZ439)

+

UGANDA

Maurosia Nambooze is a farmer and

the mother of 3-year-old Jemima

pictured here. Together with Maurosia’s

husband and elder son, they live in

Kafumu, Uganda, close to the banks of

Lake Victoria in the world’s most fertile

breeding ground for malaria mosquitos.

17

Robert Arch

Senior Director,

Takeda

What is special about

DSM265 as a potential

antimalarial drug?

I find the excellent research that was

published on DSM265 in the journal

Science Translational Medecine

particularly exciting.1 A strong

partnership with industry players was

built early on, and was an important

factor in developing this successful

molecule. Even more exciting are

DSM265’s characteristics, for

example, its safety and tolerability

profile to date and its proven activity

against P. falciparum as a single-dose

monotherapy used up to 28 days.

These characteristics could make

a huge difference to the lives of

populations suffering from malaria.

In 2015, DSM265

successfully completed

a phase IIa study in Peru.

What did the study teach

us about the molecule?

What challenges did the

team face?

The most important element of the

study was to show the efficacy of the

molecule in real-life settings. While the

molecule was shown to be a highly

efficacious selective inhibitor of

P. falciparum-DHODH (leading to

striking single/monotherapy efficacy

against P. falciparum), we did encoun-

ter some challenges; for instance the

compound is not as potent against

P. vivax. While this is disappointing,

it will not stop us from studying the

molecule’s effects against P. falciparum.

How is the controlled

human malaria infection

(CHMI) model supporting

the development of

DSM265?

While the real-life experience of

patients has been very important, the

CHMI model (Figure 1, page 18) has

helped us to learn more about the

parasite’s response to a single dose of

DSM265. With this model, we can also

carefully monitor the start of infection

and time our intervention accordingly.

This provides greater understanding of

DSM265’s effect on different stages of

the parasite’s lifecycle, which will help

us determine whether it should be

used for treatment or prevention.

What is the strategy

moving forward?

The next stage will be the phase IIb

studies to explore single doses of

DSM265 in combination with a partner

drug. These studies will define an

appropriate combination and dose for

a phase III study.

The phase III study will then determine

if DSM265 has the potential to be a

simpler treatment than the present-

day standard of care, which requires

multiple doses over several days.

This will involve testing DSM265 and

its partner drug in a larger number of

patients in a single dose to see if it will

provide efficacious treatment as well as

the data required for approval.

We are all very excited about the

development programme. The col-

laboration between MMV, Takeda and

GHIT, as well as other partners, will be

very important to its success.

This targeted molecule inhibits a vital enzyme (dihydroorotate dehydrogenase; DHODH) in the malaria parasite essential for its survival, while

the human enzyme remains unaffected at therapeutic concentrations with a wide safety margin. In 2015, the molecule successfully de-

monstrated safety and efficacy against Plasmodium falciparum in a phase IIa trial in malaria patients in Peru. Phase III trials will be the next step

to confirm this activity specifically against P. falciparum.

1 Phillips MA et al. “A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria.” Sci Transl Med. 7(296):296ra111 (2015).

(DSM265’s)

characteristics

could make a huge

difference to the lives

of populations suffering

from malaria.”

“

Development of DSM265 by MMV is being supported by Takeda Pharmaceutical Company, Japan, with funding from the Global Health

Innovative Technology Fund (GHIT) and pro bono support from AbbVie. Robert Arch explains the molecule’s exciting potential and next steps.

When asked about how malaria is being

tackled in Kafumu, Maurosia explains that

“community health-care workers have

done a lot, because every child sleeps

under a net – they are specialized in

giving out mosquito nets.”

Yet even so malaria can slip through the

net. Jemima is recovering from a bout of

malaria; she was sick with it last year too.

Fortunately, the family lives close to a

clinic and so can access medicines when

needed. On this occasion, Maurosia was

given ACT tablets to treat Jemima.

“I grind it and put it with water and sugar.

If it’s sour she will vomit, even if it’s mixed

with water,” Maurosia said. The ACT had

to be administered twice daily for 3 days.

“Just one dose would be better,” she

continued.

A single-dose cure palatable to children

would be a major advance in antimalarial

treatment. It would mean that children

like Jemima could receive a full curative

dose in one go, ensuring their complete

recovery and guarding against the

emergence of drug resistance.

DSM265

Q.

Q.

Q.

Q.


18

Controlled human malaria infection (CHMI) model

Developed with Prof. James

McCarthy from QIMR Berghofer

Medical Research Institute, Queensland,

Australia, the CHMI model tests the

blood-stage activity of candidate

medicines in volunteers inoculated

with a low number of parasites in a

tightly controlled environment prior to

receiving the investigational drug. The

model allows us to quickly understand

whether a compound will be efficacious

in humans and provides guidance on

dose selection for subsequent studies.

The model has now been adapted to

look at other scenarios such as how

molecules work in combination. In 2015,

we looked at artefenomel in combination

with DSM265. This type of study

informs the selection of partner drugs

and their doses for further development.

Based on the encouraging results of the

artefenomel and DSM265 study, a pilot

phase II combination study in patients

is planned.

In the same study to assess blood-stage

activity we can also look at transmission-

blocking capability, as shown in the

graphic above. After gametocytes

(the sexual form of the parasite) have

developed, mosquitoes are fed on the

infected blood. Then, after 10–14 days,

the number of parasites that develop

in the mosquito midgut (which could

be transmitted to another person) can

be counted. Comparison to controls

(blood samples taken prior to treatment)

allows us to determine whether the drug

candidate has transmission-blocking

potential. We are currently conducting a

pilot study with artefenomel.

One cohort of 8 volunteersper dose

One cohort of 8 volunteersper dose

Sexual parasitaemia

Clearanceof asexual parasitaemia

End ofstudy

Mosquito feeds(direct and indirect)

Rescue drug administered, if needed

Rescue drug administered

at the end

Administer drugcandidate

Inoculateparasites

D22+

10-14 D D28~D7D0

Se ual exupa asitaemmmimiimiiaaaaaaaiara ae

CCClearancelle anof ase ual f a exuparasitaemiamiaar ita

Mos(direc*

Monitor parasitaemia in volunteers*

Count parasitesin the mosquito

dd

Figure 1:

19

Developing new drugs for use in

pregnant women is extremely

challenging. Pregnant women are

excluded from trials of new drugs until

the risks and benefits are well under-

stood among non-pregnant adults,

yet drug dosing can differ between

these groups. Current WHO guidelines

allow for the use of artemisinin-

based combination therapies (ACTs) for

women with malaria in the second and

third trimester of pregnancy, but not

for the first trimester when the fetus is

most vulnerable, as there is an absence

of key safety data. Additionally, in the

absence of suitable alternatives some

malaria experts suggest that ACTs

could also be used as chemoprevention

in pregnancy, which could lead to the

problematic situation of the same

medicines being recommended

for both chemoprevention

and treatment.

New antimalarial medicines that are

well-tolerated in pregnancy are needed

for both treatment and protection. While

we cannot definitively predict which

medicines will be suitable in pregnancy,

we can identify early on which medicines

would not be. Traditionally, preclinical

studies to determine if a molecule

has a safety signal are conducted in

parallel with phase II studies. MMV

has developed a strategy to move

this testing forward so it is in parallel

with the first-in-human

studies in phase I.

This was successfully carried out for

the last two development candidates,

MMV048 and DSM265. We now

propose taking this one stage further

and making safety in pregnancy one

of the first safety tests performed in

preclinical evaluation. In this way, we

will ensure that medicines to protect

vulnerable populations are identified

as early as possible and prioritized for

further development.

Prioritizing molecules for pregnant women


DDD498

Dr Beatrice Greco

Head of the

Malaria &

Diagnostics

Innovation

Cluster, Global

Health Research

& Development

at Merck S.A.

(Switzerland)

a subsidiary

of Merck KGaA


DDD498?

DDD498 has a novel mechanism

of action: in preclinical models, it

has shown activity against parasites

resistant to currently available

antimalarials, and indications of high

potency. Owing to these attributes,

it has potential to become a highly

efficacious compound and to play

an important part in the treatment of

uncomplicated malaria in the future.

Due to its predicted long half-life,

it might have potential to protect

against malaria in endemic countries

(chemoprotection), and as it inhibits

gametocyte formation, it might also

block transmission, which would be

essential for eliminating malaria. All of

this is a promising premise for further

investigations.

What are the next steps for

the project?

In February 2016, based on the high

quality of the molecule and the data on

its biological activity, the decision was

taken to progress the compound into

the regulatory preclinical phase of drug

development.

The team is currently completing the

essential preclinical and regulatory

activities required to determine if

DDD498 can then enter into first-in-

human trials potentially in 2017. This

includes pivotal toxicology studies as

well as in vitro and in vivo studies of drug

metabolism and pharmacokinetics.

The data generated will enable us to

determine if future clinical development

is possible and what a safe starting

dose and regimen would be, as well as

the predicted therapeutic range for the

clinical trial.

We look forward to continuing the

excellent collaboration with the very

committed and supportive team at

MMV.

2015 was a big year for DDD498. Not only was the team at the University of Dundee selected to win MMV’s Project of the Year 2014

for its discovery and the details of the compound published in Nature,1 but MMV also signed a contract with Merck KGaA, Darmstadt,

Germany, to continue its future development.

Dr Beatrice Greco explains what’s exciting about the molecule as well as the next steps.

Q. Q.

20

1 Baragaña B et al. A novel multiple-stage antimalarial agent that inhibits protein synthesis. Nature. 522(7556):315-20 (2015).

Getting the formulation right

Dr Elizabeth Vadas

InSciTech Inc.,

Canada

What formulation

challenges do drug

developers face?

Poor solubility, low permeability and,

in particular, lack of potency represent

significant formulation challenges.

For example, the formulation of low

potency drugs, requiring high doses,

is technically complex, especially in

the field of malaria where we deal with

combination drugs – two different

molecules in one capsule or tablet. If,

for example, the dose of one or both

drugs is high, the tablet may become

too large to swallow. We must then

divide the dose into several smaller

tablets.

Are there any other

challenges particular to

malaria drug development?

Yes, since the target population for

malaria drugs is mainly sick children,

we must formulate for them. Specific

considerations for children include

dosage form, ease of administration

and palatability – bearing in mind the

patient is likely to already be nauseous.

Working with drug combinations

complicates formulation further as the

two active entities must be chemically

compatible; if not, we need to come up

with formulation approaches that can

separate the two active ingredients in

one dosage form. This can be a high

technical hurdle. The stability of the

dosage form in hot and humid countries

represents an additional challenge.

Ideally, we would like to achieve all this

in a single-dose cure – a goal which

increases the scientific and technical

complexity both for the drug molecule

and the formulation.

What motivates you to work

with MMV on a pro bono

basis and how have you

helped the project teams

to overcome formulation

challenges?

I have had a wonderful, productive

career in the pharmaceutical industry,

and now that I am retired I feel it is

time to give something back. I hope

that I have been able to advise the

MMV teams on potency, form selection

and other formulation requirements

before molecules enter phase I trials.

Together, we have been able to find

promising formulation approaches

for MMV048 and DSM265. The more

issues we solve at the beginning of

drug development the more likely we

are to succeed.

It is critical to get the formulation of a new drug right to ensure it is easy to administer and store, acceptable to the target patient

population, delivers the correct dosage, and has the desired effect when administered. To do so, it is important to select the correct

chemical and physical forms of a drug at an early stage in development, as formulation changes can be very costly, create delays and

result in poor quality clinical data that is difficult to interpret.

Dr Elizabeth Vadas describes the challenges of drug formulation and explains how and why she has been assisting the project teams

at MMV.

Q. Q. Q.

21


22

Aiming to stop relapsing malaria with a single- dose treatment

The Plasmodium vivax malaria parasite has the ability to

lie dormant in the liver as hypnozoites, which periodically

reactivate leading to a relapse of malaria in the absence

of a new infective mosquito bite. It is estimated to cause

around 70–80 million clinical infections every year.1

Primaquine is currently the only treatment available to kill

the dormant parasites and stop the relapse. It must be

taken once a day for 7–14 days.

MMV and GlaxoSmithKline (GSK) are developing

tafenoquine, as a potential single exposure medicine to

prevent P. vivax relapse by addressing the hypnozoite in

the liver.


1 Mendis K et al. “The neglected burden of Plasmodium vivax malaria.” Am J Trop Med Hyg. 64 (1–2 Suppl): 97–106 (2001).

Pring’s storyPring Chon is a soya bean and cassava farmer

from Oslev Village, Cambodia, where he lives with

his wife and children. He has suffered with malaria

more than 12 times in his life; on one occasion it

led to severe malaria and he had to be hospitalized.

Pring has been infected with P. vivax malaria that

lies dormant in the liver only to relapse periodically,

without warning and in the absence of a new

infective mosquito bite.

“I feel bad with this illness,” Pring explained. “When

I’m infected, I can’t work and my wife can’t work.”

This debilitating disease affects Pring regularly. In

Cambodia, artemisinin-based combination therapies

(ACTs) are used to treat blood-stage malaria

infections, leading to quick relief of symptoms;

but there are no medicines routinely used in the

country to cure malaria relapses. Without treatments

aimed at eliminating the dormant liver parasite they

continue to suffer.

CAMBODIA

When I’m

infected, I can’t

work and my

wife can’t work.”

“

+

23

Tafenoquine is an investigational medicine in phase III development. If approved, it would be the first new medicine to cure relapsing malaria

in over 60 years. Tafenoquine is being developed as a single dose to prevent malaria relapse, to be administered alongside a standard

3-day ACT to cure the immediate infection.

Tafenoquine is a member of the same chemical family as primaquine; both are associated with a risk of haemolytic side-effects in patients

lacking the enzyme glucose-6-phosphate dehydrogenase (G6PD). GSK is working with PATH to accelerate the development of a G6PD point-

of-care diagnostic test, so that patients’ G6PD status can be tested to determine if tafenoquine or primaquine can be safely administered.


tafenoquine as a future

antimalarial?

WK: Tafenoquine is a game-changer in

many ways; if approved by regulators,

it will be the first medicine indicated for

relapse prevention of P. vivax malaria

since the 1950s. It is the only tool in

the malaria pipeline for the elimination

and eradication of P. vivax malaria

that acts on the ‘hidden reservoir’ of

parasites in the liver. Furthermore, to

improve patient compliance we are

developing tafenoquine as a single-

dose treatment that could potentially

transform the treatment approach for

relapsing malaria.

How is the phase III

programme progressing?

JPK: Tafenoquine has been in phase III

clinical development since April 2014

in eight P. vivax malaria-endemic

countries investigating a single dose of

300 mg; this dose was selected based

on results of phase II dose-ranging

studies. We expect to finish recruitment

for the phase III programme in 2016.

What are the implications

of the US FDA designation

of Breakthrough Therapy

and how is engagement

with other international

regulatory authorities

progressing?

JPK: The Breakthrough Therapy

Designation was enacted as part of

the 2012 FDA Safety and Innovation

Act (FDASIA). The goal is to expedite

the development and regulatory review

of designated drugs to treat serious

or life-threatening medical conditions

when the drug may offer substantial

improvement over available therapies.

Additionally, this designation affords us

more intensive guidance from the FDA

on tafenoquine’s clinical development

plan. Stringent regulatory review of

a tafenoquine dossier by the FDA

would precede planned subsequent

registrations in malaria-endemic

countries.

How is the patient access

plan progressing and

how is each partner

contributing?

WK: MMV is working with GSK, PATH

and other groups to develop the access

plan well in advance. The partners

meet quarterly to make sure the plans

are aligned and will be delivered in

concert. GSK has been in a partnership

with us for a number of years and is

responsible for the overwhelming

majority of the drug development work;

MMV has supported GSK strategically,

tactically and financially. The Bill &

Melinda Gates Foundation, in addition

to sponsoring the new diagnostic test,

provides regulatory and patient access

expertise through their contacts in the

field.

How is the G6PD point-

of-care test progressing in

partnership with PATH?

JPK: The potential benefit of using a

new medicine versus the associated

risks of haemolytic side-effects is at the

forefront of our minds. The goal of the

PATH/GSK collaboration is to have at

least one diagnostic test suitable for

use with tafenoquine at the time of its

potential approval. We are currently

working with two diagnostic companies

to develop their differing technologies

and to assess the ability of each to fulfil

the specification that we believe would

be required.

We asked Dr Wiweka Kaszubska and Dr JP Kleim to provide an update on the phase III programme. They also explain the advantages of

having obtained a ‘Breakthrough Therapy’ regulatory designation from the US Food and Drug Administration (FDA) and discuss how they

are collaborating with other partners to ensure access to the medicine.

Dr Wiweka

Kaszubska

Vice President,

Head of Product

Development,

MMV

Dr JP Kleim

Project Leader,

GlaxoSmithKline

UK

Q.

Q.

Q. Q.

Q.

Tafenoquine

4 | Advancing the science of eradication

24

Candidates delivered in 2015

4 Advancing the science of eradication

To identify molecules that meet the

Target Candidate Profiles (TCPs)

(page 8) for next-generation medicines

to support malaria eradication, MMV’s

drug discovery team works with partners

to screen compounds for activity against

the various stages of the parasite lifecycle

(Figure 2).

To complement existing blood-stage

assays, (which identify compounds

to alleviate the symptoms of malaria),

MMV and partners have developed

new assays to screen for activity at

other lifecycle stages. Notably, in 2014

and 2015, high-throughput assays of

liver stages (to test for chemoprotection

capability) and gametocyte stages (to

test for transmission-blocking capability)

as well as assays of Plasmodium vivax

liver stages (to test for anti-relapse

activity) were established (pages 28-29).

Active compounds that meet the

required criteria are then progressed to

the ‘make–test’ cycle (Figure 2). Here

they undergo rounds of synthesis and

testing to determine whether they could

become a drug candidate, suitable for

further development.

Since 2010, 17 drug candidates

have been brought into preclinical

development (13 are still active). Each

one of these active candidates has

the potential to form part of a next-

generation medicine to support malaria

eradication.

MMV drug discovery by numbers

44 pharmaceutical and academic partners

7 million compounds screened against the blood stages of Plasmodium falciparum

25,000 chemical starting points identified

19 assays developed or in development against the critical stages of the parasite lifecycle

17 drug candidates brought forward since 2010

DSM421 Preclinical

Target indication:

Part of a single exposure radical cure and

potential for chemoprophylaxis

TCPs: Asexual blood-stage activity and

chemoprevention

Features:

• Favourable physicochemical properties

• Comparable ex-vivo activity on

P. falciparum and P. vivaxMMV Project Director: Dr Emilie Rossignol

GSK692 Preclinical

Target indication:



TCPs: Asexual blood-stage activity

Features:

• Predicted human dose < 500 mg


• Extremely rapid parasite clearance

• Inability to select resistant mutants

MMV Project Director: Dr Jörg Möhrle

Partner: GSK

AN13762 Preclinical

Target indication:



TCPs: Asexual blood-stage activity,

transmission-blocking activity and chemo-

prevention

Features:

• Reduced human dose < 50 mg


• Rapid parasite clearance

• Potential for prophylaxis

MMV Project Director: Dr Cristina Donini

Partner: Anacor

25

Does

the

co

mpound have activity against malaria?

Does it have:

17 new candidates 2010–2016

Activity against the blood stages, liver stages and/or transmission stages of the parasite?

Novel chemistry?

Desirable mechanism of action?

Attractive drug-like properties?

Does it have:Acceptable pharmacokinetics, efficacy and safety?

Developability?

An acceptable predicted dose?

4. Re

sults

2. Synthes

is

1. Hypothesis

3. Test

Make-test

cycle

Translational step

Parasitelifecycle

MMV’s drug discovery engine

Figure 2:


26

Research can be

conducted with varying

degrees of openness, as

described in the margin.

How would you define

MMV’s approach to drug

discovery?

MMV’s approach is Open Innovation.

At one end you have the ‘cathedral

approach’ that is secret and siloed, at

the other end everything is laid bare –

information, compounds and biological

tools. MMV’s approach lies between

the two. Over the years we have built

up a community that shares data and

assays among a set (or subsets) of

partners for a given project or projects.

These Open Innovation projects are

not transparent to the outside world,

rather they operate within contractual

‘bubbles’, with a semi-permeable

membrane securing confidentiality.

What are the advantages of

this approach?

Risk, cost and effort are shared among

the partners. We delude ourselves if

we think we are the best and only we

can deliver. Through collaboration we

can do so much more than we can

alone. Since 2010, our collaborations

have delivered 17 candidate molecules

for malaria – this has created a strong

pipeline, but it’s still not strong enough

to deliver the medicines we need to

defeat malaria. To achieve our mission,

we continue to enlarge our partnership

network and in turn the quality of

compounds in the pipeline.

The confidentiality membrane allows

for the key partner to generate

intellectual property and file a patent.

This potential can be a strong incentive

for pharmaceutical partners to get

involved, as well as allowing us and our

partners to help guarantee the quality of

the clinical trials and final product. New

partners have access to all the valuable

assays and expertise available, which

helps minimize duplication.

Are there any challenges?

Open innovation can only function

with an extremely competent business

development and legal group.

They need to be extremely flexible

to induce partners to join but also

sufficiently uncompromising, in terms

of accountability and alignment with

MMV’s mission, to develop affordable

medicines for vulnerable populations.

At MMV we are fortunate to have that.

Also, as we rely on donor funds we

set annual budgets which means if a

project doesn’t make the grade we

must be ruthless and terminate it.

In response to various challenges,

variations of the open model are being

tried and tested. In one example,

working with Dr Mat Todd at the

University of Sydney in Australia, we

have completely broken the membrane

and made everything open.

How does this open source

initiative work and what

have you learnt so far?

Essentially, everything related to the

project is in the public domain, such

that anyone anywhere can follow and

contribute. The idea is that it will work

by ‘natural selection’ – anyone can

take what’s there and over time there

will be evolution, in this case, delivery.

We have learnt that there is a huge

amount of goodwill and so intellectual

input, but fundamentally money and

resources are still rate limiting. If people

don’t make compounds you get stuck.

We believe in open source – but it

needs to be resourced. Intention is

also critical. You need to be clear on

what you are setting out to achieve and

direct the project accordingly.

Opening up malaria drug discovery

Open Science:

Deposition of

data in the public

domain.

Open Access:

Data, compounds,

publications etc.

made available

to maximize their

possible use

across diseases.

Open

Innovation:

Two or more

partners share

data within a

‘walled garden’

with the intention

to deliver a

product.

Open Source:

All project data

and structures are

laid bare and the

wider community

is invited to fully

engage and offer

support e.g.

advice, synthesis,

testing and in-

kind technology.

To drive the elimination and eradication of malaria,

there is an urgent need for novel compounds,

active against the various stages of the malaria

parasite lifecycle, to be discovered and developed.

To make the discovery and progression of

exciting compounds more efficient, rapid and

cost effective, MMV has pioneered new, more

open and collaborative ways of working.


Dr Jeremy Burrows, Vice President,

Head of Drug Discovery, MMV,

explains MMV’s open approach to

drug discovery.

Q.

Q.

Q.

Q.

27

Open access initiatives to catalyse drug discovery

Following the release into the public

domain of data on 20,000 compounds

active against malaria, there was a need

for scientists to access the physical

compounds with which to initiate drug

discovery programmes.

MMV launched the Malaria Box in 2011

and the Pathogen Box in 2015.

ISSUE ACTIONMore than 250

Malaria Boxes and

70 Pathogen Boxes

dispatched since

launch in 2011 and

2015, respectively

35 papers published

describing Malaria Box

screening results

Researchers screening

the Malaria Box found

hits against 16 different

protozoa, 7 helminths,

9 bacterial and

mycobacterial species,

the dengue fever

mosquito vector and

human cancer

cell lines

Wellcome Pathfinder

grants of USD 100,000

each awarded to

Prof. Chris Huston,

University of Vermont,

and Prof. Robin

Gasser, University

of Melbourne, for

research on Malaria

Box compounds

active against

cryptosporidiosis

and parasitic worms,

respectively

Dr Fabrice Boyom is investigating natural products for the treatment of human, animal, and/or plant

diseases. To help fuel his research he received MMV’s Open Access Malaria Box, a Malaria Box

Challenge Grant and recently the Pathogen Box. Dr Boyom explains how he and his team have

been using these resources.

What was your initial

reaction when you heard

about the Malaria Box

initiative?

Wow! This is a real opportunity to have

compounds to work on. As in other

poorer countries in the world, the

discovery of new drugs for parasitic

infections in Cameroon is hampered

by the lack of resources devoted to

drug discovery. It is not easy to purify

effective compounds from plants. It’s

a long and demanding process. The

Malaria Box provided a wonderful

opportunity to research compounds

that you know work.

How are you using the

compounds? What did your

research reveal?

The compounds are being screened

against Toxoplasma gondii and

Entamoeba histolytica, but also against

pathogenic yeasts and bacteria. As

a result, we identified seven anti-

Toxoplasma gondii hits, as well as

two moderately active compounds

against E. histolytica. Also, two

compounds showed highly potent

activity against various Candida spp.

and Cryptococcus neoformans (one

of which is the already known Crystal

violet). We are now optimizing two of

the compounds.

You have also recently

requested the Pathogen

Box. How will you use the

compounds?

The Pathogen Box is another great

opportunity to expand our research and

continue the work we are doing. We

will also screen the compounds against

Mycobacterium ulcerans (the causative

agent of Buruli ulcer) and eventually

against pathogenic yeasts such as

Cryptococcus neoformans.

It’s exciting to be involved in science to

save lives. Through these open access

initiatives and grants, we have not only

been able to continue our research but I

have also been able to train my students,

who can then continue the work in

Africa. I’m very grateful for the guidance

from MMV and I’m looking forward to

continuing this work in the future.

Q.

Q.

Q.

Dr Fabrice Boyom

Researcher at

the University

of Yaoundé 1,

Cameroon

1 Ascariasis, Buruli ulcer, Chagas disease, Cryptosporidiosis, Hookworm, Human African trypanosomiasis (sleeping sickness), Visceral & cutaneous leishmaniasis, Lymphatic filariasis, Malaria, Onchocerciasis (river blindness), Schistosomiasis, Trichuriasis and Tuberculosis.

The Open Access Malaria Box contains 400 diverse molecules, representative of the original

20,000 set and active against blood stage Plasmodium falciparum malaria. The box was made

available to researchers for free on request. Based on the success of the Malaria Box, MMV was

awarded a grant from the Bill & Melinda Gates Foundation for a follow-on project, the Pathogen

Box. This box also contains 400 molecules for distribution to scientists for free on request, but this

time with activity not just against malaria, but also against one of a range of neglected diseases.1


28

Historically, basic research on P. vivax has lagged behind that for Plasmodium falciparum. This is partly because P. falciparum was

considered the more deadly of the two and because P. vivax parasites were difficult to access and to work with. Even today the technical

challenge is great; the blood-stage parasites still can’t be maintained in continuous culture.

Nevertheless, the discovery and development of anti-relapse molecules has always been a key research and development (R&D) focus for MMV.

For example, over the years, investments have been made in testing new clinical candidates, developing tafenoquine with GlaxoSmithKline

(GSK) and developing new clinical models in collaboration with the Indonesian army. Up to now, the major advances in cell biology have been

made through Wellcome Trust co-funded collaborations with the Dutch Primate Centre, and Novartis-led discovery projects. Over the last year

we have seen a significant change in the assays coming through, thanks to a continued effort on the part of our collaborators, complemented

by new funding from the Bill & Melinda Gates Foundation to establish a P. vivax Malaria Consortium.

New models to discover new molecules against the relapse

The relapse of Plasmodium vivax malaria contributes

to a significant burden of disease – an estimated

70–80 million clinical infections every year. Only two anti-

relapse medicines exist (primaquine, which is available,

and tafenoquine, which is in development, pages 22-23)

and both are associated with side-effects in patients who

have a certain genetically determined enzyme (G6PD)

deficiency.

Develop and employ new models to discover new

molecules that are active against the dormant liver stage

of P. vivax malaria.


How does the assay

work and what are its

advantages?

The assay allows us to see the impact

of various test compounds on small

and large liver P. vivax forms. We

culture the human liver cell line in an

8-well plate and then add P. vivax

sporozoites (the liver-infective stages

of the parasite) into each well a day

later. We then add the test compounds

to the cultures in triplicate at a range

of concentrations. Six days later, we

count the small and large parasite

forms (believed to be hypnozoites

and schizonts, respectively) take the

average and compare them with the

control wells.

Our system is in vitro and uses the

human liver cell line, which means we

can handle many more compounds

and concentrations at the same time.

As we use the same cell line, the

findings are more robust, compared

to a humanized mouse model, for

example.

We have been working with 96-well

plates, but are now moving to 384-

well plates, which will then enable us

to screen yet more compounds in one

go. With this assay, depending on the

stage at which we add the compound,

we can look at either the effect of the

compound on the development of

small and large forms (potential for

chemoprevention) or the effect on

fully developed forms (potential for

radical cure – killing of hypnozoites and

relapse prevention).

How many compounds

have you been able to

screen and what have you

found so far?

We finished screening the first

25 compounds from MMV in the

chemoprevention model and are in

the process of testing 100 more. We

have found some molecules with very

good potential. Next, we will screen the

Pathogen Box compounds (page 27).

Our goal for the year is to validate

the 96-well plate, initiate the 384-well

plate format and screen up to 1,000

compounds.

What has it been like to

work with MMV and the

Gates’ P. vivax Malaria

Consortium?

The project is managed with an

industry-style approach so the

timelines are tight which can be

challenging, but I do enjoy it. I enjoy

understanding the different research

perspectives and because the funding

is stable we can progress smoothly. If

just one molecule screened from our

system ultimately treats people it will

be a goal fulfilled.

Dr Jetsumon

Sattabongkot

Prachumsri

Head of the

Mahidol Vivax

Research Unit,

Thailand

In 2014, a team of researchers from Mahidol University, Thailand, was able to establish a P. vivax ‘hypnozoite’ cell-based in vitro assay to

screen up to 1,000 compounds a year. Dr Jetsumon Sattabongkot Prachumsri talks about the assay, what it has told us so far and what

it’s like to work with the Consortium.

Q.

Q. Q.

100x P. vivax liver stage development

in vitro day 7 post sporozoite infection

29

How is your work to

establish a P. vivax

‘hypnozoite’ cell-based

in vitro assay progressing?

It’s really exciting, we’ve had several

breakthroughs in the last couple of

years. We are now able to culture

primary human hepatocytes for

more than 4 weeks, infect them

with sporozoites and get parasite

development all the way to invading

reticulocytes.

All of this has now been achieved in a

384-well plate format with which we

can attempt high-throughput screening

for the first time. We have begun by

screening 27 of MMV’s compounds

several times to help refine the assay.

We expect to screen at least 1,000

compounds this year for MMV.


this assay?

Because we can maintain the primary

human hepatocytes in culture for

more than 4 weeks, we can routinely

do radical cure screens and assess

hypnozoite activity from days 5–9 post-

sporozoite invasion. We can also look

for relapse in vitro from as early as day 21

and as late as days 33–35.

We have found that human hepatocytes

prefer to be confined in a 3D space.

So by optimizing the ‘microfeature’

design at the bottom of each well we

can promote optimal development of

hepatocytes and the parasite. As this

is all conducted in a 384-well format

our screening is both high-content and

high-throughput.

What has it been like to

work with MMV and the

Gates’ P. vivax Malaria

Consortium?

It’s a good example of how sharing

information early can be very helpful.

It’s a high-risk project so working

individually through independent

grant systems would not have been

successful. Although, in a sense, the

groups are competitors, we routinely

share information through interactions

in the Consortium. When we have

something that does or doesn’t work,

we inform the other groups and vice

versa. It works very well – for example,

we got confirmation of what the

hypnozoite looks like in two different

in vitro models and a mouse model. It’s an

example of how the Gates’ Consortium

model can work to solve big problems.

Working with other members of the

Consortium has been critical. The

biggest challenge is getting access to

the sporozoites so that we can actually

do the assays. We are grateful for the

contributions of Jetsumon Prachumsri,

Chiara Andolini and Francois Nosten

in the field in Thailand who provide us

with infected mosquitoes.

MMV was involved right from the

beginning as advisors and contributors

to all the discussions. They are the

leader in the field of malaria drug

discovery. Being able to access all the

different compounds and test systems

in their network was invaluable in

refining and validating our assay. We

hope they can now reap the rewards

by using the models to find the next

drug to kill the hypnozoite.

Prof. Dennis Kyle

Distinguished

University Health

Professor,

University of

South Florida,

USA

In 2015, a second team of researchers was also able to establish a P. vivax ‘hypnozoite’ cell-based in vitro assay. Prof. Dennis Kyle

explains the progress, the advantages of their assay and what it’s been like working with the Consortium.

Q.

Q.

Q.


30

MMVProject of the Year

2015

GSK692 – a novel compound steadfast in the face of resistance

The team at GSK,

Tres Cantos, Spain

GSK692 is an antimalarial

compound with a novel mode of action

which enables it to kill the malaria

parasite quickly. Its overall properties

indicate it could form part of a single-

dose cure and it has a low propensity

to generate resistance in laboratory

studies as well as activity against current

drug-resistant strains – key attributes

for a next-generation antimalarial. In

recognition of this, the GSK692 project

team has won MMV’s 2015 Project of

the Year award and MMV’s External

Scientific Advisory Committee (ESAC)

has approved the compound as a

clinical candidate for further research.

GlaxoSmithKline (GSK) and MMV

have worked in a productive and open

collaboration on malaria drug discovery

for several years. GSK’s facility at Tres

Cantos in Spain houses one of MMV’s

centres of excellence for screening and

testing new compounds in biological

assays, transmission-blocking models

and parasite-killing studies. It is

expected that further clinical candidates

will emerge from the MMV/GSK

collaboration in the future – following in

the footsteps of GSK692.

Its fast mode of

action could make it

a suitable replacement

for artemisinin, the

current gold standard

treatment.”

“

31


GSK692?

LS: GSK692 is special because it

combines a number of desirable

properties for an antimalarial. It targets

blood-stage activity of the Plasmodium

falciparum and Plasmodium vivax

parasites. It provides a rapid response

when tested in vivo in laboratory

models of malaria. Importantly, this

is complemented by a rapid in vitro

response. The molecule also displays

an extremely low propensity to select

for resistance in vitro, hence, we predict

a low rate of selection for resistance in

the field. Its fast mode of action could

make it a suitable replacement for

artemisinin, the current gold standard

treatment. Also, GSK692 is not

structurally related to artemisinin and

has a unique mode of action, which

is of paramount importance when

developing effective, novel combination

treatments for a disease that has a

history of developing drug resistance.

How was the compound

discovered?

LS: The molecule was identified in

collaboration with MMV through a

programme which screened the entire

GSK corporate compound collection

against malaria at Tres Cantos in

Spain in 2010. This programme led

to the identification of what we call

the ChEMBL TCAMS (Tres Cantos

Antimalarial Set). The results were

published in Nature1 in 2010 and made

publicly available to the global drug

discovery community.

The next step was to triage the active

compounds, using innovative tools

such as assays, to determine speed

of killing and transmission-blocking

potential as well as GSK’s rigorous

quality criteria. Ferrer, a pharmaceutical

company based in Barcelona, then

joined the team working with GSK

and MMV to further improve the series

until 2013 when they stopped their

malaria research activities. The joint

programme focused on improving the

molecules’ developability properties,

like solubility and physicochemical

properties. GSK692 emerged as the

best molecule.

What are the next steps for

the project?

PW: As GSK692 has now been

approved as a clinical candidate by

the ESAC, the next step is to prepare

a larger quantity of the compound for

regulatory studies, which will determine

whether it is safe to progress to clinical

trials. The plan would then be to

start a phase I clinical trial looking at

tolerability and pharmacokinetics in

human volunteers and studies in the

controlled human malaria infection

model (page 18) to explore efficacy.

What value has MMV

added to the project as a

partner?

LS: MMV provides overall guidance

based on its extensive experience in

the discovery and development of

antimalarial molecules. Specifically,

MMV has been fundamental in the

final profiling of the molecule’s activity

against the various stages of the

parasite’s lifecycle by providing access

to critical biological assays through its

established network of collaborators.

MMV’s Project Director Paul Willis

and other MMV staff members act

as consultants. Their support and

guidance has helped us overcome

the challenges that arose during the

project’s progress. The consistent

level of open communication in

this partnership has significantly

contributed to the success of the

project and the molecule’s selection as

a potential new medicine.

Why does the collaboration

between MMV and GSK

work so well? What does

GSK bring to malaria drug

discovery?

PW: There has been an excellent

collaborative atmosphere – both

sides respect and value each other’s

contributions. It means we can discuss

the science in an open and transparent

manner. In addition to the drug

discovery projects, GSK houses one

of our screening centers of excellence

at Tres Cantos. They run several key

biological assays for malaria, providing

data on efficacy, transmission-blocking

potential and the rate of killing of the

malaria parasite for all projects in the

MMV drug discovery portfolio. Their

broad malaria expertise and drug

discovery knowledge makes for a really

powerful, promising and beneficial

collaboration. To illustrate this, GSK

also had another candidate – GSK030

– approved last year and there are

several promising new projects in the

portfolio which we hope will deliver

exciting new drug candidates in the

future.

Dr Paul Willis

Director, Drug

Discovery, MMV

Dr Laura Sanz

Tres Cantos

Medicine

Development

Campus,

GlaxoSmithKline,

Spain

Dr Paul Willis and Dr Laura Sanz talk about the award, the compound and the collaboration.

1 Gamo FJ et al. “Thousands of chemical starting points for antimalarial lead identification.” Nature. 20;465(7296):305-10 (2010).

Q.

Q.Q.

Q.

Q.

5 | Getting better medicines to more people

32

Dr Borghini, you have

led the development of

Pyramax tablets and

granules on behalf of MMV

since 2006. What was

it about the project that

inspired your commitment?

IB: Initially, I was struck by the high

efficacy results demonstrated in phase II

studies. With 98% cure rates, Pyramax

showed tremendous potential.

Then I had the opportunity to go

to Burkina Faso, where I met with

doctors and malaria patients. When

you make a trip like that, you quickly

come to understand why we do the

work we do – the need is enormous. I

was impressed by the team I met and

inspired by their dedication. The project

became even more meaningful to me.

Developing treatment options for children

5 Getting better medicines to more people

Children are the hardest hit by malaria – around 70% of

those that die are under 5 years of age. Yet typically in

drug development, medicines are developed for adults

before child-friendly versions are pursued.

Developing and improving access to child-friendly

formulations of existing antimalarials for treatment

(artemisinin-based combination therapies; ACTs), and

chemoprevention (sulfadoxine-pyrimethamine; SP+AQ).

Developing next-generation medicines for children in

parallel with adult formulations.


Dr Isabelle

Borghini

Director, Product

Development,

MMV

Mr Won June

Chang

CEO, Shin Poong

Pharmaceutical

Dr Isabelle Borghini and Mr Won June Chang talk about the development of

Pyramax tablets and granules and the value of the partnership.

Q.

MMV has long recognized that developing better medicines for children helps address the most vulnerable patient population at greatest

risk of dying from malaria. The first product successfully co-developed by MMV and partners was Coartem® Dispersible, launched by Novartis

in 2009. To date, 300 million treatments of this cherry-flavoured dispersible product have been distributed, making it the most widely-used

quality ACT for children.

In 2015, Pyramax® granules (pyronaridine-artesunate), developed by Shin Poong Pharmaceutical and MMV, received a positive scientific

opinion under Article 58 from the European Medicines Agency (EMA), becoming the second ACT specifically designed for paediatric use to

receive approval from a stringent regulatory authority.

A third ACT co-developed by MMV (with Sigma-Tau) was Eurartesim® (dihydroartemisinin-piperaquine). Eurartesim was approved by the EMA

in 2011 and received WHO prequalification in 2015. Its paediatric formulation has just completed clinical development and is expected to be

submitted for EMA approval in 2016.


Pyramax?

WJC: It is the first ACT approved by

a stringent regulatory authority (SRA)

for treatment of both P. falciparum and

P. vivax malaria. This is really useful

in areas where both species cause

infections and in particular where access

to differential diagnosis is limited.

Importantly, the medicine is available

in two formulations, a tablet for adults

and children over 20 kg and specifically

formulated, taste-neutral granules for

children and infants between 5 kg and

20 kg. This child-friendly formulation

helps ensure they get the full curative

dose they need. Both formulations can

be administered with or without food

and only need to be taken once a day

for 3 days, making administration and

adherence easier than with current

twice-daily dosing regimens.

What was the biggest

challenge in the

development of the

combination and how did

you overcome it?

IB: During the phase III programme,

we conducted a phase I relative

bioavailability study in healthy

volunteers, in which we detected a

liver safety signal. We immediately

put the phase III programme on hold

and prepared a data package to be

reviewed by a panel of the world’s

top hepatic safety experts. They

scrutinized the data and made the

recommendation to continue the

programme. This was a make-or-break

moment for the Pyramax development

programme. Pyramax then went on

to receive positive scientific opinion

from the EMA in 2012 for treatment

of a single malaria episode in areas

of low transmission with evidence of

artemisinin resistance.

Moving forward, we designed

additional studies to understand the

mechanims underlying this safety

signal and continued very close

monitoring of liver function in patients

recruited in the trials. We also began

working with the West African Network

for Clinical Trials of Antimalarial Drugs

(WANECAM), led by Prof. Abdoulaye

Djimde, University of Science,

Techniques and Technologies of

Bamako, Mali. Pyramax was included

as one of four antimalarials trialled

in a large, phase IIIb/IV multicentre

study where patients were treated

with the same medicine more than

once during a 2-year follow-up period.

WANECAM was a 4,757-patient trial

that has generated a large data set.

As a result, Pyramax was shown to

be as well tolerated and efficacious on

re-treatment as on first administration

leading the EMA to provide positive

scientific opinion without geographical

or dosing restrictions for both the tablet

and granule formulations.

What was the value of the

partnership with MMV?

WJC: In addition to MMV’s scientific

expertise, MMV’s dedication and

high-level global networks have been

invaluable. MMV provided the know-

how to drive the scientific development

and the coordination to manage the

multi-nation clinical studies. They also

provided significant support to prepare

the dossier for submission to the EMA.

What are the next steps to

ensure Pyramax granules

reach as many vulnerable

children as possible?

WJC: Today, the partnership

is expanding beyond scientific

development into patient access. We

are working to support inclusion of

Pyramax in WHO’s Standard Treatment

Guidelines and Essential Medicines

List, which will support approvals in

malaria-endemic countries. At the

end of February 2016, Pyramax, as a

tablet formulation, had been registered

in 13 malaria-endemic countries, was

under review in 14, and was ready for

submission in many other endemic

countries. For the granule formulation,

we expect either new approvals or line

extension registrations in all countries

that have registered the tablet.

How did you feel when you

received the news from the

EMA?

IB: When it finally came, I was

absolutely overwhelmed with joy. It was

enormously satisfying to see that the

EMA assessed that the data supported

safety and efficacy of Pyramax on re-

treatment. I was also elated for the

project team and happy to have played

my part. In R&D you don’t often get to

work on projects that make it to the

end of development. I am thrilled to

continue to be part of the team that will

now ensure that Pyramax achieves the

widest possible patient access. That’s

what success is all about.

Q.

Q.

Q.

Q.

Q.

With Pyramax granules and tablets, we are proud that for the first time ever the paediatric formulation of an antimalarial was made available at the same time as the adult formulation with a label allowing unrestricted worldwide use.”

“

Dr Tim Wells Chief Scientific Officer, MMVEssential Medicines

upport approvals in

countries. At the

016, Pyramax, as a

had been registered

emic countries, was

4, and was ready for

any other endemic

ggranule formulation,

Chief Scientific Officer, MMV

33


34

Facilitating sustainable uptake of injectable artesunate

Globally around 438,000 people die each year of severe malaria, around 70% of whom are under the age of 5.1 In 2011, the WHO

recommended injectable artesunate (Inj AS) as first-line treatment for severe malaria, as it saves more lives than quinine.2,3 In anticipation

of this policy change and to help improve its access, MMV worked with Guilin Pharmaceutical to enable them to obtain WHO prequalification in

2010 for their Inj AS product – Artesun®.

MMV then quickly began work to increase access to Inj AS in Nigeria and the Democratic Republic of Congo – two countries with the highest

severe malaria burden in the world. Based on this experience, MMV established a severe malaria consortium with the Clinton Health Access

Initiative (CHAI) and the Malaria Consortium (MC) to implement the MMV-led Improving Severe Malaria Outcomes (ISMO) project. In 2013, the

project was awarded a UNITAID grant to continue scale-up in Nigeria and five other high-burden African countries (Cameroon, Ethiopia, Kenya,

Malawi and Uganda).

Slow uptake of injectable artesunate – the WHO-preferred

treatment for severe malaria – costs lives.

Mobilizing new financing, and developing and

coordinating a multi-stakeholder consortium to undertake

a multi-country 3-year scale-up of injectable artesunate.


1 World Health Organization. World Malaria Report 2015. (2015): http://www.who.int/malaria/publications/world-malaria-report-2015/report/en/

2 Dondorp AM et al. “Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial.” The Lancet. 376(9753):1647-57 (2010).

3 Dondorp A et al. “Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial.” The Lancet. 366(9487): 717-25 (2005).

As the ISMO project comes

to a close in mid-2016,

what has been achieved?

As of December 2015, across the

six ISMO countries, the proportion

of injectable artesunate treatments

procured in the public sector compared

to quinine was 99.5% in 2015,

(compared to 16% in 2013), and the

average proportion of patients treated

with injectable artesunate versus

quinine was 85.5%. These figures alone

confirm that during the ISMO project, a

major shift to better treatment for severe

malaria took place. There were several

key steps along the way.

First, thanks to CHAI and MC, we were

able to ensure treatment policies were

updated in all of the countries.

Second, we have trained more than

18,000 health-care workers in more

than 1,650 health-care facilities –

approximately 50% more than the

original objective. Through the training

we were able to expand provision

of severe malaria care beyond large

hospitals.

Third, despite the initial limitations of in-

country medical quantification systems,

we were able to successfully quantify

the correct amount of drugs based

on need, so that there were almost no

stock-outs at the central medical stores.

And finally, we have sought to diversify

sources of quality Inj AS, identifying

additional manufacturers interested in

pursuing WHO prequalification, as a

means of ensuring competitiveness and

bolstering supply security in the market.

What have you learnt?

There has been a wealth of learning

that could be applied to other projects:

When implementing a new health

project, you need to consider

administrative lead times in

ministries of health – on average

it took 4 months for countries to

review and sign memorandums of

understanding.

Even if you are helping bring

critically-needed life-saving

medicines into a country, you may

have to pay customs duties or seek

appropriate waivers.

When it comes to quantifying

a newly launched product,

epidemiological data can serve as a

basis for first estimates, but it’s more

accurate to monitor distribution at

the health-care facility level following

the first deliveries.

Before you determine your

monitoring and evaluation indicators,

you need to ensure that appropriate

national systems for data collection

exist. Creating short-term parallel

systems to collect data just for

donor-funded projects is not optimal.

Training is key and most effective

when the drugs are already

available. When people are well

trained they are comfortable using

the drugs.

What was it like to work on

the ISMO project?

It has been a fantastic learning and

collaborative experience working

with our implementing partners,

CHAI and MC; our procurement

agent, Missionpharma; and the drug

manufacturer, Guilin. It’s also been very

satisfying to develop close working

relationships with both the Global

Fund and the US President’s Malaria

Initiative to harmonize our procurement

activities.

My overall feeling is extremely positive

– health workers who have used Inj AS

have consistently responded very

positively about their experiences

using the medicine. In addition, we

have already received feedback from

UNITAID, the major funder for this

project, that ISMO has achieved

its catalytic impact, in line with its

original objectives. I think when the

end users and the donor are satisfied,

the project team can be happy!

Alexis Kamdjou

MMV’s Country

and Procurement

Liaison Manager

based in

Cameroon

Alexis Kamdjou works with teams in the six countries providing technical and analytical support to implement the

UNITAID-funded ISMO project. As the project nears the end of its 3-year grant, Alexis talks about his experiences and

what has been learnt.

Q.

Q.

Q.

3535

Kamaragi’s storyTwo-year-old Kamaragi was suffering

from high fever when his mother brought

him to Luweero Hospital in Uganda. He

was diagnosed with severe malaria.

Fortunately, Kamaragi was given

injectable artesunate (Inj AS) and the next

day he was able to sit upright in bed and

his fever had gone. The worry and panic

on his mother’s face changed to relief as

she realized her son would survive.

Uganda has one of the highest burdens

of severe malaria in the world. Over

666,000 in-patient malaria cases were

registered in 2015 alone. On the same

day that Kamaragi was admitted, three

other children were also suffering from

severe malaria at Luweero Hospital;

fortunately, all of them received Inj AS

and recovered.

Thanks to the ISMO project, 1.5 million

vials of Inj AS were distributed throughout

Uganda, with the potential to treat up to

250,000 children like Kamaragi and to

save an additional 10,000 lives compared

to treatment with quinine.

“The roll-out of injectable artesunate has

helped Uganda to deal with the recent

malaria epidemic,” explained Kamaragi’s

physician Dr Byamukama. “Within the

public sector, the efforts have resulted in

a complete switch from quinine to Inj AS

to treat severe malaria.”

+

UGANDA

Since receiving

prequalification in 2010,

52.9 million vials of

Artesun® have been

shipped to malaria-

endemic countries,

saving an estimated

additional 300,000–

350,000 children’s lives

compared to treatment

with quinine.

“

Lelio Marmora UNITAID Executive Director

Children with severe malaria are typically given intravenous quinine, a cumbersome treatment which needs to be administered over a week. There is a better way: Inj AS is more effective than quinine in reducing malaria mortality in children and is quick to administer. Through its partners MMV, CHAI and the Malaria Consortium, UNITAID’s commitment of USD 34 million since 2013 to create a market for Inj AS is helping to improve severe malaria outcomes for millions.”


36

Buying time to save lives with rectal artesunate

WHO Guidelines for the treatment of malaria1 recommend

the use of rectal artesunate (RAS) for pre-referral

management of severe malaria. A single dose significantly

reduces the risk of death and permanent disability.2.3

Despite these recommendations, currently there is no

WHO-prequalified product.

Continuing the early work of WHO-TDR,4 defining

requirements for WHO-prequalification of rectal

artesunate; working with pharmaceutical partners, Cipla

and Strides Arcolab, to submit their products for WHO

prequalification and optimizing their use in low-resource

settings.


1 World Health Organization. Guidelines for the treatment of malaria. Second edition. (2010): http://www.who.int/malaria/publications/atoz/9789241549127/en/

2 World Health Organization. Malaria in children under five. (2016): http://www.who.int/malaria/areas/high_ risk_groups/children/en/

3 Gomes MF et al. “Pre-referral rectal artesunate to prevent death and disability in severe malaria: a placebo-controlled trial.” The Lancet. 373(9663):557-66 (2009).

4 WHO-TDR: World Health Organization Special Programme for Research and Training in Tropical Diseases.

5 World Health Organization. Rectal artesunate testing and delivery. (2016): http://www.who.int/tdr/research/malaria/rectal_artesunate/en/

How could rectal

artesunate improve

management of severe

malaria in Uganda?

Today, RAS has only been used in a

few operational research projects in

Uganda, but studies show it leads to

better patient outcomes. We still get

a large number of children with severe

malaria and the first point of contact

for care is a Community Health Worker

for around 60% of cases. These health

workers are voluntary and trained to

deliver basic medical care only, so

Inj AS would not be possible while RAS

would be. As such, in my view, this

intervention could have a big impact –

it could help to save lots of lives from

severe malaria at the community level.


using RAS as a pre-referral

intervention?

It’s really a groundbreaking intervention

– referral can take a long time with

our roads and transport system – we

don’t have ambulances. The mother

is usually the caregiver and often has

other children at home. It can take

time to figure out care of the remaining

children and how to transport the

sick child to hospital. RAS can hold

the ground and delay severe disease

until children can get recommended

treatment.

Do you have any concerns

about the implementation

of RAS?

There have been some concerns that

RAS could be misused; it is not intended

as curative treatment for malaria,

and administration of RAS must be

followed up with a full recommended

course of treatment (such as injectable

artesunate and/or ACT). And at the

community level, given the challenge

of patient transport, a framework will

need to be put in place to ensure that

referral to higher level facilities does

happen.

All medicines can be abused. Good

training in ethical conduct and

supervision is always a must with a

new intervention.


WHO prequalification from

your perspective?

It provides reassurance that there is a

good manufacturing process and the

product has good efficacy. Also, most

sources of funding can’t be assigned

to a product which is not prequalified

and so without it, access to finances

and therefore to the medicines, is

limited.

Dr Jimmy Opigo

Programme

Manager for

the National

Malaria Control

Programme in

Uganda

Dr Jimmy Opigo explains the potential benefits and drawbacks of RAS and the importance of WHO prequalification.

Q.

Q. Q.

Q.

If detected quickly, an uncomplicated malaria infection can almost always be treated successfully with highly effective

oral medicines artemisinin-based combination therapy (ACT); however, if left untreated it can quickly progress to severe

malaria, a life-threatening condition that can kill a patient within a few hours. The first point-of-care for many patients with

severe malaria is a community-level health-care worker or primary care facility. Patients presenting with severe malaria

should be treated as quickly as possible with injectable artesunate (Inj AS); however, most local health posts do not have

the drug or personnel trained in its administration, and so patients need to be referred to higher-level facilities. In such

cases, WHO recommends the use of RAS as a pre-referral intervention. RAS buys time before Inj AS can be administered

– and can mean the difference between life and death.5

With funding from UNITAID, MMV has been working with two Indian pharmaceutical companies, Cipla and Strides

Arcolab to obtain WHO prequalification for their RAS products. Reaching a significant milestone in 2015, both companies

submitted dossiers for review.

In February 2016, MMV, the US President’s Malaria Initiative, UNICEF, and Médecins Sans Frontières convened a

meeting in Nairobi, Kenya, inviting RAS stakeholders from 13 countries to discuss experiences and challenges relating to

implementation of this intervention. The recommendations and key findings from the meeting will help countries implement

RAS at the community level and save lives. MMV has also begun working with implementing partners and potential host

countries to design pilot introduction programmes for RAS.

37

Aiming for elimination

Mass Drug

Administration

(MDA):

Everyone in a

given population

receives

medicine to cure

any infection

(symptomatic or

asymptomatic)

and prevent

reinfection in the

short term.

Focal MDA

(fMDA) for

malaria:

Antimalarials

are provided to

anyone testing

positive and

anyone in the

household of the

person testing

positive.

Case

investigation:

Follow-up

of passively

detected,

lab-confirmed

cases (with

characterization

by age, sex,

residence, recent

travel that may

have led to

infection etc.)

and visit to their

households and

neighbourhoods

to seek and

treat other cases

and potentially

provide

prophylaxis.

Many people living in malaria-endemic regions

have been repeatedly exposed to malaria and

have developed semi-immunity. Thus, they might

carry the parasite yet not show any symptoms.

These asymptomatic carriers, along with ill

patients, constitute a human reservoir of parasites,

perpetuating the cycle of malaria transmission.

MDA is a tool to clear the human reservoir

of parasites and reduce malaria dramatically

in target communities, making elimination

feasible. MMV and partners are developing new

medicines with safety and efficacy profiles for

use in MDA.


1 The ‘Team’ included the Zambia National Malaria Control Programme, provincial, district and local health officials, MACEPA & Tulane University School of Public Health.

Can you explain how MDA

was rolled out in Zambia?

A team of partners1 developed a pilot

project in Southern Province in a high-

transmission area, where in some places

50–60% of the population were infected

with malaria at the end of the transmission

season. We mapped out the health facility

catchment areas and randomly divided

them into three groups: MDA, fMDA

or the control group. All groups were

provided with good insecticide-treated

net coverage, indoor residual spraying,

malaria prevention during pregnancy,

and case management (with laboratory

testing, treatment and case investigation

where possible). We did two rounds of the

interventions each year for 2 years.

What were the key findings?

With the first year of data evaluation,

we saw enormous reductions in malaria

cases in health facilities, through

community outreach and in malaria

prevalence rates across all groups, with

the greatest reduction of around 90% in

the MDA group, 80% in the fMDA and

70% in the control. We were not surprised

to see the impact was so positive in the

control since they were getting the best

care, in terms of prevention and treatment

as mentioned, and possibly benefited

from a community effect – the overall

reservoir was reduced by the trial.

The aim was to shrink the case

burden enough so that individual case

investigation becomes feasible. We were

able to get to that point in a low

transmission area in 1 year with MDA.

What role do you

believe MDA has as we

move towards malaria

elimination?

It has a key role to play in getting us to

malaria elimination – I think of it as an

accelerator. It can take transmission from

fairly high to very low levels in a short time.

Our study also shows that you might also

get there with fMDA but it would probably

take longer than with MDA.

Why was Eurartesim®

(dihydroartemisinin-

piperaquine: DHA-PQP)

selected for the trial?

MDA benefits from a highly effective

and long-acting drug that both clears

infections and protects against reinfection,

which is why we chose Eurartesim. The

prophylactic effect is probably critical.

An acceptable safety profile is also

fundamental: you are giving medicines

to entire populations of people, most of

whom are not sick.

In the future, a single-dose drug would

be great; permitting a one-time directly

observed treatment enabling us to

ensure everyone receives a complete

treatment. That said, in Zambia, the vast

majority of people took all three doses as

recommended – perhaps because we

have been working there for some time

developing strong community relations,

another critical factor for successful MDA.

Dr Richard Steketee, Project Director,

MACEPA, explains what the

study revealed and the necessary

attributes of medicines for MDA.

Q.Q.

Q.

Q.

The Malaria Control and Elimination Partnership in Africa (MACEPA) has been working in Zambia for more than a

decade to support the country’s efforts to improve malaria control and ultimately eliminate malaria. Starting in 2014,

the MACEPA team collaborated with the National Malaria Control Programme and supported Zambian health officials to

conduct one of the largest MDA studies to date.


38

Fatou Touray’s story Mother and trader

“During the rainy season my children

usually suffer from malaria twice. When

they suffer, or a close relative suffers

from malaria, I have to stop everything

to help care for him or her. That means

all our farm and community activities are

affected.’’

“Children don’t like medicines and are

always afraid but we still give them the

SMC drugs. It has reduced the burden of

malaria in my house and family at large.

My children are not even suffering from

malaria anymore thanks to the SMC

medicines.”

GAMBIA

+

Protecting children at their most vulnerable

To protect children in areas of high seasonal malaria

transmission across the Sahel, the World Health Organization

(WHO) recommends seasonal malaria chemoprevention

(SMC) with sulfadoxine-pyrimethamine and amodiaquine

(SP+AQ) in regions where the combination remains

effective.1 Ensuring sufficient high-quality medicines are

available and correctly administered is a logistical challenge.

MMV and partners have produced SMC training materials

and are supporting their implementation in collaboration

with the SMC working group within the West Africa Roll

Back Malaria Network (WARN). Also, since 2014, as part

of the UNITAID-funded ACCESS-SMC Consortium,2 MMV

is supporting scale-up in seven countries in the Sahel.


Prof. Jean Louis

Ndiaye

Cheikh Anta

Diop University,

Dakar, Senegal

What are the biggest

challenges in the

implementation of SMC?

The lack of a child formulation of SP+AQ

is a big challenge. It means we must

crush bitter tablets, making it very difficult

to administer them to youngsters. Also,

having enough medicines is challenging.

Last year we didn’t get the quantity we

needed to reach all the children.

Another challenge is the lack of a stan-

dardized approach to monitoring and

evaluation to measure the public health

impact of SMC and the prevalence of

molecular markers for drug resistance.

We know that pharmacovigilance sys-

tems are very weak in many countries,

which makes it difficult to know the num-

ber of adverse events associated with

SP+AQ, even if we know it is generally

well tolerated.

How are these challenges

being overcome?

Guilin has developed a dispersible tablet

that was granted a favourable opinion by

the Expert Review Panel for insertion on

the Global Fund list of malaria products.

This formulation can now be purchased

by international funders for the 2016

campaign. It was also submitted to WHO

prequalification and a verdict is expected

in 2016.

Guilin is confident that there will be

sufficient drugs available this year. Also,

MMV has signed an agreement with

a manufacturer, S Kant Healthcare, to

develop a second child-friendly tablet.

While ACCESS-SMC has developed a

quantification tool to help forecasting.

The SMC working group is harmonizing

training and ensuring all countries have

the same tools. One day of the SMC

training will be reserved to focus on

pharmacovigilance. It is also conducting

an impact and evaluation programme

with donor funding in selected areas.

However, the challenge remains to

obtain and maintain funding for these

activities in all areas that could benefit

from them.

Prof. Jean Louis Ndiaye was involved in the early SMC pilot studies and its scale-up in Senegal. He explains how the challenges to realizing its

maximum impact are being tackled.

Q. Q.

1 WHO Policy Recommendation: Seasonal Malaria Chemoprevention (SMC) for Plasmodium falciparum malaria control in highly seasonal transmission areas of the Sahel sub-region in Africa. Geneva: World Health Organization Global Malaria Programme; March 2012: www.who.int/malaria/publications/atoz/smc_policy_recommendation_en_032012.pdf

2 The UNITAID-funded ACCESS-SMC Consortium includes: the Malaria Consortium (prime recipient), Catholic Relief Services (joint lead), MMV, Management Sciences for Health, Speak Up Africa and the London School of Hygiene & Tropical Medicine.

3 Cairns M et al. “Estimating the potential public health impact of seasonal malaria chemoprevention in African children.” Nat Commun. 3:881 (2012).

4 WHO/GMP Technical Expert Group On Preventive Chemotherapy, Geneva 4–6 May 2011. Report of the technical consultation on seasonal malaria chemoprevention: www.who.int/malaria/mpac/feb2012/smc_teg_report.pdf

5 Lubell Y et al. “Cost-effectiveness of parenteral artesunate for treating children with severe malaria in sub-Saharan Africa.” Bull World Health Organ. 89(7):504-12 (2011).

In some parts of Africa, annual malaria cases are concentrated in the 4-month rainy season. Around 39 million African children under 5 years of

age live in these regions and an estimated 152,000 die from malaria each year.3 Most of these children live in the Sahel and sub-Sahel regions

of Africa where SMC with SP+AQ has been shown to be a cost-effective solution to prevent around 75% of malaria episodes: high-quality SMC

drugs cost ~USD 1 per season, while inpatient care for a case of severe malaria is estimated to cost USD 12–75.3,4,5

In 2015, the ACCESS-SMC project reached 3 million children across the Sahel leading to reports of empty beds in malaria wards. In 2016, the

goal is to reach 6.5 million children.

39

Improving malaria chemoprevention and treatment during pregnancy

Every year, 125 million pregnancies around the world

are at risk from malaria.1 In Africa alone, approximately

10,000 women and 200,000 babies die annually as a

consequence.2 Pregnant women have an increased risk

of life-threatening outcomes, including cerebral malaria

or severe anaemia.3 To diminish the risk of malaria

during pregnancy, the World Health Organization (WHO)

recommends a specific chemoprevention strategy,

however, its acceptance and use is quite low. HIV-positive

pregnant women are particularly vulnerable, as, owing

to drug interaction concerns, there is no recommended

chemoprevention option for them. Additionally, there

are concerns about the risk of declining effectiveness

of the current chemoprevention option and a shortage

of pregnancy safety data for most of the currently

recommended malaria treatments.

1. Work to improve coverage of intermittent preventive

treatment in pregnancy (IPTp)4 with sulfadoxine-

pyrimethamine (SP) in areas where it remains effective.

2. Undertake a safety study in Tanzania testing

dihydroartemisinin-piperaquine (DHA-PQP) as an

alternative option for IPTp.

3. Gather data to better define the safety profile of

currently used artemisinin-based combination

therapies during pregnancy, particularly during the first

trimester when the fetus is most vulnerable.

4. Work with a leading biosimulation partner to predict

drug–drug interactions between widely used

medicines for HIV-positive pregnant women and future

malaria chemoprevention options.


To protect pregnant women living

in areas of moderate-to-high

malaria transmission, for several years

WHO has recommended IPTp by

administering the drug sulfadoxine-

pyrimethamine (SP) ideally at a

minimum of three antenatal care visits,

at least a month apart. Unfortunately,

IPTp coverage is very low – only 24%

of pregnant women in sub-Saharan

Africa receive the minimum dosing.5 In

addition, there are worrying signs that

SP’s chemopreventive efficacy may be

undermined in the future by emerging

drug resistance. In line with current WHO

recommendations, MMV has supported

the Roll Back Malaria Partnership’s Call

to Action,5 an advocacy effort outlining

specific actions by national health

entities, donors, the pharmaceutical

industry and civil society to achieve

greater access to and acceptance of

IPTp where and while it is still effective.

Meanwhile, to address the need for

more research on new IPTp options,

MMV and the London School of Hygiene

& Tropical Medicine are conducting

a safety study of Eurartesim® (DHA-

PQP) in pregnant women in Tanzania.

Specifically, this study will closely

evaluate the cardiac safety of DHA-PQP

in this patient group, building on other

phase IV safety research that MMV and

partners have already conducted in

non-pregnant patients.

For treatment of malaria in pregnancy,

WHO recommends artemisinin-based

combination therapy (ACT) during

the second and third trimesters,6 but

additional data are needed to confirm

their safety and tolerability during the

first trimester. Additionally, the dose of

different ACTs needed during pregnancy

remains uncertain, given the significant

changes in the metabolism of expectant

women during the first trimester.

MMV is planning to establish a registry

that tracks outcomes of pregnant

women exposed to antimalarials to

build a more robust evidence base

about the impact of specific medicines

on pregnancy and new-born outcomes.

The first step will be to establish

this registry in Mozambique with the

Manhiça Foundation which will follow

women who receive DHA-PQP as part

of a Mass Drug Administration pilot

programme, if they discover they are

pregnant in the 2-month period that

follows. The data will enable us to better

understand the tolerability of DHA-PQP

during pregnancy.

1 Manyando C et al. “A systematic review of the safety and efficacy of artemether-lumefantrine against uncomplicated Plasmodium falciparum malaria during pregnancy.” Malaria J. 11:141 (2012).

2 Dellicour S et al. “Quantifying the number of pregnancies at risk of malaria in 2007: a demographic study.”PLoS Med. 7(1):e1000221 (2010).

3 Schantz-Dunn J & Nour NM. “Malaria and pregnancy: a global health perspective”. Rev Obstet Gynecol. 2(3): 186–192 (2009).

4 IPTp is the administration of a full course of an effective antimalarial treatment. It should only be administered to pregnant women living at risk of malaria after their first trimester and at a minimum of 1-month intervals.

5 Chico M et al. “Global call to action: maximize the public health impact of intermittent preventive treatment of malaria in pregnancy in sub-Saharan Africa.” Malar J. 14(1):207 (2015).

6 Guidelines for the treatment of malaria. Third edition. Geneva: World Health Organization; (2015): http://apps.who.int/iris/bitstrem/10665/162441/ 1/9789241549127_eng.pdf

“

Dr Clara Menéndez Director of ISGlobal’s Maternal, Infant and

Reproductive Health Initiative

Malaria during pregnancy is a serious threat to maternal and neonatal health. The development of interventions for malaria control in this most vulnerable group is urgently needed. Given its position and mission, MMV has a strategic and fundamental role to play in addressing the unmet needs of malaria in pregnancy.”

6 | Financial view

40

As a not-for-profit Swiss foundation set up

under statutes dated 15 November 1999,

Medicines for Malaria Venture (MMV) is exempt

from cantonal and federal taxes and is the

equivalent of an exempt organization under

Section 501(c) (3) of the United States Internal

Revenue Code. Furthermore, from 1 January

2011, the Swiss Federal Council granted MMV

the status of ‘Other International Organization’

conferring certain privileges and immunities

including exemption from VAT in Switzerland –

representing an estimated additional contribu-

tion from Switzerland to MMV of up to one million

Swiss Francs (CHF) per annum.

Portfolio funding

MMV receives funding and support from government

agencies, private foundations, international

organizations, corporate foundations and private

individuals (Figure 3). MMV also receives indirect

investment from its partners, who contribute

expertise, human resources and facilities.

These funds are used to finance MMV’s portfolio

of research and development (R&D) projects to

develop new, effective and affordable medicines

for the treatment and prevention of malaria.

They also support targeted access and product

management (APM) interventions to help ensure

that vulnerable populations in malaria-endemic

countries can access new malaria medicines.

We estimate that for every USD 1 invested,

MMV leverages approximately USD 3.5 of R&D

value (i.e. USD 1 in matched funds for external

costs plus USD 1.50 in in-kind contributions). In

2015, our two largest donors, the Bill & Melinda

Gates Foundation and the UK Department for

International Development (DFID), extended

programmatic supplements to their already sig-

nificant long-term commitments, which were

renewed in 2013. Moreover, thanks to dynamic

financial management coupled with proactive

fundraising, MMV’s R&D portfolio and APM

activities for the year were realized. MMV’s drug

R&D and APM activities and corresponding

expenditures in 2015 (USD 57.3 million and

USD 13.7 million, respectively) were both

above those in 2014 (USD 49.5 million and

USD 8.7 million, respectively). Overall, MMV’s

total expenditure of USD 80.6 million increased

by 20% compared with USD 67.2 million in

2014, mainly thanks to the above-mentioned

generous supplements.

Since its foundation in 1999, MMV has spent

USD 709 million to build the world’s largest R&D

portfolio of new and innovative antimalarial

medicines. With partners, MMV has brought

forward six new antimalarials, some of which are

already being used to treat patients in malaria-

endemic countries. In addition, during 2015

the Drugs for Neglected Diseases initiative trans-

ferred its malaria portfolio to MMV, with MMV

taking on the responsibility for the lifecycle

mana gement of two additional launched products.

The business plan estimates a minimum

of USD 350 million over the period 2016–2020

to sustain this work. With approximately

USD 200 million available, (USD 157 million out-

standing committed pledges for 2016–2020

at the end of 2015, as well as USD 48 million

cash brought forward to 2016), the organization

is currently tracking a shortfall of USD 150 million

in 2018–2020. MMV has several pending

proposals to donors and remains active in its

resource mobilization and advocacy activities.

FINANCIAL

VIEW

6

Financial year to 31 December 2015

Figure 3: Total funding received/pledged from 1999 to 2020 – USD 893 million as at 31 December 2015

Bill & Melinda Gates Foundation 60.00%

United Kingdom Department for International Development (DFID) 14.50%

Netherlands Minister for Development Cooperation 3.90%

Wellcome Trust 3.30%

UNITAID 2.50%

United States Agency for International Development (USAID) 3.20%

Irish Aid 2.00%

Swiss Government SDC 1.90%

World Health Organization/Roll Back Malaria (WHO/RBM) 0.50%

National Institutes of Health (NIH) 1.30%

Spanish Agency for International Development 1.20%

Australian Government Department of Foreign Affairs and Trade (DFAT) 1.00%

Global Health Innovative Technology Fund (GHIT) 0.90%

World Bank 0.90%

ExxonMobil Foundation 0.80%

Rockefeller Foundation 0.60%

Newcrest Mining Limited 0.40%

Merck KGaA 0.40%

Norwegian Agency for Development Cooperation (NORAD) 0.20%

Malaria Consortium 0.20%

BHP Billiton 0.10%

Individual and other donors 0.10%

Direction de la Coopération Internationale de Monaco (DCI) 0.04%

EU CRIMALDDI 0.01%

41

Details

MMV income

2015 USD 86,788,114

2014 USD 79,221,703

2013 USD 62,662,422

2012 USD 57,984,195

2011 USD 67,285,068

2010 USD 58,122,675

2009 USD 42,180,117

2008 USD 55,148,885

2007 USD 76,965,380

2006 USD 30,618,703

2005 USD 44,770,355

2004 USD 28,705,652

2003 USD 21,712,944

2002 USD 10,586,792

2001 USD 13,599,677

2000 USD 7,606,949

Research & development expenditure

2015 USD 57,330,528

2014 USD 49,537,276

2013 USD 50,165,812

2012 USD 60,756,529

2011 USD 40,330,004

2010 USD 42,544,044

2009 USD 44,298,951

2008 USD 46,028,889

2007 USD 41,494,679

2006 USD 46,943,252

2005 USD 27,166,334

2004 USD 23,805,411

2003 USD 16,950,454

2002 USD 10,353,468

2001 USD 6,709,653

2000 USD 2,280,748

Management and auditing

Relationships with two major Swiss banks allow

us to effectively manage our global banking

relationships and diversify risk. The banks

provide services such as current accounts,

investment and cash management facilities in

multiple currencies. MMV’s accounts are audited

annually by KPMG.

Financial reporting standards

The 2015 consolidated financial statements

were prepared in compliance with Swiss GAAP

FER. Until 2013, MMV had followed

International Financial Reporting Standards

(IFRS). The transition to Swiss GAAP FER in

2014 did not significantly alter transparency

and disclosure. The organization’s operating

procedures are constantly updated in line with

evolving requirements.

The 2015 financial statements were also prepared

in compliance with the Swiss Code of Obligations.

Foundation capital

By 31 December 2003, the stipulated foundation

capital of USD 4 million was fully subscribed

(in a Swiss foundation it is a legal requirement

that the foundation capital should be constituted

without delay in order to provide a degree

of financial security for the foundation).

The foundation capital remained unchanged

at 31 December 2015.

Donations and pledges 2015

(see Note 6 Donations)

Cash donations received in the bank amounted

to a total of USD 88 million with income

recognized in the previous year (2014) of USD

2.1 million, income deferred from the previous

year (2014) of USD 5.8 million and income

deferred to the following year (2016) of USD

11.1 million. Current 2015 income, to be received

in early 2016 amounted to USD 5.8 million.

Income of USD 0.1 million was recognized from

MMV North America Inc.

Management and administration

Management and administration cost increases

were kept consistently low during 2015.

MMV’s staff headcount increased to 59 from 55

in 2014. The ratio of management and

administration expenditure to overall spending

decreased to 7.1% from 8.3% in 2014 (7.3%

from 8.6% in 2014 if board and stakeholders’

expenses are included).

Figure 4: MMV expenditure 2015

Total: USD 80.6 million

Financial year to 31 December 2015

R&D 71%

Access & Product Management 17%

General & Administration 7%

External Relations & Advocacy 4%

Foundation Board & Stakeholders 1%

6 | Financial view

42

New pledges received in 2015

Financial year ahead to December 2016

MMV operates in a complex multi-currency

environment. It receives the bulk of donations in

US Dollars and UK Pounds Sterling, and a

smaller portion in other currencies such as

Swiss Francs (CHF), Euros (EUR) and Australian

Dollars (AUD). Cash outflows for projects are

also mostly in USD, which is the standard

currency used in the various specific contractual

agreements signed with each project partner

and therefore a natural cover for financial

exchange risk. On the other hand, many

operational expenses are in CHF. The resulting

exposure or exchange risk is hedged, generally

in January of each year and according to the

budget, in order to provide a nominal fixed

average USD/CHF budget rate for the period.

The accounts are kept in US dollars.

The philosophy underlying MMV’s financial

management is that of prudent, conservative

control, including appropriate return on interim

treasury investments. Forecasting various long-

term funding and income scenarios enables

MMV to manage its growing R&D portfolio more

effectively. It also provides a baseline analysis for

fundraising activities aimed at financing the

portfolio in line with long-term projections.

Given the unsteady financial environment and

market conditions, it is evident that the portfolio,

cash flow and new potential fundraising

opportunities have to be managed dynamically

and seamlessly.

Focus on sustainability: R&D and APM

In 2015, MMV continued to prepare, scale-up

and launch activities to ensure market access to

medicines emerging from its pipeline. In

alignment with MMV’s partnership model,

access and product management activities

conducted with partners enable MMV to achieve

its overarching goal of major health impact from

its medicines. Moreover, in the context of

malaria elimination and eradication, a second

and critical series of investments are now

urgently needed to spur on R&D for the next-

generation antimalarial drugs to meet that goal.

Although fundraising remains successful and

significant additional funds were sourced in

2015, major fundraising efforts will be required

in 2016 and even more in 2017 and beyond, as

MMV strives to meet the projected financial

requirements of its growing portfolio.

Financial modelling

Financial modelling suggests that, in spite of

additional future funding pledges for MMV in

2016 and pending proposals to donors, future

R&D and APM activities will remain underfunded.

The long-term financial projections for future

MMV overall spending over 2016–2020 is USD

350 million. This figure represents a mix of R&D,

product launch and APM-related spending,

including much needed innovation in treatments

for malaria in pregnancy, Plasmodium vivax

malaria, transmission blocking and other

technologies for elimination and eradication.

These financial statements and all forward-

looking financial figures should be considered

as management’s best estimates based on

information available at the time of printing.

Financial tables

The financial tables and notes that follow are

extracted from the Swiss GAAP FER compliant

accounts.

Figure 5: MMV income and expenditure to date and scenario 2016–2020

0

10

20

30

40

50

60

70

80

90

100

110

120

USD

in m

illio

n

2000 2002 2003 2004 2007 2008 2009 2011 2012 2013 2014 2015 2016 2018 2019 2020201720052001 2006 2010

Carried forward from previous year

Total income for the year

Total expenditure for the year

DONOR Amount (in millions) Period

United Kingdom Department for International Development (DFID) £5.0 (USD 7.5) 2015–2016

WHO Consultative Expert Working Group(‘Exploiting the Pathogen Box’ project)

USD 1.4 2015–2016

Total (USD equivalent) 8.9

MMV is grateful for these and previous commitments from its many donors.

43

MMV CONSOLIDATED STATEMENT OF FINANCIAL POSITION

31 Dec 2015 31 Dec 2014

USD USD

ASSETS Notes

CURRENT ASSETS

Cash and Cash Equivalents 3 48 491 563 38 057 339

Donations Receivable 6 5 819 726 2 081 748

Project Reimbursements Receivable – –

Accounts Receivable 625 258 2 503 016

Tax Receivable 6 908 6 002

Prepaids 602 867 447 087

Prepaid R&D Commitments 7 2 011 373 2 288 560

Prepaid APM Commitments 7 1 129 558 3 234 746

Derived Financial Instruments 13 180 734 –

TOTAL CURRENT ASSETS 58 867 987 48 618 498

LONG-TERM ASSETS

Long Term Receivables 2 578 398 886 861

Guarantees 16 191 260 191 523

Fixed Assets, Net 4 421 101 313 595

TOTAL LONG-TERM ASSETS 3 190 759 1 391 979

TOTAL ASSETS 62 058 746 50 010 477

LIABILITIES AND CAPITAL & RESERVES

CURRENT LIABILITIES

Accrued R&D Commitments 7 7 701 012 6 823 803

Accrued APM Commitments 7 1 224 186 2 347 264

Deferred Income 6 11 100 125 5 759 025

Other Creditors 1 386 171 875 267

Accrued Expenses 1 830 471 1 724 238

Short-Term Provisions 5 511 543 450 056

Donations Reimbursement Payables 9 339 058 320 653

Derived Financial Instruments 13 200 373 –

TOTAL CURRENT LIABILITIES 24 292 939 18 300 306

RESTRICTED FUNDS

Restricted Operating Funds 10 888 037 10 435 263

TOTAL RESTRICTED FUNDS 10 888 037 10 435 263

CAPITAL & RESERVES

Foundation Capital 4 000 000 4 000 000

Unrestricted Operating Funds 22 877 770 17 274 908

TOTAL CAPITAL & RESERVES 26 877 770 21 274 908

TOTAL LIABILITIES AND CAPITAL & RESERVES 62 058 746 50 010 477

6 | Financial view

44

MMV CONSOLIDATED STATEMENT OF COMPREHENSIVE INCOME

2015 2014

Continuing Operations USD USD

INCOME Notes

DONATION REVENUES

Private Foundations & Individual Donors 53 276 366 43 215 524

UN Agencies 7 912 360 7 288 713

Government Agencies 23 697 931 25 152 286

Corporates & Corporate Foundations 1 507 188 1 367 836

Total Restricted Donation 25 875 249 24 516 099

Total Unrestricted Donation 60 518 596 52 508 260

TOTAL DONATION REVENUES 6 86 393 845 77 024 359

OTHER INCOME 9 394 269 2 197 344

TOTAL INCOME 86 788 114 79 221 703

EXPENDITURE

RESEARCH & DEVELOPMENT EXPENDITURE

Project Grants 7 43 872 944 37 609 518

Project-Related Variable Expenditure 7 12 903 996 11 533 558

Expert Scientific Advisory Council Expenses 553 588 394 200

TOTAL RESEARCH & DEVELOPMENT EXPENDITURE 57 330 528 49 537 276

ACCESS & PRODUCT MANAGEMENT EXPENDITURE

Project Expenditure 7 11 823 226 6 803 784

Access-Related Variable Expenditure 1 777 512 1 824 705

Access & Product Management Advisory Committee 78 447 104 494

TOTAL ACCESS & PRODUCT MANAGEMENT EXPENDITURE 13 679 185 8 732 983

EXTERNAL RELATIONS & ADVOCACY EXPENDITURE

ER&A-Related Variable Expenditure 3 041 891 2 652 442

Fundraising 20 012 43 619

Communications 184 298 173 515

TOTAL EXTERNAL RELATIONS & ADVOCACY EXPENDITURE 3 246 201 2 869 576

FOUNDATION BOARD & STAKEHOLDER EXPENDITURE 14 165 251 172 950

GENERAL & ADMINISTRATION EXPENDITURE

Staff-related Benefits/Compensation 8 3 483 653 3 439 573

Office and Occupancy 11 1 369 720 1 238 742

Travel Expenses 48 842 58 044

Professional and Legal Fees 159 413 77 859

Training, Education and Journals 46 366 23 940

IT expenses 344 175 497 180

Depreciation 4 160 388 105 574

Other 100 051 172 083

TOTAL GENERAL & ADMINISTRATION EXPENDITURE 5 712 608 5 612 995

OTHER EXPENSES 9 481 507 320 653

TOTAL EXPENDITURE 80 615 280 67 246 433

RESULT FROM OPERATING ACTIVITIES 6 172 834 11 975 270

Interest Income 155 962 101 405

Financial Expenses (142 882) (41 588)

Foreign Currency Translation Differences 10 (130 278) (1 337 363)

Net Financial Result (117 198) (1 277 546)

(LOSS)/SURPLUS FOR THE PERIOD 6 055 636 10 697 724

ALLOCATIONS

Transfer (To)/From Operations Reserve (452 774) (7 395 853)

Transfer (To)/From Donor Restricted Reserve (5 602 862) (3 301 871)

(6 055 636) (10 697 724)

45

MMV CONSOLIDATED STATEMENT OF CHANGES IN EQUITY

Balance at

1 Jan 2014

Internal Funds

Transfer

Gain for the

Period

Balance at

31 Dec 2014

Gain/(Loss) for

the Period

Balance at

31 Dec 2015

Restricted Operating Funds 7 525 410 (392 018) 3 301 871 10 435 263 452 774 10 888 037

TOTAL RESTRICTED OPERATING FUNDS 7 525 410 (392 018) 3 301 871 10 435 263 452 774 10 888 037

Foundation Capital 4 000 000 – – 4 000 000 – 4 000 000

Unrestricted Operation Funds 9 487 037 392 018 7 395 853 17 274 908 5 602 862 22 877 770

TOTAL UNRESTRICTED FUNDS 13 487 037 392 018 7 395 853 21 274 908 5 602 862 26 877 770

MMV CONSOLIDATED STATEMENT OF CASH FLOW

2015 2014

USD USD

Notes

(LOSS)/SURPLUS FOR THE YEAR 6 055 636 10 697 724

Adjustments for:

Increase/(Decrease) in Provisions 5 61 487 10 765

Depreciation 4 160 388 105 574

OPERATING RESULT BEFORE WORKING CAPITAL CHANGES 6 277 511 10 814 063

CASH FLOW FROM OPERATING ACTIVITY

(Increase) in Donations Receivable (3 728 369) (1 631 759)

Decrease/(Increase) in Project Balance Reimbursements – 5 710

(Increase)/Decrease in Accounts Receivable 1 876 308 (2 476 888)

(Increase)/Decrease in Tax Receivable (906) (700)

(Increase) in Project-Related Prepaid Expenses 7 2 380 475 (4 070 650)

(Increase)/Decrease in Prepaid Expenses (155 780) (103 116)

Increase in Accrued R&D Commitments 7 877 209 58 510

Increase in Accrued APM Commitments 7 (1 123 078) 1 800 580

Increase in Deferred Income 6 5 341 100 1 631 143

Increase in Other Creditors 511 144 103 922

(Decrease)/Increase in Accrued Expenses 106 233 (1 165 220)

Increase in Donations Reimbursement Payables 141 215 320 653

(Increase) in Long-Term Receivable (1 691 537) –

Unrealized Foreign Currency (Gain)/Loss 42 843 382 066

CASH FLOW RESULTING FROM OPERATING ACTIVITY 4 576 857 (5 145 749)

CASH FLOW FROM INVESTMENT ACTIVITY

Decrease/(Increase) in Guarantees 3 824 (5 201)

(Increase) in Derivative Financial Instruments 19 639 –

(Increase) in Fixed Assets 4 (267 895) (189 483)

CASH FLOW RESULTING FROM INVESTMENT ACTIVITY (244 432) (194 684)

NET (DECREASE)/INCREASE OF CASH AND CASH EQUIVALENTS 10 609 936 5 473 630

Cash & Cash Equivalents at Beginning of Year 38 057 339 32 954 528

Effect of Exchange Rate Fluctuations on Cash Held (175 712) (370 819)

Cash & Cash Equivalents at End of Year 48 491 563 38 057 339

6 | Financial view

46

1. ORGANIZATION

MEDICINES FOR MALARIA VENTURE (‘MMV’) is

a Swiss foundation, established as a not-for-profit

legal entity, registered in Geneva under statutes

dated 15 November 1999. It is managed by a

foundation council, a chief executive officer and

six senior managers.

With its head office in Geneva, the aim of MMV

is to bring public and private sector partners

together to fund, and provide managerial and

logistical support, for the discovery and devel-

opment of new medicines for the treatment and

prevention of malaria. The products should be af-

fordable and appropriate for use by populations

in developing countries.

As with all Swiss foundations, Medicines for

Malaria Venture is monitored by the Swiss Federal

Supervisory Board for Foundations.

2. SIGNIFICANT ACCOUNTING

POLICIES

The significant accounting policies adopted

by MMV in the preparation of the consolidated

financial statements are set out below.

Statement of compliance

The consolidated financial statements for the year

ending 31 December 2015 were approved for issue

by the MMV board on 12 March 2016.

The consolidated financial statements have

been prepared in accordance with the articles of

incorporation of MMV, the applicable provisions

of the Swiss Code of Obligations and the Swiss

Generally Accepted Accounting Principles (Swiss

GAAP FER/ RPC).

As donations from governments are not being ad-

dressed in the Swiss GAAP FER 21, the organization

has decided to retain the accounting treatment pre-

scribed by IAS 20, namely recognize income up to

the amount of expenditure allocated by government,

the difference being recognized as deferred income.

The consolidated financial statements have been

prepared on the historical cost basis, except where

a standard requires a different measurement basis.

The consolidated financial statements give a true

and fair view of the organization’s financial position,

the results of its operations and the cash flows.

Certain prior-year amounts have been reclassified

to conform with the current year’s presentation.

Basis of preparation

The consolidated financial statements are pre-

sented in US dollars, since the majority of MMV’s

activities are conducted in this currency (group

functional and presentation currency).

Fair value is the amount for which a financial as-

set, liability or instrument could be exchanged

between knowledgeable and willing parties in an

arm’s length transaction.

The preparation of consolidated financial state-

ments in conformity with Swiss GAAP FER

requires management to make judgements,

estimates and assumptions that affect the ap-

plication of policies and reported amounts of

assets and liabilities, income and expenditure.

The estimates and associated assumptions are

based on historical experience and various other

factors that are believed to be reasonable under

the circumstances, the results of which form the

basis of making the judgements about carrying

values of assets and liabilities that are not readily

apparent from other sources. Actual results may

differ from these estimates. If in the future such

estimates and assumptions, which are based on

management’s best judgement at the date of the

consolidated financial statements, deviate from

the actual circumstances, the original estimates

and assumptions will be modified as appropriate

in the year in which the circumstances change.

Judgements made by management in the appli-

cation of Swiss GAAP FER that have significant

effect on the consolidated financial statements

and estimates with a significant risk of material

adjustment in the next year are discussed below.

Foreign currency transactions

Transactions in foreign currencies are translated

at the foreign exchange rate ruling at the date of

the transaction. Monetary assets and liabilities

denominated in foreign currencies at the Consol-

idated Statement of Financial Position date are

translated to USD at the foreign exchange rate

ruling at that date. Foreign exchange differences

arising on translation are recognized in the Con-

solidated Statement of Comprehensive Income.

Non-monetary assets and liabilities that are

measured in terms of historical cost in a foreign

currency are translated using the exchange rate

at the date of the transaction.

The following exchange rates were used at year end:

2015

1 CHF = USD 1.00899

1 EUR = USD 1.09254

1 GBP = USD 1.48236

1 AUD = USD 0.72875

2014

1 CHF = USD 1.0105

1 EUR = USD 1.2155

1 GBP = USD 1.5532

1 AUD = USD 0.8156

Cash and cash equivalents

Cash and cash equivalents comprise cash bal-

ances and short-term money market deposits

with original maturities of three months or less.

Fixed or tangible assets

Fixed assets are stated at cost less accumulated

depreciation. Depreciation is charged to the Con-

solidated Statement of Comprehensive Income

on a straight line basis over the estimated useful

lives of the assets. The estimated useful lives of

assets are as follows:

Office furniture 5 years > CHF 1,000

Fixtures

and installations 3 years > CHF 1,000

Computers

and equipment 3 years > CHF 5,000

Impairment

The carrying amounts of MMV’s assets are re-

viewed at each Consolidated Statement of Finan-

cial Position date to determine whether there is an

indication of impairment. If any such indication ex-

ists, the asset’s recoverable amount is estimated.

An impairment loss is recognized in the Consoli-

dated Statement of Comprehensive Income when-

ever the carrying amount of an asset exceeds its

recoverable amount.

The recoverable amount of an asset is the greater

of its value in use and its fair value less costs to

sell. In assessing value in use, the estimated future

cash flows are discounted to their present value

using a pre-tax discount rate that reflects current

market assessments of time, value for money and

the risks specific to the asset.

Provisions

A provision is recognized in the Consolidated State-

ment of Financial Position when MMV has a present

legal or constructive obligation as a result of a past

event, and it is probable that an outflow of economic

benefits will be required to settle the obligation.

Foundation capital

The foundation capital is fully subscribed at USD

4,000,000 as stipulated under the original legal

statutes. Under normal circumstances, founda-

tion capital may be used during the year to meet

cash flow shortfalls, but should be replenished

before closing at year end. Foundation capital to-

gether with the residual operations reserve serves

to maintain the viability of the organization, for

6 months, until other funding sources can be found.

NOTES TO THE CONSOLIDATED FINANCIAL STATEMENTS AS OF 31 DECEMBER 2015

47

Revenue recognition

An unconditional grant is recognized as revenue

in the Consolidated Statement of Comprehen-

sive Income when the grant becomes receiv-

able. Any other grant which has performance,

timing or other conditions is recognized in the

Consolidated Statement of Financial Position as

revenue once the foundation has complied with

the stipulated conditions. If the conditions have

not yet been fully complied with, then this grant

component is reported as a contingent asset as

disclosed in Note 12. They are considered as

unrestricted funds, unless the donor stipulates a

specific restriction.

A reconciliation between donations received in

cash and income recognized in the Consolidated

Statement of Comprehensive Income is shown in

Note 6.

Government grants are recognized as income for

the allowable expenses incurred in the current

year. At year end, the difference between the in-

come recognized and the cumulative expenses

incurred is accounted for as deferred income.

When the donor wishes to see a donation allo-

cated to a specific cause, the donation is con-

sidered to be an allocated fund. Allocated funds

that have not been used at the end of the year are

presented in a separate section of the Consoli-

dated Statement of Financial Position.

Contributions in kind

Occasionally MMV receives donations in kind, pri-

marily in the form of free use of goods or services

or preferential discounts. These contributions in

kind are not stated in the Statement of Compre-

hensive Income as this type of contribution is dif-

ficult to valorize.

Operations reserve

The accumulated restricted and unrestricted

operation funds represent excess of core grants

over expenditure since the inception of MMV.

These funds are available to be utilized for future

operations and project funding costs in accord-

ance with the donor’s requirements.

Research and development expenditure

Expenditure and grants allocated for research

and development activities undertaken with the

prospect of gaining new scientific or technical

knowledge and understanding are recorded on

the basis of contracts with grantees. In the event

that a portion of a grant is unpaid at the year end,

it is included under current liabilities. Expenses

paid before year end for the following period are

recorded as Prepaid R&D Commitments in current

assets and as Prepaid in Note 7.

Regulatory and other uncertainties inherent in the

development of new products in this sector pre-

clude MMV from capitalizing development costs.

Income tax and status

MMV received exoneration from income tax from

the Geneva cantonal and Swiss federal authorities

from the year 2000 for an indeterminate period.

A further agreement was signed on 8 December

2010 with the Swiss Federal Council under new

provisions of the recently promulgated Swiss Host

State Act, to grant MMV certain privileges and im-

munities – effective as of 1 January 2011.

The principal advantages for MMV as a Swiss

foundation with ‘Other International Organization’

status are the following:

Exoneration from all direct and indirect

federal, cantonal and communal taxes

(this was originally acquired by decree with

the Geneva cantonal and Swiss federal

authorities, but now formalized directly with

the Swiss government within the accord);

Exoneration from VAT on all goods and

services acquired for the sole use of the

foundation within Switzerland and abroad;

Unrestricted access to work permits for non-

Swiss, non-EU nationals

MMV will deal directly with the Swiss Mission

in Geneva for all such issues.

Basis of consolidation

MMV has established a special purpose entity

(SPE) for fundraising in North America (MMV,

North America, Inc.). MMV does not have any

direct or indirect shareholdings in this entity.

An SPE is consolidated if, based on an evaluation

of the substance of its relationship with MMV and

the SPE’s risks and rewards, MMV concludes it

controls the SPE. The SPE is not fully controlled

by MMV, but was established under such terms

and conditions that it imposes strict limitations

on the decision-making powers of the SPE’s

management with the result that MMV receives

the majority of the benefits related to the SPE’s

operations and net assets while being exposed

to the majority of risks incident to the SPE’s

activities, and retaining the majority of the residual

or ownership risks related to the SPE or its assets.

MMV appoints the board members of the SPE.

In accordance with Swiss GAAP FER 30

and based on the facts above, MMV North

America Inc. is fully consolidated in these

consolidated financial statements on a line by

line basis since 2011.

List of organizations consolidated in 2014:

Transactions eliminated on consolidation

All intra-group balances and transactions, and

any unrealized gains and losses arising from intra-

group transactions, are eliminated in preparing

the consolidated financial statements.

Accounting estimates and judgements

Certain critical accounting judgements in

applying MMV accounting policies are described

below.

Revenue recognition – MMV enters into complex

grant contracts that contain numerous provisions

related to performance, reporting and spending.

These criteria are monitored by both the scientific

programme and finance teams to assess progress

according to grant milestones and objectives. The

evaluation of progress requires judgement, as it is

based on subjective evaluations and discussions

with programme participants and sponsors.

Research and development expenditure –

MMV’s research and development expenditure

is generally not direct expenditure, but is in the

form of grants and contracts with external parties

who perform certain tasks at their request.

These requests are formalized by contracts

and agreements that outline the requested

services and development effort. Progress

against expectations is difficult to measure, and

measurement criteria are generally not defined

in grant agreements. We review research plans

and activities regularly to adjust annual funding

levels prospectively. Additionally, actual research

and development timing and execution are often

different than the original plans. These factors

lead to subjectivity in the timing and recognition

of research and development expenditure.

Country United States of America

Name and domicile MMV, North America, Inc. Delaware

Functional currency USD

% controlled by MMV N/A

Direct/Indirect N/A

6 | Financial view

48

The fire insurance value of the tangible fixed assets is USD 1,785,912 (2014: USD 1,717,850).

4. FIXED ASSETS

The effective rates on deposits have moved within the following ranges:

3. CASH AND CASH EQUIVALENTS

31 December 2015 31 December 2014

USD USD

Cash 8 283 1 513

Bank Balances 44 483 280 34 055 826

Money Market Deposits 4 000 000 4 000 000

TOTAL CASH AND CASH EQUIVALENTS 48 491 563 38 057 339

2015 2014

Low % High % Low % High %

US Dollar (USD) 0.00 0.27 0.00 0.20

Swiss Franc (CHF) – 0.75 0.00 0.01 0.05

British Pound (GBP) 0.00 0.00 0.00 0.00

Euro (EUR) – 0.75 0.00 0.01 0.05

Australian Dollar (AUD) 0.00 0.00 0.00 0.00

2014 Fixtures & Office Computers Total

Installations Furniture & Equipment

USD USD USD USD

COST

At 1 January 2014 492 511 395 462 527 241 1 415 214

Additions 60 302 44 260 84 921 189 483

Disposals – (503) (13 111) (13 614)

AT 31 DECEMBER 2014 552 813 439 219 599 051 1 591 082

ACCUMULATED DEPRECIATION

At 1 January 2014 362 709 343 426 479 393 1 185 528

Charge for the Year 38 040 18 731 48 802 105 574

Disposals – (503) (13 110) (13 614)

AT 31 DECEMBER 2014 400 749 361 654 515 085 1 277 488

NET BOOK VALUE

AT 31 DECEMBER 2014 152 064 77 565 83 966 313 595

2015 Fixtures & Office Computers Total

Installations Furniture & Equipment

USD USD USD USD

COST

At 1 January 2015 552 813 439 219 599 051 1 591 083

Additions 24 760 231 111 12 501 268 372

Disposals (23 032) (1 704) (12 964) (37 700)

AT 31 DECEMBER 2015 554 541 668 626 598 588 1 821 755

ACCUMULATED DEPRECIATION:

At 1 January 2015 400 749 361 654 515 085 1 277 488

Charge for the Year 37 560 95 835 26 993 160 388

Disposals (23 032) (1 704) (12 486) (37 222)

AT 31 DECEMBER 2015 415 277 455 785 529 592 1 400 654

NET BOOK VALUE

AT 31 DECEMBER 2015 139 264 212 841 68 996 421 101

49

5. PROVISIONS

6. DONATIONS

Below is a summary of donations received or committed during 2015:

On the total donations recognized in the Consolidated Statement of Comprehensive Income, USD 112,240 were received through MMV, North America, Inc.

Unused Vacation Reserve Total Provisions

USD USD

BALANCE AT 1 JANUARY 2014 439 291 439 291

Use/Release 2014 (439 291) (439 291)

Allocation for the Year 450 056 450 056

BALANCE AT 31 DECEMBER 2014 450 056 450 056

Use/Release 2015 (450 056) (450 056)

Allocation for the Year 511 543 511 543

BALANCE AT 31 DECEMBER 2015 511 543 511 543

Cash

Received

2015

USD

Income

Recognized

during

Previous Year

USD

Income

Deferred from

Previous Year

USD

Income

Deferred to

Following Year

USD

Current Year

Income to be

Received

USD

Unrealized

Foreign

Exchange

Gain/(Loss)

USD

Total Income

as per

Statement of

Comprehen-

sive Income

USD

Bill & Melinda Gates Foundation 42 429 918 – – – – – 42 429 918

Bill & Melinda Gates Foundation (Innovation Fund) 810 000 – – – – – 810 000

Bill & Melinda Gates Foundation (Pathogen Box) 1 647 064 – – – – – 1 647 064

Bill & Melinda Gates Foundation (QIMR) 2 092 726 – – – – – 2 092 726

Wellcome Trust 800 000 – – – 800 000 – 1 600 000

GHIT 3 174 222 – – – 97 500 – 3 271 722

Swiss Government (DEZA/SDC) 1 716 000 – – – – – 1 716 000

UK Government (DFID) 16 866 640 – 5 759 025 (9 764 532) – – 12 861 133

US Government (USAID) 2 601 631 – – – 2 380 785 – 4 982 416

Irish Aid 1 123 000 – – – – – 1 123 000

Australian Government (DFAT) 2 629 666 – – (1 335 593) – – 1 294 074

Norwegian Government (NORAD) 589 550 – – – – – 589 550

National Institues of Health (NIH) 1 034 870 (343 844) – – 440 732 – 1 131 758

UNITAID 6 181 967 (1 241 557) – – 1 747 950 – 6 688 360

World Health Organization (WHO) 1 224 000 – – – – – 1 224 000

ExxonMobil 500 000 – – – – – 500 000

Newcrest Mining Limited 665 939 (236 619) – – 182 188 – 611 508

Malaria Consortium (SMC) 1 473 513 (157 817) – – – – 1 315 696

Merck KGaA 324 772 (98 911) – – 167 572 (752) 392 681

Individual Donors 112 240 (3 000) – – 3 000 – 112 240

TOTAL RECEIVED 87 997 718 (2 081 747) 5 759 025 (11 100 125) 5 819 726 (752) 86 393 845

6 | Financial view

50

7. P

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ilot

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an M

ala

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65 8

42

465 8

42

449 5

08

16 3

34

−

Queensla

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60

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1

39 7

57

139 7

57

138 8

75

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−

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61

QIM

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and

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2 1

13 3

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1 3

29 0

94

1 3

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94

−

784 2

22

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ase

IIa

2 8

68 5

09

2 8

68 5

09

2 4

01 9

51

466 5

58

−

62

DS

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DH

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rs 2

868 5

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2 8

68 5

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2 4

01 9

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466 5

58

−

GH

IT, Ta

ked

a

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ase

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16 0

21 8

99

16 0

21 8

99

11 3

36 8

90

4 6

85 0

09

−

63

OZ

439

15 2

17 0

12

15 2

17 0

12

11 3

36 8

90

3 8

80 1

22

−

Sanofi

64

KA

E 6

09

804 8

87

804 8

87

−

804 8

87

−

Nova

rtis

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te for

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ical D

iseases

Ph

ase

III

3 7

28 4

57

3 7

28 4

57

3 7

40 0

74

(11 6

17)

−

65

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noq

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rela

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pre

ventio

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768 1

23

2 7

68 1

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79 7

40

(11 6

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GS

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66

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noq

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P. v

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n 9

60 3

34

960 3

34

960 3

34

−

−

GS

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Ph

ase

IV

3 6

65 7

30

3 1

90 3

65

3 1

47 5

63

42 8

02

475 3

65

67

Pyr

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ax

® (p

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ine-a

rtesu

nate

) 1

22 2

67

122 2

67

111 4

83

10 7

84

−

Shin

Poong P

harm

aceutical C

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68

Safe

ty/e

fficacy

of re

treatm

ent w

ith A

CTs

(W

AN

EC

AM

stu

dy)

2 8

90 6

67

2 4

15 3

01

2 3

92 3

51

22 9

50

475 3

65

Univ

ers

ity

of B

am

ako

69

Pyr

am

ax®

(p

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nate

) new

paed

iatr

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ula

tion

283 2

26

283 2

26

274 1

59

9 0

68

−

Shin

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harm

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o

70

Ext

end

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acity

build

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369 5

70

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70

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−

−

Univ

ers

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of V

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TA

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&D

45 8

84 3

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72 9

44

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33

7 7

01 0

12

2 0

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73

6 | Financial view

52

Project grants represent the awards to the

projects as specified above, directly managed

and supervised by MMV.

Project-related variable expenditures include all

legal advice/services for contract negotiations

(IPR), organization and travel for project meetings/

reviews, MMV scientific personnel compensation

and various scientific project consultancies.

Expenditure for this MMV support totalled USD

12,903,996 and USD 11,533,558 in 2015 and 2014,

respectively.

Project reimbursements receivable

These refer to unused balances of project grants

previously committed, which are returned to

MMV by the project partners as stipulated in the

individual contractual agreements on termination

or reorganization of R&D projects.

8. PERSONNEL EXPENSES

There were 57 employees at 31 December 2015,

excluding temporary staff members (2014: 55).

The pension plan covers all employees for death

and disability benefits. Cover for retirement

benefits begins in the year following each

employee’s 24th birthday. The retirement pension

is based on the level of the retirement credits, the

interest rate to be credited and the conversion

rate to be applied at retirement age. Risk benefits

are related to pensionable salary.

The occupational benefits are provided by a

collective foundation, Profond, according to a

defined contribution benefit plan: investment

yield has no impact on premiums; the employer

does not guarantee the benefit amount. The plan

is funded by the contribution of MMV and the

employees.

7. PROJECT GRANTS (CONTINUED)

Pension Plan Statistics 2015 2014

USD USD

Capital Ratio (%) 105.9 107.4

Economic Part of the Entity as of 1 January – –

Economic Part of the Entity as of 31 December – –

Occupational Benefits Included in Personnel Expenditures 1 764 783 1 703 149

Pension Fund (Asset)/Liability – (320)

Awarded

2015 (USD)

Final

Allocation

2015 (USD)

Paid 2015

(USD)

Related to

2015 paid in

2016 (USD)

Prepaid

2015 for 2016

(USD)

Project Partners

Introduction of New Product/Oversee

Launched Product11 132 558 10 185 765 9 120 857 1 064 908 946 793

1 Policy Revision 35 113 35 113 35 113 – – Government of Democratic Republic of the Congo

2 Eurartesim® 235 803 181 352 180 726 626 54 451 National Institute Malaria Research, India; Imperial

College London; Sigma-Tau Industrie Farmaceu-

tiche Riunite, Italy

3 Pyramax® General 11 857 11 857 11 857 – – Medicines for Malaria Venture

4 Pyramax® CANTAM Study 38 167 38 167 28 167 10 000 – Central African Network on Tuberculosis, HIV/AIDS

and Malaria

5 Injectable Artesunate – General 92 516 72 516 42 516 30 000 20 000 Medicines for Malaria Venture

6 Malaria in Pregnancy (IPTp) 481 961 271 082 117 871 153 211 210 879 London School of Hygiene & Tropical Medicine

7 OZ439 7 642 7 642 7 642 – – Medicines for Malaria Venture

8 Seasonal Malaria Chemoprevention 168 327 168 327 127 327 41 000 – RBM West Africa sub-Regional Network (WARN)

9 Improving Severe Malaria Outcomes 9 976 838 9 315 375 8 492 908 822 467 661 463 Clinton Health Access Initiative; Malaria Consortium;

MissionPharma

10 RAS General 82 587 82 587 74 983 7 604 – Cipla Ltd; Strides Pharma Global Pte. Ltd

11 ASMQ – Low Cost, Paediatric, Market Assessment 1 748 1 748 1 748 – – Cipla Ltd

Input to R&D 649 489 466 724 460 904 5 820 182 765

12 VIVAX – Market Research to Support Tafenoquine 71 998 71 998 71 998 – – GlaxoSmithKline Services

13 VIVAX – Strategy Development 390 857 240 883 240 883 – 149 974 World Health Organization

14 India Comprehensive Case Management Pilot 186 634 153 844 148 024 5 820 32 791 National Institute Malaria Research India; NVBCDP

Odisha

Gather & Generate Information 499 400 499 400 419 152 80 248 –

15 Market Intelligence - General 243 462 243 462 178 964 64 499 – BroadReach Healthcare GmbH; ec4u expert

consulting (Schweiz) ag

16 Market Volumes (Market Size & Segmentation) 188 437 188 437 172 688 15 749 – Government of Zambia; Government of Uganda,

IMS Health

17 SMS for Life – Tanzania 67 500 67 500 67 500 – – Swiss TPH

New Projects/Pilots 485 899 485 899 439 290 46 609 –

18 Newcrest Alliance 2 228 2 228 2 228 – – Newcrest Mining Ltd

19 Mass Drug Administration Programming (Lihir) 478 487 478 487 431 878 46 609 – Newcrest Mining Ltd; ISGlobal Barcelona Institute

For Global Health

20 DSM265 5 185 5 185 5 185 – – Medicines for Malaria Venture

Access Events & Misc. Project Costs 185 438 185 438 158 836 26 602 –

21 Events & Conferences 62 856 62 856 62 856 – – Medicines for Malaria Venture

22 Miscellaneous Project Costs 122 582 122 582 95 980 26 602 – Medicines for Malaria Venture

TOTAL 12 952 784 11 823 226 10 599 040 1 224 186 1 129 558

53

2015 2014

USD USD

Less than One Year 917 372 919 654

Between One and Five Years 1 326 643 2 240 648

More than Five Years – –

TOTAL 2 244 015 3 160 302

9. OTHER INCOME AND OTHER EXPENSES

In the course of 2015 MMV reimbursed an amount of USD 461,868 to a donor,

the Global Health Initiative Technology Fund (GHIT), owing to the period-termination

earmarked grant funded by GHIT. This amount represented the unused part of a grant

received in 2014.

10. FOREIGN CURRENCY TRANSLATION DIFFERENCES FOR FOREIGN

OPERATIONS

In order to minimize the potential adverse effect of foreign exchange fluctuations, the

MMV liquidity is deposited in bank accounts denominated in foreign currencies pro rata

to the breakdown of total expenditure by currency (natural hedging).

11. LEASES

Non-cancellable operating lease rentals are payable as follows:

MMV has several operating leases. These leases generally run for a period of 5 years,

with an option to renew the lease after that date. During the year ended 31 December

2015, USD 952,038 were recognized as an expense in the Consolidated Statement of

Comprehensive Income in respect of operating leases (2014: USD 920,577).

12. CONTINGENT ASSETS

As per current contractual agreements, and depending on satisfactory reporting to

donors, contingent assets related to donations are as follows:

OTHER INCOME 2015 2014

USD USD

Project Reimbursements from Previous Years – 2 100 000

Royalties 289 690 25 000

Tax at Source Commission 25 650 28 855

Other 78 929 43 488

OTHER INCOME 394 269 2 197 343

OTHER EXPENSES 2015 2014

USD USD

Donation Reimbursement (461 868) (320 653)

Derivatives Financial Instruments (19 639) –

OTHER EXPENSES (481 507) (320 653)

FOREIGN EXCHANGE GAIN/(LOSS) 2015 2014

USD USD

Exchange Gain/(Loss) from CHF 440 534 (769 580)

Exchange Gain/(Loss) from EUR 32 085 (93 629)

Exchange (Loss) from GBP (401 762) (479 089)

Exchange (Loss)/Gain from AUD (201 135) 4 935

FOREIGN EXCHANGE (LOSS) (130 278) (1 337 363)

2015 2014

USD USD

Less than One Year 69 259 235 74 331 769

Between One and Five Years 95 611 540 133 256 162

More than Five Years – –

TOTAL 157 870 775 207 587 931

6 | Financial view

54

13. DERIVATIVE FINANCIAL INSTRUMENTS

Derivative financial instruments used for hedging

balance sheet items are recognized at fair value

on the date a derivative contract is entered into

and are recorded as other receivables or other

current liabilities. Derivatives are subsequently

re-measured to their current fair value at each bal-

ance sheet date, with unrealized gains and losses

recognized in the income statement.

MMV uses currency options to hedge its expo-

sure to foreign currency risk.

14. RELATED PARTIES

MMV has a related party relationship with its

board members, executive officers and MMV

North America Inc.

Board members serve on a voluntary basis and

receive no remuneration. They are compensated

for travel and accommodation for participation

in board meetings and receive a per diem

allowance to cover incidental expenses during

these events.

15. RISK MANAGEMENT

The foundation council has overall responsibility

for organizing and supervising risk management.

The audit committee monitors management’s ap-

proach to risk management in compliance with

the organization’s principles and procedures and

verifies that risks are managed appropriately in

light of the current risks faced by the organiza-

tion. Based on a risk identification carried out pe-

riodically, MMV’s essential risks are assessed in

respect of likelihood and impact and documented

in a risk analysis report. The management has the

responsibility to monitor and supervise the sub-

stantial risks.

For risks related to accounting principles and

financial reporting, a risk analysis was carried out.

Controls in line with the Internal Control System

have been defined and measures resulting from

this have been implemented in order to minimize

the risks related to accounting principles and

financial reporting.

16. GUARANTEES

Guarantees concern office rental only and are re-

coverable on vacating the premises subject to the

prevailing contracts.

17. CAPITAL COMMITMENTS

AND CONTINGENCIES

MMV encounters certain risks and uncertainties

in conducting its affairs. These risks and uncer-

tainties have financial statement implications. In

all instances, these have been considered in the

consolidated financial statements, despite the fact

that the outcomes of these uncertainties cannot

be predicted with absolute certainty. Management

has concluded that provisions for these risks are

appropriate, and any adverse resolution of these

uncertainties will not have a material impact on the

financial position or results of the foundation.

18. AUDITORS

KPMG SA, Geneva, has been MMV’s statutory

auditor since the fiscal year 2003. Following a

competitive bidding in 2012, KPMG was reap-

pointed as the statutory auditor. The current lead

auditor, Pierre-Henri Pingeon, has acted in this

capacity since 2010.

During the fiscal year 2015, MMV paid a total

of USD 210,846 (2014, USD 153,502) to its

auditors. This amount was split as follows:

• Audit services (including special audit reports to

donors): USD 182,869 (2014: USD 153,502);

• Other services: USD 27,977 (2014: USD nil).

19. SUBSEQUENT EVENTS

No events have occurred between balance date

and the date of this report that require adjustment

to, or disclosure in, these financial statements.

2015 2014

Positive Value Negative Value Purpose Positive Value Negative Value Purpose

Options Currency Transactions 180 734 (200 373) Hedging – – N/A

TOTAL FINANCIAL INSTRUMENTS 180 734 (200 373) – – – –

BOARD MEMBERS 2015 2014

USD USD

Board members and meetings

165 251 172 950

55

REPORT OF THE AUDITORS TO THE BOARD OF MMV

56

Dr Dennis Schmatz

Former Vice President,

Head of Tsukuba

Research Institute,

Merck-Banyu Research

Laboratories, Japan

Dr David Bowen

Independent Advisor, USA

Mr Ray Chambers

United Nations Secretary-

General’s Special Envoy

for Health in Agenda

2030 and for Malaria;

Co-Founder of Malaria

No More, USA

Dr David Reddy

CEO, MMV, Switzerland

Ms Wendy Taylor

Director, Center for

Accelerating Innovation

and Impact at USAID,

USA

MMV North America Inc. Board

Dr Dennis Schmatz

Former Vice President,

Head of Tsukuba

Research Institute,

Merck-Banyu Research

Laboratories, Japan

Mr Ray Chambers1



for Health in Agenda

2030 and for Malaria;

Co-Founder of Malaria

No More, USA

Mr Per Wold-Olsen2

Chairman of MMV

Board, former President

of Human Health

Intercontinental Region,

Merck & Co., Inc., Middle

East & Africa; former

Member of Merck’s

Management Committee;

Chairman GN Store

Nord A/S, Denmark;

Board Member of Gilead

Sciences Inc., USA; Board

Member of Novo A/S and

Exiqon A/S, Denmark

Mr Alan Court

Senior Advisor to the



for Health in Agenda 2030

and for Malaria (Board

observer)

Dr David Brandling-

Bennett

Former Senior Advisor,

Malaria, Bill & Melinda

Gates Foundation, USA

Dr Robert Newman

Country Director, US

Centers for Disease

Control and Prevention,

Cambodia; Formerly

Director of Global Malaria

Programme, WHO

Mr Gabriel Jaramillo

Former General Manager

of the Global Fund to

Fight AIDS, Tuberculosis

and Malaria, Switzerland

Prof. Michael Ferguson3

Regius Professor of Life

Sciences and Associate

Dean for Research

Strategy, University of

Dundee, Scotland

Dr Winston Gutteridge

Former Chief, Product

R&D, Special Programme

for Research and Training

in Tropical Diseases,

WHO, Switzerland

Dr David Reddy

CEO, MMV, Switzerland

Dr Wendy Sanhai

Associate Professor

(adj), School of Medicine,

Duke University, USA

Ambassador

(Dr) Konji Sebati

CEO, Innovative

Pharmaceutical

Association of South

Africa, Johannesburg,

South Africa

Dr Ernest Darkoh3

Chairman & Founding

Partner, BroadReach

Healthcare, South Africa

Dr Pedro Alonso,

Director, WHO Global

Malaria Programme,

Switzerland

Ms Joy Phumaphi,

Co-Chair of the

Independent Expert

Review Group for Every

Woman Every Child; Chair

of the Global Leaders

Council for Reproductive

Health; and Executive

Secretary of ALMA, USA

From left to right – back row followed by front

Not pictured:

MMV Board

Behind the scenes

7

1 After 4 years as Chairman of MMV’s Board of Directors, in November 2015, Mr Ray Chambers, the United Nations Secretary-General’s Special Envoy for Financing the Health Millennium Development Goals and for Malaria, stepped down, entrusting the role to MMV’s Vice Chair, Mr Per Wold-Olsen. The appointment of Mr Wold-Olsen as Chairman was ratified by the Board of Directors. Mr Chambers will continue to serve on the MMV Board as a non-Executive Director.

2 Mr Per Wold-Olsen, former President of Human Health Intercontinental Region, Merck & Co., Inc, joined MMV’s Board in 2008 and has been Vice-Chair since May 2013. Mr Wold-Olsen holds an MBA and has extensive global leadership experience and knowledge of the health-care industry from his many years in the pharmaceutical industry. His extensive expertise encompasses product development, commercialization, and developing world and access issues.

3 Dr Fatoumata Nafo-Traore, Executive Director of WHO RBM, resigned from the MMV Board.

Prof. Mike Ferguson and Dr Ernest Darkoh were re-elected for second and third terms, respectively.

57

Expert Scientific Advisory Committee (ESAC)

Dr John Pottage

Co-Chairman MMV

ESAC (Development);

Chief Scientific and Medi-

cal Officer, ViiV Healthcare,

USA

Dr Dennis Schmatz

Co-Chairman MMV

ESAC (Discovery); former

Vice-President, Head of

Tsukuba Research

Institute, Merck-Banyu

Research Laboratories,

Japan

Dr Aileen Allsop

Former Vice-President

for Science Policy, R&D,

AstraZeneca, UK

Prof. Thomas Baillie

Vice Provost, Strategic

Initiatives, University of

Washington, USA

Dr Tesfaye Biftu

Principal Scientist, Merck

and Co., USA

Dr Robert Clay

Consultant, Highbury

Regulatory Science

Limited and Chief

Regulatory Officer,

Kinapse Ltd., UK

Prof. Umberto

D’Alessandro

Theme Leader, Disease

Control and Elimination,

Medical Research Council,

the Gambia

Dr Michael Dunne

Chief Medical Officer,

Durata Therapeutics, USA

Prof. Paul Fish

Chair of Medicinal

Chemistry, University

College London, UK

Prof. Kasturi Haldar

Rev. Julius Nieuwland,

CSC Professor of

Biological Sciences,

Director, Center for

Rare and Neglected

Diseases, University

of Notre Dame, USA

Prof. Dennis Kyle

Distinguished University

Health Professor, College

of Public Health, University

of South Florida, USA

Dr Marcus Lacerda

Director of Learning and

Research at the Fundação

de Medicina Tropical

Dr Heitor Vieira Dourado,

Brazil

Prof. John Lambert

Chief Medical Officer,

Global Head Medical

Affairs and Consulting,

PAREXEL International, UK

Dr Mary Mader

Senior Research Advisor,

Discovery Chemistry

Research and

Technologies, Eli Lilly

and Company, USA

Dr Christine Manyando

Head of Public Health

Department, Tropical

Diseases Research

Centre, Zambia

Dr George Mooney

KGM Pharma Consulting

LLC, USA

Prof. François Nosten

Director, Shoklo

Malaria Research Unit,

part of the Wellcome

Trust–Mahidol–Oxford

University Tropical

Medicine Research

Programme, Thailand

Dr Paul Reider

Pharmaceutical Specialist

and Lecturer, Department

of Chemistry, Princeton

University, USA

Dr David Roberts

Independent Scientific

Consultant, UK

Prof. Dennis Shanks

Army Malaria Institute,

Australia

Dr Peter Siegl

Director, Siegl Pharma

Consulting LLC, USA

Dr Sodiomon Sirima

Centre National de

Recherche et de

Formation sur le

Paludisme, Burkina Faso

Dr Per Sjoberg

Partner, Eureda, Sweden

Prof. Dennis Smith

Former Vice-President,

PGRD, Pfizer, UK

Dr Klaus Urbahns

Head of Discovery

Technologies at Merck

Group, Germany

Dr Elizabeth Vadas

InSciTech Inc, Canada

Dr Neena Valecha

Director, National

Institute of Malaria

Research, India

Dr Thomas Wellems

Chief, Laboratory of

Malaria and Vector

Research, National

Institute of Allergy and

Infectious Diseases, USA

Dr Matthew Wyvratt

Senior Vice-President,

Drug Discovery, Motif

BioSciences, Inc., USA

Access & Product Management Advisory Committee (APMAC)

Prof. Christian

Lengeler, Chairman of

MMV APMAC; Head,

Health Interventions Unit,

Swiss Tropical and Public

Health Institute,

Switzerland

Dr Neena Valecha

Vice-Chairman of MMV

APMAC; Director, National

Institute of Malaria

Research, India

Ms Valentina Buj

Health Specialist (Malaria

Partnerships), UNICEF,

USA

Dr Elizabeth Chizema

Director of Disease

Control, Surveillance

and Research, Ministry

of Health, Zambia

Dr Graciela Diap

Associate Staff of DNDi

and FACT Medical

Coordinator, Spain

Dr Alexander Dodoo

Director at WHO Collabo-

rating Centre for Advocacy

and Training in Pharmaco-

vigilance, Ghana

Dr Gunther Faber

Chairman, One Family

Health, UK

Dr Douglas Lungu

Mzuzu Central Hospital,

Malawi

Dr David McGibney

Pharmaceutical

Research and Develop-

ment Expert; Consultant

Pharmaceutical Physician,

UK

Prof. Ric Price

Associative Professor,

Menzies School of Health

Research, Darwin,

Australia

Dr Melanie Renshaw

Chief Technical Advisor,

ALMA, Kenya

Dr Claude Emile

Rwagacondo

Coordinator of West

and Central Africa Roll

Back Malaria Network,

Senegal

Dr GS Sonal

Additional Director and

Head of Malaria Division

of the National Vector

Borne Disease Control

Programme, India

Dr Richard Steketee

Science Director, Malaria

Control Program and

MACEPA, PATH, USA

Prof. Andy Stergachis

Professor of

Epidemiology and Global

Health, Adjunct

Professor of Pharmacy

and Health Services,

Director of the Global

Medicines Program,

University of Washington,

USA

Dr Brenda Waning

Chief, Global Drug Facility,

Stop TB Partnership,

Switzerland

Global Safety Board

Dr Trevor Gibbs

Co-Chairman of MMV

Global Safety Board;

Senior Vice-President,

Pharmacovigilance &

Medical Governance,

GlaxoSmithKline, UK

Dr Stephan Duparc

Co-Chairman of MMV

Global Safety Board; Chief

Medical Officer, MMV,

Switzerland

Sir Colin Dollery,

Senior Consultant,

GlaxoSmithKline Research

and Development, UK

Dr Neil Garbet

Independent Consultant

Pharma ceutical Physician

and Consulting Partner to

Kinapse Ltd, UK

Dr David McGibney

Pharmaceutical Research

and Development Expert;

Consultant Pharmaceutical

Physician, UK

Prof. Tim Hammond

Preclinical Safety

Consulting Ltd, UK

7 | Behind the scenes

58

Nada Abla Geiser

Senior Drug Metabolism & Pharmacokinetics

(DMPK) Scientist, Drug Discovery

Marc Adamy

Director, Product Development

Samantha Akakpo

Regulatory Safety Advisor

Nicole Andenmatten

Translational Medicine Scientist

Nada Araeipour

Associate Director, Business Development

Adam Aspinall

Director, Product Strategy & Management

Muriel Aubert

Project Coordinator, Translational Medicine

Jaya Banerji

Director, Advocacy & Communications

Chris Barker

Travel Coordinator

Lidiya Bebrevska

Associate Director, Translational Medicine

Keeva Beke

Legal Coordinator

Soazig Bertrand

Finance Officer

Susan Bianchi

Business Development Assistant

Sophie Biguenet

Medical Director

Benjamin Blasco

Research Scientist, Drug Discovery

Grégory Bonnaud

Finance Director

Isabelle Borghini-Fuhrer

Director, Product Development

Jeremy Burrows

Vice-President, Head of Drug Discovery

Andrea Buscaglia

Chief Financial Officer

Brice Campo

Director, Drug Discovery

Stephan Chalon

Medical Director

John Clare

IT Manager

Marion Colombani

Senior Legal Officer

Maud Couturier

Strategic Meetings Officer

Gelavizh Daghigh

Office Administrator

Helen Demarest

Associate Director, Clinical Operations

Heidi Divecha

R&D Administrative Officer

Christina do Paço

External Relations Officer

Matthew Doherty

Manager, Donor & Stakeholder Relations

Cristina Donini

Director, Translational Medicine

Celia Doudou

Legal Officer

Angelique Doy

Drug Discovery Coordinator

James Duffy

Associate Director, Drug Discovery

Stephan Duparc

Chief Medical Officer

Mélanie Dupuy

Junior Financial Controller

Myriam El Gaaloul

Senior Clinical Scientist

Fanny Escudié

Project Coordinator, Drug Discovery

Sylvie Fonteilles-Drabek

Executive Vice-President, Head of Legal

Nathalie Gobeau

Associate Director, Pharmacometrics,

Translational Medicine

Petra Grand

External Relations Coordinator

Joan Herbert

Director, Business Development

Heike Huegel-Koerpert

Project Manager, Translational Medicine

Pierre Hugo

Senior Director, Access

& Product Management

MMV staffMarch 2016

59

George Jagoe

Executive Vice-President, Access


Sandra Johnson

Associate Director, Outsourcing

& Relationship Management

Alexis Kamdjou

Country & Procurement Liaison Manager

Franziska Karyabwite

Vice-President, Head of Human Resources

Wiweka Kaszubska


Product Development

Elizabeth Kernen

Administrative Assistant

Eun Jin Ko

Finance Intern

Benoit Laleu

Research Scientist, Drug Discovery

Didier Leroy


Andrea Lucard

Executive Vice-President,

Head of External Relations

Adrienne MacDonald

Online Communications Officer

Fiona Macintyre

Director, Clinical Development

Simona Mag Valigova

Legal Officer

Maud Majeres Lugand

Research and Projects Manager,

Access & Product Management

Neil McCarthy

Vice-President, Head of External Relations

Jörg Möhrle



Alessandra Monaco

Translational Medicine Scientist

Alice Neequaye

Quality Officer & Archivist

Peter Okeyo

External Relations Intern

Gabrielle Pena

Archiving Assistant

Elise Penarrieta

Discovery Intern

Alicja Poczatenko

Legal Officer

Elizabeth Poll

Communications Manager

Hanu Ramachandruni

Senior Director, Technical

Product Development

Anya Ramalho

Executive Vice-President,

Business Development

David Reddy

Chief Executive Officer (CEO)

Wendy Redford

Human Resources Generalist

Véronique Reusse

Human Resources Recruitment Partner

Emilie Rossignol

Project Manager, Translational Medicine

Mélanie Rouillier

Project Coordinator, Drug Discovery

Thomas Rückle

Director, Translational Medicine

Anouchka Smits Bayala

Product Development Coordinator

Tareq Sunderji

Legal Administrative Officer

Yuko Takase

Finance Officer

André-Marie Tchouatieu

Associate Director, Access


Kim Van der Weijde

Access Intern

Helen Weir

Personal Assistant to the CEO

Timothy Wells

Chief Scientific Officer

Paul Willis


Antonia Wolff

Project Coordinator,


Defeating Malaria Together

MMV is grateful for the support in 2015 from the following institutional donors:

MMV is also grateful for the support received from private individuals.

International Centre Cointrin

Route de Pré-Bois 20, PO Box 1826

1215 Geneva 15, Switzerland

Tel. +41 22 555 03 00

Fax +41 22 555 03 69

[email protected]

www.mmv.org

Editors Elizabeth Poll & Jaya Banerji, MMV

Designer ComStone - Pierre Chassany, Geneva, Switzerland

Printer Atar Roto Presse SA, Geneva, Switzerland

Lithograph Catherine Vogt, Carouge, Switzerland

Photographs BMC St Jude (p. 13), Pierre Chassany (p. 53), Samuel Choudhury* (pp. 20 & 21), Carl Craft/MMV (p. 2), Pearl Gan/Oxford

University Centre Research Unit (OURCRU)/Eijkman Oxford University Research Unit (EOCRU)/The Wellcome Trust

(Covers front and back), Pierre Hugo/MMV (p. 35), Muhammed Joof (p. 38), Benjamin Moldenhauer (p. 29), Elizabeth

Poll/MMV (pp. 15 & 19), Jetsumon Sattabongkot Prachumsri (p. 28), Damien Schumann (pp. 14 & 22), Nicolas

Spuhler (p. 58), Kim van der Weijde/MMV (p. 16), W Studios, New York (p. 56) and Anna Wang/MMV (pp. 5, 11 & 41).

Small portrait photos provided by interviewees.

* Photograph from Swiss Malaria Group photo contest 2013 ‘Malaria: the BIG Picture’

National Institutes

of Health (NIH/NIAID)

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MMV Annual_Report_2015, My Interview

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