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ANNUAL REPORT

2013


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.


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 and registered in Switzerland.

MMV’s mission is to reduce the burden of malaria in disease-endemic countries by discovering, developing and facilitating access to 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.

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Message from the Chairman and CEO

Message from Yvonne Chaka Chaka

Expediting access to approved medicines

New medicines for vulnerable populations

New medicines to drive elimination and eradication

Financial view

Behind the scenes

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PAGE 10

PAGE 12

PAGE 18

PAGE 24

PAGE 36

PAGE 52

Æ The long walk

Æ Keeping

Æ Expanding the

Æ Developing

Æ Developing a single-

to a malariafree world

malaria centre stage

range and use of ACTs

medicines for children

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PAGE 10

PAGE 12

PAGE 18

Æ Improving

Æ Protecting

dose malaria cure PAGE 26

Æ New tools to ÆKey

achievements PAGE 8

malaria case management

the most vulnerable

PAGE 15

PAGE 20

accelerate drug development PAGE 27

Æ Targeting Æ Saving more

Æ Optimizing

lives with injectable artesunate

pre-referral treatment for severe malaria

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PAGE 22

Æ MMV portfolio

– 4th quarter 2013 PAGE 23

the relapse PAGE 28

Æ MMV Project of

the Year 2013: tafenoquine PAGE 30

Æ Blocking transmission PAGE 32

Æ Open source drug

discovery PAGE 34

Æ The Malaria Box

and Pathogen Box

Poster: Malaria and children (infographic) MMV portfolio – 4th quarter 2013

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© May 2014 Medicines for Malaria Venture

All 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.

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1 | Message from the Chairman and CEO

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1 The long walk to a malaria-free world Message from the Chairman and CEO Mr Ray Chambers Chairman of the Board

It always seems impossible until it’s done.” Nelson Mandela (1918–2013) Former President of South Africa

S

ince 2000, malaria deaths have been on the decline and around 3.3 million lives have been saved thanks to the concerted efforts of the malaria community.1 This is an impressive achievement, yet around 3.4 billion people are still at risk from the disease and more than 600,000 die each year.1 Although the annual number of malaria deaths is on a downward trend, the pace of decline is slowing and the goal of eradication remains challenging, particularly with current tools. It’s clear that we must intensify our activities today to ensure we are well equipped to be able to complete the long walk to a malaria-free world tomorrow. There is no other way. With this belief firmly in mind, 2013 was a landmark year at MMV. Working with our Board and Stakeholders, we refocused our strategy for the next 5 years on the development and delivery of malaria medicines to enable elimination and eradication, addressing short-, medium- and long-term goals.

Dr David Reddy MMV’s CEO

In the short-term, we are working on interventions that can be delivered to the market in the next several years to address the needs of the most vulnerable populations; children and pregnant women. Interventions include the development of new paediatric artemisinin-based combination therapies (ACTs) (pages 18–19) and the scale-up of a preventive drug regimen to protect children in areas of high seasonal malaria in the Sahel sub-region of Africa (pages 20–21). With the support of a major grant from UNITAID, we are also focusing on the prequalification of rectal artesunate, a pre-referral form of treatment that has important life-saving potential for children threatened by severe malaria (page 22). Our medium- and long-term goals are to develop a first- and next-generation, single-dose therapy that can completely cure all forms of malaria, provide some protection from subsequent infections and block its transmission to others (pages 24–33). This is an ambitious target, yet one that is critical to make eradication feasible.

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World Health Organization. “World Malaria Report 2013”: www.who.int/malaria/publications/world_ malaria_report_2013/en/

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1 | Message from the Chairman and CEO

Æ

“ We have also shown we can develop compounds faster.”

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To meet such high targets, together with our partners, we must work smarter, better and faster than ever before. We have come several steps closer to a single-dose cure for the two main malaria-causing parasites in man (Plasmodium falciparum and Plasmodium vivax). OZ439 has shown great potential as a single-dose cure against the blood stage of both parasites. The team is working hard to do the groundwork for the start of the Phase IIB trial with a partner drug in 2014 (page 26). What’s more, with encouraging in vitro data suggesting the compound may be efficacious against potential artemisinin-resistant strains of malaria, we are looking at strategies that could help accelerate its journey to patients. Tafenoquine, in development with GSK, is our lead contender for a radical cure of relapsing P. vivax malaria and it too shows potential as a singledose cure (pages 30–31).

Following successful completion of the Phase IIB trial in 2013, tafenoquine entered Phase III in April 2014. If successful, it could become the only new drug in 60 years approved to cure relapsing malaria. In recognition of the team’s dedication and the project’s potential, the tafenoquine team received the MMV Project of the Year award 2013. We have also shown we can develop compounds faster. With DSM265, for example, we succeeded in demonstrating its antimalarial potential using the recently validated human Challenge Model (page 27) in 6 months as opposed to the 2 years it would have taken through conventional trials. Innovative tools such as this and pharmacokinetic/pharmacodynamic modelling provide us with new insights and the answers we need, at a lower cost and in less time than before. They have helped us gather evidence supporting the single-dose capability of a number of compounds in clinical development in our portfolio.


Meanwhile, thanks to the work of our discovery team and partners, there are several other promising compounds targeting malaria elimination and eradication progressing through the pipeline to join those in clinical development. With such a constellation of compounds to choose from, we are in a position to raise the bar in terms of quality for those that we progress into humans. Through our research and development work, we will ensure that there are new, effective and affordable antimalarial medicines available to cure people suffering from malaria in the future. Through our access work, we ensure people will have access to effective medicines today. Since WHO-prequalification in 2010, 12 million vials of Artesun®, Guilin Pharmaceutical’s MMV-supported injectable artesunate for severe malaria, have been delivered – saving an estimated additional 80,000–90,000 lives compared to treatment with quinine. In 2013, UNITAID pledged funding to an MMV-led consortium, to continue to improve access to this lifesaving, high-quality antimalarial.

Although the walk towards a malaria-free world might be long, we are not alone. We have the support and partnership of our donors, a highly committed Board of Directors and expert advisory committees for both our science and access work, an extensive network of collaborators, and a dedicated team firmly in place.

“ We will ensure that there are

new, effective and affordable antimalarial medicines available to cure people suffering from malaria in the future.”

Nelson Mandela was an inspirational man who understood what it meant to dedicate his life to the seemingly impossible cause of freedom for his people, and rightly said that “it always seems impossible until it’s done.” At MMV, we are committed to discovering and developing the high-quality medicines needed to save as many lives as possible, rapidly and safely; medicines that will help to eventually eradicate malaria. We will not stop until our job is truly done. z

2013 was also a landmark year for funding. We entered into an intense period of grant applications with our two largest donors, the Bill & Melinda Gates Foundation and UK Department for International Development (DFID), and were successful in securing new multi-year commitments from both. In addition, we received commitments from four new donors: the governments of Australia and Norway, as well as UNITAID and Japan’s Global Health Innovation and Technology Fund (GHIT Fund).

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1 | Message from the Chairman and CEO

Key achievements Phase IIB study conducted at 7 trial sites demonstrates superiority of single-dose

tafenoquine

200 million treatments of ÂŽ

Coartem Dispersible (child-friendly artemether-lumefantrine, developed with Novartis) delivered to children in need in 55 countries since 2009 at a no-profit price.

plus chloroquine compared with chloroquine alone to cure relapsing malaria. On this basis, tafenoquine entered Phase III trials in April 2014 – taking it closer to becoming the only new drug for this indication in over 60 years.

160 Malaria Boxes dispatched to 27 countries since November 2011, to help catalyse malaria and neglected disease drug research.

9 new compounds targeting malaria eradication, progressed from discovery to preclinical or clinical development, are being researched in 16 locations.

In 2013,

six donors from six countries pledged new or continued support, demonstrating their belief in our vision of a world without malaria.

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First antimalarial compound researched on African soil,

MMV390048

,

set to enter Phase I in 2014 in Cape Town, South Africa.


Over 12 million vials of ®

Artesun

(Guilin Pharmaceutical’s MMV-supported injectable artesunate) for severe malaria delivered to 15 countries since 2010 – saving an estimated additional 80,000–90,000 lives compared to treatment with quinine.

Eurartesim® (dihydroartemisinin-piperaquine; developed with Sigma-Tau) approved for use in 4 malaria-endemic countries and throughout Europe.

Pyramax® (pyronaridine-artesunate developed with Shin Poong) receives first malaria-endemic country approval from Vietnam.

OZ439 together with piperaquine or ferroquine selected for Phase IIB single-dose, combination studies to be conducted in 6 countries.

Drug–drug interaction studies completed in Bangkok, Thailand with

primaquine and Eurartesim®, and primaquine and Pyramax® indicate both combinations could be used safely to create regimens to potentially cure, block transmission and prevent the relapse of malaria.

Data generated by the

Challenge Model, a new tool developed by the QIMR Berghofer Medical Research Institute, Brisbane, Australia and MMV to accelerate the clinical development of antimalarials, supports the antimalarial potential of

DSM265 as a one-dose cure.

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2 Keeping malaria centre stage Yvonne Chaka Chaka Roll Back Malaria Goodwill Ambassador

“ Over the years, I have come to realize that like malaria itself, the issues we face are far from meek and mild.”

I

want to take this opportunity to applaud you; to applaud you for being part of the fight against malaria. It’s a long and challenging fight and one that is far from over, but it’s a fight we are winning: since 2000, malaria deaths in young children have fallen by half. That’s hundreds of thousands of children, who thanks to the efforts of people like you, are now able to play with their friends, go to school and most important of all, have a future. We all have our reasons for joining the fight. Mine came after a performance in Gabon in 2004. We played to a packed crowd and had a brilliant time. But when we returned home to South Africa, my dear friend and backing singer, Phumzile Ntuli, became very ill. We didn’t know what was wrong and neither did the doctors. Three days later, she was rushed to hospital. She had severe malaria, fell into a coma and on June 23 she died. Phumzile was a fighter, she always had been. Ever since she was a young girl, she fought through the boundaries of poverty to pursue her passion for music and raise a family. How could she not fight through this? How could this fun-loving, strong and extremely gifted musician be robbed of her life? It seemed so unjust.

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I grew up in South Africa where HIV gets a lot of airtime, but I didn’t really know anything about malaria. After Phumzile passed away, I felt I had to learn more about this disease that could take a life so easily. I was shocked when I learnt that it takes hundreds of thousands of lives every year and mostly those of children, and threatens the lives of millions more. I knew then I had to lend my voice to the fight. About 6 months later, I was invited by UNICEF to be their Goodwill Ambassador against Malaria and later became Global Ambassador to Roll Back Malaria. As an Ambassador, I have travelled across Africa, from remote villages to sprawling cities, to meet the women and children affected by malaria and make their voices heard. I have also been honoured to meet the many dedicated scientists, activists and politicians engaged in the fight against this ancient foe. Over the years, I have come to realize that like malaria itself, the issues we face are far from meek and mild. The parasite changes fast, learns new tricks and, sooner or later, overcomes the best man-made defences. It has managed to develop resistance to one antimalarial after another. If we don’t develop new ammunition, like medicines and insecticides that work, malaria cases and deaths will increase again, reversing the great progress that has been made to date.


“ More than 600,000 people, mostly young children, continue to die from malaria every year.”

On top of the scientific challenges we face, there are many operational challenges to overcome; what good is a brand new drug, if it doesn’t reach the people that need it? Yet, I know ensuring that people in the farthest flung outposts of Africa, Asia and South America have access to the tools to protect and save them is no easy task. These are the people that suffer the most: my beloved neighbours, friends and fellow citizens. If we’re serious about improving global prosperity in today’s interconnected world, we cannot neglect this task and leave them behind. This is why investing in continuous scientific and operational research is so vital. The malaria parasite presents not one, but many challenges. Fortunately, thanks to funding from numerous governments, foundations and companies, malaria research today is no longer the poor cousin of research in other diseases. Product

Development Partnerships (PDPs) like Medicines for Malaria Venture (MMV) have worked wonders, filling the pipeline of innovative technologies with new drugs, diagnostics, insecticides and vaccines. PDPs work by harnessing the expertise of the public and private sectors, increasingly drawing on the capabilities from within malaria-plagued countries themselves to find effective solutions that the poorest and most vulnerable can afford. This year, 2014, is a celebratory year. It’s the year the first antimalarial compound to be researched on African soil will venture out of the laboratory, where it has shown great promise, and be put to the test in people. This is a truly exciting development and could not have happened without the support of organizations like MMV. That it is happening on my continent makes me proud and gives me hope that we will one day overcome this terrible disease. But research takes time and money.

Currently available funding is simply not sufficient to develop the tools we require and get them to the people in need. More than 600,000 people, mostly young children, continue to die from malaria every year. This is such a heart-breaking loss of young lives. So much has been achieved, yet the end of the fight is not yet in sight and the sad truth is that children continue to die. The work cannot stop now. The pipeline needs to remain funded until we have the medicines we need. I know that MMV has pledged to continue to develop new medicines for malaria until the disease is eradicated. With thoughts in my heart of Phumzile and the millions of others who have lost their lives to malaria, I too, will continue to sing and lend my voice to malaria’s defeat. We must keep malaria centre stage, redouble our efforts and finally close the curtain on this ancient foe. z

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3 Expediting access to approved medicines

Expanding the range and use of ACTs CoartemÂŽ Dispersible (artemether-lumefantrine)

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Swiss Agency for Therapeutic Products. TPP: Target Product Profile. Valecha N et al. “An open-label, randomised study of dihydroartemisininpiperaquine versus artesunate-mefloquine for falciparum malaria in Asia.� PLoS One. 5(7):e11880 (2010). Duparc S et al. “Safety and efficacy of pyronaridineartesunate in uncomplicated acute malaria: an integrated analysis of individual patient data from six randomized clinical trials.� Malar J. 12:70 (2013).

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Approved by Swissmedic1 (2008) and prequalified by WHO (2009) Indication: Acute, uncomplicated Plasmodium falciparum malaria in infants and children weighing between 5–35 kg and 12 years of age or less TPP:2 3-day artemisinin-based combination therapy Features: t5BJMPSFETQFDJýDBMMZUPDIJMESFOTOFFET sweet tasting, dispersible formulation t&BTZBENJOJTUSBUJPOBOEFOTVSFTBDDVSBUF dosing for children t8FMMFTUBCMJTIFETBGFUZQSPýMF CBTFEPO widespread use of parent drug, CoartemŽ Project Leader: Dr Heiner Grueninger, Novartis Pharma AG, Switzerland MMV Project Director: Adam Aspinall

EurartesimÂŽ

PyramaxÂŽ

(dihydroartemisinin-piperaquine)

(pyronaridine-artesunate)

Approved by the European Medicines Agency (EMA) (2011) Registered in Europe, Cambodia, Ghana, Tanzania and Burkina Faso Indication: Acute, uncomplicated P. falciparum malaria in adults and children aged 6 months or over and weighing 5 kg or more TPP:2 3-day artemisinin-based combination therapy Features: t-POHEVSBUJPOPGBDUJPOUPQSPUFDUBHBJOTU re-infection3 t4JNQMFPODFBEBZEPTJOHGPSEBZT Project Leader: Gianemilio Stern, Sigma-Tau Partner: Sigma-Tau Industrie Farmaceutiche Riunite, Italy MMV Project Director: Aleksandra Misiorowska

Approved by the South Korea Food and Drug Administration (2011); positive scientific opinion granted by EMA under Article 58 (2012); added to WHO’s list of prequalified medicines (2012) Registered in South Korea and Vietnam Indication: Acute uncomplicated P. falciparum and blood-stage Plasmodium vivax malaria in adults and children weighing 20 kg or more, in areas of low transmission with evidence of artemisinin resistance. Single treatment course in any given patient. TPP:2 3-day artemisinin-based combination therapy Features: t0OMZ"$5TQFDJýDBMMZBQQSPWFEUPUSFBU both uncomplicated P. falciparum and P. vivax malaria t4JNQMFPODFBEBZEPTJOHGPSEBZT t-POHEVSBUJPOPGBDUJPOUPQSPUFDUBHBJOTU re-infection4 Project Leader: Dr Isabelle BorghiniFuhrer, MMV Partner: Shin Poong Pharmaceutical Co. -UE 4PVUI,PSFB


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Rueangweerayut R et al. “Pyronaridineartesunate versus mefloquine plus artesunate for malaria.” N Engl J Med. 366(14):1298309 (2012). INESS: INDEPTH Effectiveness and Safety Studies of Antimalarial drugs in Africa. EDCTP: European and Developing Countries Clinical Trials Partnership. WANECAM: West African Network for Clinical Trials of Antimalarial Drugs.

ISSUE

SOLUTION

ACTION

There is a limited range of highquality fixed-dose medicines available to treat malaria. Use of low-quality medicines can lead to reduced efficacy and the development of resistance to artemisinin and partner drugs, the components of current first-line treatment for malaria.

Make a range of high-quality, lowcost treatments available to meet the needs of different patients and settings, and thereby push out lower quality options.

MMV and partners develop, register and gather evidence to support the introduction of high-quality ACTs, Coartem Dispersible, Eurartesim and Pyramax, into disease-endemic countries.

A

approved by stringent regulatory authorities. To help gather evidence to guide the optimal and widespread use of these new ACTs, MMV has been working with partners to study how they fare in the real world. First, MMV and Sigma-Tau provided Eurartesim for the INESS6 Phase IV platform to gather safety and effectiveness data. Second, with the support of EDCTP,7 MMV is working with WANECAM8 on a longitudinal Phase IIIB/IV trial in Mali, Burkina Faso and Guinea comparing the safety and efficacy of repeated use of Eurartesim and Pyramax with that of currently used ACTs in the

region [artemether-lumefantrine (AL) or artesunate-amodiaquine (ASAQ)].

Q

200 million treatments of Coartem® Dispersible delivered

rtemisinin-based combination therapies (ACTs) are the current WHO-recommended standard of care for uncomplicated malaria. They are highly efficacious (with cure rates between 94–99%), and work quickly.5 Thanks to donor investment in recent years, procurement of ACTs has steadily increased. Furthermore, the introduction of different ACT combinations since 2008 has provided countries with a greater choice of treatments to include in national malaria treatment guidelines. In 2011 and 2012, two new ACTs, Eurartesim and Pyramax, were

Dr Keziah Malm Ghana’s National Malaria Control Progamme provides an insight into the real-world advantages of multiple first-line ACTs, which were first instituted in Ghana in 2007. In your experience, what are the advantages of having multiple first-line antimalarials? It gives patients a choice, which means that those who experience adverse reactions with one drug can select another. In the case of treatment failure with one drug, it’s also advantageous to have an alternative, rather than switching straight away to intravenous quinine or artesunate, which is much more complicated to administer. It also reduces the pressure on one manufacturer and, in case of stock-outs at the point-ofcare, one product can be substituted for another.

Q

How did you ensure a smooth transition from single to multiple first-line therapies in Ghana? One of the most important ingredients was appropriate behaviour change communications and the involvement of key stakeholders in the entire process. Also, because the market and supply chain becomes more complex with multiple therapies, monitoring becomes more important. The National Health Service in Ghana has been collaborating with the Society for Private Medical Practitioners and pharmaceutical organizations to improve monitoring. Even so, there is still more work to be done to scale-up the current levels of distribution/use and adherence to guidelines.

This research is particularly important for Pyramax as elevations in liver enzymes were noted in a small number of patients following treatment with the medicine. As a result, the EMA approved Pyramax with a label for one-time use only. Interim data from the WANECAM trial has now been submitted to the EMA to apply for a change in the Pyramax label to allow for retreatment.

By the end of 2013, over 200 million treatments of Coartem® Dispersible, the first high-quality paediatric artemisinin-based combination therapy (ACT), had been delivered to 50 malaria-endemic countries. Novartis and MMV jointly developed the medicine specifically to meet the needs of children. The tablet disperses easily in approximately 10 ml of liquid and its sweet cherry flavour makes it easy to administer.

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3 | Expediting access to approved medicines

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Expanding the range and use of ACTs (continued)

Prof. Abdoulaye Djimde University of Science, Techniques and Technologies of Bamako, Mali, talks about the WANECAM1 trial and what it has revealed so far How is the WANECAM trial progressing and what has it revealed so far about currently available antimalarials? The trial began in 2009 and completed patient recruitment just ahead of schedule in mid December 2013, with 4722 patients from seven centres in Mali, Burkina Faso and Guinea. We were able to achieve this huge milestone thanks to the hard work of the team. All patients will now be followed for 2 years. On average, each patient is expected to have three episodes of malaria, so by the end of the trial we will have data on more than 1200 cases of malaria. It’s a huge trial, one of the largest ever of antimalarials.

Q

It has been fantastic to have the backing of the MMV team.”

So far, we have obtained enough data points to be able to assess whether Pyramax is as well tolerated for repeat treatments as it is for the first. The final analysis is pending, but the preliminary data is encouraging. The trial also looks at the real-life safety of Eurartesim. Interim analyses are planned once 50% of the patients have reached the 2-year follow-up mark.

Q

In addition to the scientific findings, what else have you learnt through working with WANECAM and conducting the trials? It has been a tremendous learning experience on a number of levels. It’s the first time our university has taken on the responsibility of trial sponsor. We already knew the rules of the game as principal investigators (PIs) but being a sponsor is something else entirely. You are ultimately responsible for the trial, dealing with severe adverse events and reporting them to various regulatory authorities and deciding whether the trial should continue. In addition to the main funding from EDCTP,2 it has been fantastic to have the backing of the MMV team, not just in terms of finance. The funding is good, but the technical expertise and experience of running trials has really helped us to get to where we are. I don’t know if we would have been able to pull it off on our own.

Q

What’s next after this study has been completed? Today, WANECAM1 is a really solid network. Each of the various teams operates as if we were one large team. We all know each other very well, the PIs, clinical coordinators, scientists, pharmacists, even the drivers. We are now ready to put ourselves on the market for similar trials, which I think are going to become increasingly necessary as we move towards malaria elimination and eradication. z 1 2

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WANECAM: West African Network for Clinical Trials of Antimalarial Drugs. EDCTP: European and Developing Countries Clinical Trials Partnership.


Improving malaria case management ISSUE

SOLUTION

ACTION

Presumptive management of malaria, without diagnosis, results in the irrational use of antimalarials and incorrect treatment. Moreover, it prevents the identification of areas with a large reservoir of infection.

In 2012, WHO launched the “T3: Test. Treat. Track.” initiative, recommending that every suspected malaria case be tested, every confirmed case be treated with a quality antimalarial, and all cases be tracked timely and accurately.

MMV and partners implement a T3 initiative, the Comprehensive Case Management Programme (CCMP) in Odisha, India, to reduce malaria transmission.

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Accredited Social Health Activists (ASHAs) work at the community level to diagnose malaria, including Plasmodium vivax, with the recent introduction of bivalent rapid diagnostic tests (RDTs), and treat patients in line with national guidelines. In the intervention blocks, the uninterrupted supply of RDTs and antimalarials is assured along with supportive supervision of ASHAs. CCMP has also introduced patient cards to identify repeat cases and possible P. vivax relapses, as well as an electronic data-management system to enable the proactive use of epidemiological data for timely action.

he National Institute of Malaria Research and the National Vector Borne Disease Control Programme (NVBDCP), Odisha, with technical and financial support from MMV, are implementing the CCMP in four districts of Odisha, across four different transmission settings. The goal is to ensure universal access to timely diagnosis, treatment and radical cure1 at the community level, and assess its impact on malaria transmission. In each district, there is an intervention and control “block”, each comprising 100,000–150,000 people. In all the blocks,

Dr Madan Mohan Pradhan Deputy Director Health Services, NVBDCP, Ministry of Health & Family Welfare, Odisha.

Q

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Radical cure of P. vivax malaria involves eliminating hypnozoites (dormant liver-stage parasites) to prevent relapses. Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an inherited abnormality that causes the loss of a red blood cell enzyme. People who are G6PD deficient can suffer from serious adverse effects from the antimalarial drug primaquine.

What excites you about CCMP?

CCMP allows us to reattribute patient data from outpatient clinics in towns to the village where a patient lives. This means that we can identify highburden areas and really focus our resources accordingly. For example, the microscopist in Hindol block realized that more cases were coming from a certain area, which led us to conduct a mass survey, and detect and treat a large reservoir of asymptomatic carriers. We believe this averted a malaria outbreak. It’s also exciting to see that everyone involved in the CCMP programme is

really dedicated and committed to its success. The ASHAs are improving their ability to diagnose and treat malaria correctly, which means more patients are getting the right medicine.

Q

What challenges have you faced during the roll-out of the programme and how have you overcome them? Poor access, stock-outs and inconsistent quality of service were the main challenges. To overcome them, we revised the quantification system, created buffer-stocks, retrained the ASHAs, provided supportive supervision and are now also identifying alternative providers in remote areas. It’s been a substantial undertaking. Another challenge is to identify patients with G6PD deficiency.2 The national guidelines stipulate that all G6PD “normal” patients with P. vivax malaria

should be treated with primaquine. But we don’t have a way to diagnose G6PD deficiency. ASHAs have been trained to inform patients of the signs of haemolysis and, that should they experience them, they must discontinue treatment and return to the health facility. How will the data collected be used to further reduce malaria transmission? By 2015, we will have a clearer picture of transmission; we will have identified areas with pockets of high transmission and will also have a clearer view of asymptomatic and imported cases. As we say in these parts, “malaria is local and focal”, but often in a big programme we end up taking an umbrella approach. With the CCMP data, we will be able to adapt our control measures accordingly and optimally. z

Q

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3 | Expediting access to approved medicines

Saving more lives with injectable artesunate

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2

3 4

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World Health Organization. “World Malaria Report 2013”: www.who.int/malaria/ publications/world_ malaria_report_2013/ en/ Médecins Sans Frontières. “Making the Switch: Ensuring access to improved treatment for severe malaria in Africa.” April 2011: www.msf. org/article/malariamaking-switch TPP: Target Product Profile. Dondorp AM et al. “Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an openlabel, randomised trial.” Lancet. 376(9753):1647-57 (2010). Dondorp A et al. “Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial.” Lancet. 366 (9487):717-25 (2005).

ISSUE

SOLUTION

ACTION

Slow uptake of injectable artesunate – WHO-preferred treatment for severe malaria – costs lives.

Expedite the uptake of injectable artesunate in malariaendemic countries through a range of coordinated, country-driven activities.

MMV and partners support increased use of injectable artesunate in seven high-burden countries (Nigeria, the Democratic Republic of the Congo [DRC], Malawi, Uganda, Kenya, Ethiopia and Cameroon).

T

In July 2012, working with the National Malaria Control Programme (NMCP) and CHAI, MMV set out to help six Nigerian states make the switch. This involved raising awareness about the benefits of injectable artesunate, securing funding for the medicine, training health-care workers, quantifying the need and monitoring the impact of the switch. Today, the drug is being procured with state funds in four of the six states.

here are around 5.6 million cases of severe malaria every year, leading to an estimated 627,000 deaths, mostly of children under 5 years of age.1 Based on research demonstrating the superiority of injectable artesunate for the treatment of severe malaria over quinine, the previous standard of care, WHO updated its standard treatment guidelines in 2011, recommending injectable artesunate as the preferred treatment. Médecins Sans Frontières estimates that approximately 200,000 additional lives could be saved each year if countries made the switch.2 In response, MMV joined forces with relevant partners to increase the uptake and use of injectable artesunate across the malaria-endemic world. The work began with two countries, Nigeria and the DRC, that together represent 30% of the global population at risk.1

Dr Philippe Lukanu Ngwala General Reference Hospital, Kimpese district, DRC, one of the principal investigators of the MATIAS study explains the advantages of using artesunate.

Q

What were the main clinical differences you observed between the two treatments in the study? Overall, we observed fewer deaths with artesunate than with quinine (1.7% versus 3.7%). We also observed fewer side effects with artesunate than with quinine. Side effects with quinine

16

In the DRC, currently, 30% of severe malaria cases are treated with injectable artesunate. The goal is to reach 100% coverage by 2016. To gather the evidence to support this switch and better understand the operational challenges, MMV, Swiss TPH and Kinshasa School of Public Health, undertook a study, known as MATIAS (Malaria Treatment with Injectable Artesunate), to compare injectable artesunate treatment with quinine in four districts in the DRC.

included ringing in the ears (tinnitus) and low-blood sugar (hypoglycaemia). These issues can really limit quinine’s usage in primary health care. Some patients even refuse to take it following resolution of acute symptoms. Third, we observed a quicker reduction in symptoms with artesunate compared to quinine.

Q

How did the health-care workers’ perceptions of the two treatments differ? In general, they found artesunate to be easier and quicker to administer than quinine. This means they win time that can be spent providing care for other patients.

Injectable artesunate WHO-prequalified product Indication: Severe malaria TPP:3 Severe malaria Potential impact: 22.5% reduction in mortality compared to previous standard of care in Africa4 and a 34.7% reduction in Asia5 Implementing partners: Clinton Health Access Initiative (CHAI), Malaria Consortium and Swiss Tropical and Public Health Institute (Swiss TPH) MMV Project Director: Pierre Hugo

Q

Based on your experience, what are the challenges to making a nationwide switch from quinine to artesunate? The biggest challenge is the cost of medicines, particularly in a low resource context. Although the overall cost of the two medicines is similar when you take into consideration all the factors, such as a shorter hospital stay, the face value of artesunate is higher than quinine, which may be a deterrent. I think without a subsidy, it will be difficult to make a complete switch to injectable artesunate.


12 million vials of Guilin’s injectable artesunate have been delivered.”

B

ased on the knowledge acquired in the DRC and Nigeria, MMV has established a severe malaria consortium with CHAI and the Malaria Consortium. In 2013, this MMV-led team was awarded a UNITAID grant of USD 34 million to fund procurement and scale-up of injectable artesunate across 13 of the 36 states in Nigeria and in five other high-burden African countries (Cameroon, Ethiopia, Kenya, Malawi and Uganda). Based on case estimates, up to 50 million vials of injectable artesunate

may be needed each year. Yet, currently, only 10 million vials are being manufactured annually, leaving 80% of severe malaria patients without access to the drug. The UNITAID project seeks to reduce this gap by stimulating greater market competition and eventually lowering prices for this important drug. Since WHO prequalification in 2010, close to 12 million vials of Guilin’s injectable artesunate have been delivered and are estimated to have saved between 80,000–90,000 additional lives compared to treatment with quinine. z

17


4 | New medicines for vulnerable populations

4

New medicines for vulnerable populations

Developing medicines for children 1

TPP: Target Product Profile. 2 World Health Organization, “World Malaria Report 2013�: www.who.int/malaria/ publications/world_ malaria_report_2013/ en/ 3 Price RN et al. “Vivax malaria: Neglected and not benign.� Am J Trop Med Hyg. 77:79–87 (2007). 4 Talisuna A et al. “Repeated treatment with fixed-dose artesunateamodiaquine vs. artemetherlumefantrine in Ugandan children under 5 years of age with uncomplicated malaria.� Poster presentation at American Society of Tropical Medicine and Hygiene Annual Meeting, Nov 2013. 5 Vitor-Silva S et al. “Malaria is associated with poor school performance in an endemic area of the Brazilian Amazon.� Malar J. 8:230 (2009).

EurartesimÂŽ Paediatric

PyramaxÂŽ Paediatric

Children are the hardest hit

(dihydroartemisinin-piperaquine)

(pyronaridine-artesunate)

Æ77% of those who die from malaria

Patient confirmatory Target Indication: Acute, uncomplicated Plasmodium falciparum malaria in infants and children weighing 5–24 kg TPP:1 3-day artemisinin-based combination therapy Project Leader: Gianemilio Stern, Sigma-Tau Industrie Farmaceutiche Riunite, Italy MMV Project Director: Aleksandra Misiorowska

Patient confirmatory Target Indication: Acute, uncomplicated P. falciparum and blood-stage Plasmodium vivax malaria in adults and children weighing 5–20 kg TPP:1 3-day artemisinin-based combination therapy Project Leader: Dr Isabelle BorghiniFuhrer, MMV Partners: Shin Poong Pharmaceutical Co. -UE 4PVUI,PSFBBOE 6OJWFSTJUZPG*PXB  64"

ISSUE

SOLUTION

ACTION

Children are the hardest hit by malaria, but to date there has only been one high-quality paediatric artemisinin-based combination therapy (ACT) developed.

Develop paediatric formulations of new high-quality antimalarials.

MMV and partners develop and register paediatric formulations of the recently approved ACTs, EurartesimÂŽ and PyramaxÂŽ.

C

adults; they absorb and metabolize medicines differently. Additionally, antimalarial medicines are bitter; a child already nauseous from malaria may vomit the medicine and not receive a complete curative dose. Children need palatable medicines adapted to their weight and age.

hildren under the age of 5 years are the main victims of malaria. Yet few antimalarial medicines have been developed with children’s needs in mind, with the exception of CoartemŽ Dispersible, developed by the MMV/ Novartis partnership. This is an issue, because children are not simply little

18

are children under 5 years of age2 ÆThat’s ~483,000 young lives lost every year2 ÆOr one child every minute2 ÆOne episode of malaria keeps a child from school or an adult from work for at least 3 days3 ÆIn high-transmission areas children may suffer up to 26 episodes of malaria over 2 years4 ÆMalaria has adverse effects on cognitive development: even one episode of malaria can compromise a child’s school performance5

MMV aims to address this imbalance. Child-friendly formulations of the recently approved Pyramax and Eurartesim are under development and are expected to be submitted for regulatory approval in 2014 and 2015, respectively.


Dr Isabelle Borghini-Fuhrer Director, Product Development, MMV, talks about the progress made and challenges of developing paediatric medicines.

Q

What progress has been made to develop a paediatric formulation of Pyramax? The current Pyramax tablets are approved to treat patients that are at least 20 kg. To address the needs of smaller patients the MMV/Shin Poong partnership have also developed a special granule formulation, which can be dispersed in a small amount of liquid. This will be much more suitable for children. The clinical studies have been completed, and the dossier will be submitted to the European Medicines Agency towards the end of 2014.

Q

What are the challenges in the development of child-friendly medicines? Recruiting children into clinical trials has very special ethical considerations and

rightly so, as they are fragile, particularly as they are still developing. As a result, obtaining informed consent for a child to be involved in a study is more delicate than for an adult. It is therefore, safer to first start a trial with adults and be reassured about the risk–benefit profile of the drug before moving into children. These factors mean the development process for paediatric medicines is more complex and lengthy. Palatability is also a big issue in developing antimalarials for children, since these medicines can be very bitter making it difficult to administer a full dose to the child. Dosage is key for antimalarials; we must ensure a child gets enough medicine to cure them and to prevent the development of drug resistance. This can make formulation development more complex.

Q

What lessons can be applied to the development of nextgeneration paediatric medicines? One of the key things we have learnt is to think about the paediatric formulation

right from the outset and even consider developing an adapted paediatric formulation that could be used in adults. We have also learnt how to ensure the stability of medicines in very warm and humid conditions. We now know which formulations and packaging can resist the heat. In addition, our access team has conducted market research, determining the importance of palatability and minimizing the volume of added liquid needed to administer the medicine. It’s also really important to find trial sites with experienced paediatricians who are malaria experts. The children enrolled in the trial must be monitored every 6 to 8 hours, and remain hospitalized, so it’s key to have somewhere nearby for the mother or family members to stay. Thankfully, we now have a really good network. One of our investigators in Gabon for the Pyramax paediatric trial, said that the medicine worked so quickly it made follow-up difficult as the children were already outside playing football and not in their beds!

The Mundia family – regularly afflicted by malaria “Malaria is a nightmare for us,” was the immediate reaction from Christopher Mundia when asked about the malaria situation in his home area of Chipulukusu Township, Ndola, Zambia. Swampy vegetation surrounds the township, contributing to high malaria transmission all year round. Christopher’s daughter, Phyllis, is just recovering from the disease. “Phyllis was treated last week. Look at her; she still looks pale,” Christopher commented. Unfortunately, a child suffering from malaria is not a rare occurrence in the Mundia household. “We have two children under 5 years who get malaria six to seven times a year,” said Christopher. “We also have a 7-year-old and a 9-year-old who both needed to be hospitalized with severe malaria. Our home is devastated by malaria.”

“Malaria seriously affects our economic situation,” said Agness Mundia, Phyllis’s mother. “I cannot engage in any form of productive activity to supplement my husband’s salary, as I am often at home nursing one child after another. Sometimes I have to be in hospital with the children, nursing them because they are severely ill and require quinine in a drip for treatment.” Christopher added “My workplace has cautioned me several times because of the repeated need to assist my wife with our sick children.” Fortunately, the family live just 3 km away from the nearest clinic, where they can access high-quality artemisininbased combination therapies at no cost. “If there were no drugs in the health facilities, we would never be able to afford to keep buying them to give to the children. These drugs are very important to us; they form part of our daily lives because of the situation we live in.” z

19


4 | New medicines for vulnerable populations

Protecting the most vulnerable ISSUE

SOLUTION

ACTION

In some parts of Africa, more than 60% of malaria cases occur in just 4 months of the year, during the rainy season.1 Around 39 million African children under 5 years of age live in these regions and an estimated 152,000 die from malaria each year.2

In March 2012, WHO-recommended seasonal malaria chemoprevention (SMC)3 with sulfadoxinepyrimethamine and amodiaquine (SP+AQ) for children aged between 3 and 59 months in areas of high seasonal malaria transmission across the Sahel sub-region, where SP and AQ remain effective.1 In east and southern Africa, there are high levels of resistance to SP.

As part of the West Africa Roll Back Malaria (RBM) SMC working group, MMV is working to support the implementation of SMC in the Sahel sub-region; and with Guilin to develop child-friendly formulations.

T

In addition, MMV is assisting Guilin to obtain WHO prequalification for a coblistered formulation of SP+AQ and develop a child-friendly dispersible formulation of two doses reflecting WHO recommendations. This will make the medicine easier to take and thus encourage patient adherence.

he West Africa RBM SMC working group, comprising malariaendemic country institutions, malaria control programme managers and international partners, was established to support countries in their planning, implementation and monitoring of SMC. As part of the group, MMV provides technical support to determine drug demand and ensure relevant supply, as well as operational support in the form of an SMC tool kit, based on WHO’s SMC Field Guide, to facilitate planning, training and monitoring.

Sulfadoxinepyrimethamine + amodiaquine (SP+AQ) Under review for WHO prequalification Indication: SMC for children in areas of highly seasonal transmission across the Sahel sub-region1 TPP:4 Intermittent chemoprevention Potential impact: t3FEVDFTNBMBSJBJODJEFODFQSPWFEUP prevent around 75% of malaria episodes1 t$PTUFGGFDUJWFIJHIRVBMJUZ4.$ESVH DPTUT_64%QFSTFBTPOUPQSPUFDUB child from malaria Partners: (VJMJO1IBSNBDFVUJDBM$P-UE $IJOB BOE-POEPO4DIPPMPG)ZHJFOF 5SPQJDBM.FEJDJOF 6OJUFE,JOHEPN MMV Project Director: Aleksandra Misiorowska 1

2

3

4

20

WHO Policy Recommendation: “Seasonal Malaria Chemoprevention (SMC) for Plasmodium falciparum malaria control in highly seasonal transmission areas of the Sahel sub-region in Africa�. March 2012: www.who.int/malaria/publications/atoz/smc_policy_ recommendation_en_032012.pdf Cairns M et al. “Estimating the potential public health impact of seasonal malaria chemoprevention in African children.� Nat Commun. 3:881 (2012). Seasonal Malaria Chemoprevention: previously termed intermittent preventive treatment in children, is the intermittent administration of full treatment courses of an effective antimalarial medicine during the malaria season to prevent malarial illness. TPP: Target Product Profile.


Prof. Jean Louis Ndiaye Cheikh Anta Diop University of Dakar, Senegal, conducted a pilot study from 2011 to 2012 combining SMC with home management of malaria. He explains the challenges and the potential impact of SMC.

Q

What impact do you believe SMC can have for the children of Senegal and the wider Sahel region? Based on our pilot study we know that SMC can protect around 83% of children from malaria. This means that, free from malaria, children are able to attend school and parents are able to go to work. It also means the workload of health workers is reduced during the transmission season. We are starting to see empty hospital beds in districts where SMC is implemented. In addition, during SMC rounds, when a volunteer comes across a sick child, he/she will then be referred to a health centre; so SMC is acting as a screening programme and improving overall health care in rural villages. At the national level, I believe it can help us reach the pre-elimination stage of malaria control.

Based on your experience in Senegal, what key hurdles must be overcome to ensure widespread implementation of SMC across the Sahel? The key is to ensure countries secure sufficient quantities of the medicines in a timely fashion. This is particularly important for SMC – if you miss the season, you have missed the opportunity to use and benefit from this preventive strategy. To avoid this, it’s important to communicate the importance of SMC and to mobilize adequate funding.

Q

Today, there is only one manufacturer producing SP+AQ that is approved for purchase by the Global Fund. We need to ensure that this company has the capacity to manufacture sufficient quantities. We also need to work on ensuring people (mostly mothers, caregivers and community health workers) are sensitized to the use and importance of SMC, to ensure drug compliance. At the moment, we have two drugs that are coblistered, which means we cannot be sure that children are always receiving both the medicines at the same time.

Also, there is no infant formulation. When you are treating young children and giving them tablets it is not really easy, especially as AQ is very bitter. You sometimes see children running out of the house when the time comes to take their medicine. If they don’t take the complete course there can be problems with under dosing, which can then lead to drug resistance. What do you think is the likelihood that drug resistance to the current SMC drug regimen will emerge? How will this be managed? We might see resistance emerging. During the implementation pilot, we saw that there was an increase in molecular markers for drug resistance in the SMC districts. It wasn’t at a level where we need to be concerned at the moment, but it is something we must monitor at least every 2 years. There are some places in east and southern Africa where you probably would not be able to use SP+AQ because of the levels of resistance. In Senegal, we should have 3–5 years of effective SMC, combined with artemisinin-based combination therapy for treatment; with this, I think we can move to pre-elimination. z

Q

21


4 | New medicines for vulnerable populations

Optimizing pre-referral treatment for severe malaria

1

2 3

World Health Organization. “Malaria in children under five”: www.who.int/malaria/ areas/high_risk_ groups/children/en/ TPP: Target Product Profile World Health Organization. “Rectal artesunate testing and delivery”: www.who.int/ tdr/research/malaria/ rectal_artesunate/en/

22

ISSUE

SOLUTION

ACTION

Rectal artesunate can substantially reduce the risk of death or disability for patients with severe malaria who are unable to receive oral treatment or access injections.1 Today, however, no WHO-prequalified product is available.

Obtain WHO prequalification for rectal artesunate.

1. Identify interested and competent pharmaceutical partners, support activities to demonstrate quality and bioequivalence of products to support WHO prequalification. 2. Optimize the use of rectal artesunate in low-resource settings.

W

bioequivalent to that used in WHO-TDR’s studies will be in a position to seek WHO prequalification. MMV is working with partners to conduct bioequivalence studies and prepare for launch in malaria-endemic countries. The goal is to bring a WHO-prequalified version of rectal artesunate to patients in 2016.

ith the support of UNITAID, MMV is working to obtain WHO prequalification of a rectal artesunate product for pre-referral management of patients with severe malaria. MMV has identified interested and proficient pharmaceutical partners to manufacture rectal artesunate and is working with them to obtain WHO prequalification for their products. This process will build on clinical studies led by the World Health Organization Special Programme for Research and Training in Tropical Diseases (WHO-TDR), which demonstrated the benefits of rectal artesunate. Moving forward, manufacturers that are able to demonstrate their product is

To this end, MMV is conducting market research to optimize the use of the drug. The first step is to understand current guidance and practice regarding prereferral treatment for severe malaria in priority countries. The next step will be to quantify the demand for rectal artesunate, ultimately, to ensure manufacturers can meet that demand. z

Rectal artesunate Preparing for WHO prequalification Indication: Pre-referral treatment for severe malaria TPP:2 Severe malaria Potential impact: A single dose reduces the risk of death by half in children when the time for referral exceeds 6 hours3 MMV Project Director: Pierre Hugo


MMV portfolio – 4th quarter 2013 Research Lead optimization

Translational Preclinical

Development

Human volunteers

Patient exploratory

Patient confirmatory

Rectal artesunate

Novartis

Novartis

P218 DHFR

DSM265

OZ439/PQP

Miniportfolio

1 project

(Biotec/Monash Univ./London School of Hygiene & Trop Med)

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

(Monash Univ./ Univ. Nebraska/ Swiss TPH)

ELQ-300

OZ439/FQ

KAE609

Tafenoquine

SP+AQ

(Univ. South Florida/Oregon Health & Science Univ.)

Sanofi

Novartis

GSK

(sulfadoxinepyrimethamine + amodiaquine) Guilin

GSK

GSK

Miniportfolio

3 projects

Sanofi

Sanofi

Miniportfolio

Orthologue Leads

AstraZeneca

AstraZeneca

Miniportfolio

Whole Cell Leads

21A092

KAF156

(Drexel Univ./ Univ. Washington)

Novartis

MMV390048 (Univ. Cape Town)

Azithromycinchloroquine (AZ-CQ)

APM Under review

MMV/WHO-TDR

Approved

Artemetherlumefantrine dispersible 1 Novartis

Pfizer

Artesunate for injection 2 Guilin

Pyronaridineartesunate paediatric

Dihydroartemisininpiperaquine 3

Shin Poong/ Univ. Iowa

Sigma-Tau

Dihydroartemisininpiperaquine paediatric

Pyronaridineartesunate 4 Shin Poong/ Univ. Iowa

Sigma-Tau

Celgene

Anacor

Heterocycles

Oxaboroles

Artesunateamodiaquine 5

(+)-SJ557733 St Jude/Rutgers

Univ. Campinas Heterocycles

DNDi/Sanofi

Liverpool School of Trop Med/ Univ. Liverpool

Artesunatemefloquine 6

Tetraoxanes

Cipla/DNDi

Daiichi-Sankyo Screening

*

Univ. Texas Southwestern/ Monash Univ./ Univ. Washington DHODH

Takeda Screening

Univ. Cape Town Aminoyridines

Eisai

Univ. Dundee

Screening

Heterocycles

MMV

Univ. Sydney

Pathogen Box

Open Source Drug Discovery

TPP: Target Product Profile 3-day cure/artemisinin-based combination therapies Single-dose cure Severe malaria Intermittent chemoprevention Relapse prevention TCP: Target Candidate Profile Fast clearance (TCP1) Long duration (TCP2) Relapse prevention (TCP3a) Transmission blocking (TCP3b) Chemoprevention (TCP4) Non-artemisinin-based therapy Artemisinin-based therapy Included in MMV portfolio post registration First approval by WHO prequalification, or by regulatory bodies who are ICH members or observers

Merck Serono

16 projects

Amino-alcohols

GOVERNANCE

Other projects

1 Brand name: Coartem® Dispersible, generic by Ajanta 2 Brand name: Artesun® 3 Brand name: Eurartesim® 4 Brand name: Pyramax® 5 Brand names: CoarsucamTM, ASAQ/Winthrop®, FDC generics by Ajanta, Ipca, Guilin, co-blistered generics by Strides, Cipla 6 Also Acino/Mepha product (co-blistered)

Access and Product Management

APMAC

ESAC Expert Scientific Advisory Committee GSB Global Safety Board

Access and Product Management Advisory Committee

APAC Authorization for Phase III/Advancement Committee

MMV Board of Directors/Executive Committee/Financial Audit Committee

23

*


5 New medicines to drive elimination and eradication

T

he goal to eradicate malaria cannot be achieved with current medicines.1 To determine and exactly define the medicines that are needed for eradication, the Malaria Eradication Research Agenda (malERA) initiative drew on the knowledge of malaria

experts from around the world and defined two key Target Product Profiles (TPPs): Single Exposure Radical Cure and Prophylaxis (SERCaP), the silver bullet malaria cure, and Single Exposure Chemoprotection (SEC). All of these clinical attributes will, however, not be

OZ439

KAE609

KAF156

Patient exploratory

Patient exploratory

Patient exploratory

Target indication: Acute uncomplicated malaria TPP:2 Single-dose cure TCPs:3 1 (fast clearance) & 3b (transmission blocking) Features: t'BTUSFEVDUJPOPGQBSBTJUFT TJNJMBSUP artemisinin t1PUFOUJBMGPSBPOFEPTFDVSFBOE therefore improved patient adherence4 t1PUFOUJBMUPCMPDLUSBOTNJTTJPO5 t1PUFOUJBMUPUSFBUBSUFNJTJOJOSFTJTUBOU strains of malaria Project Leader: Dr Marc Adamy, MMV OZ439/4-aminoquinoline development partner:4BOPĂ˝ Discovery partners: 6OJWFSTJUZPG/FCSBTLB .FEJDBM$FOUFS 64".POBTI6OJWFSTJUZ  "VTUSBMJB4XJTT5SPQJDBMBOE1VCMJD)FBMUI Institute, Switzerland

Target indication: Acute uncomplicated malaria TPP:2 Single-dose cure TCPs:3  GBTUDMFBSBODF  MPOHEVSBUJPO  & 3b (transmission blocking) Features: t1PUFOUJBMGPSBPOFEPTFDVSF BOE therefore improved patient adherence6 t)JHIMZQPUFOUBOESBQJEBOUJNBMBSJBMBDUJPO7 t1PUFOUJBMUPUSFBUBSUFNJTJOJOSFTJTUBOU strains of malaria t1PUFOUJBMUPCMPDLUSBOTNJTTJPO7 Project Leader: Dr Roger Waltzman, Novartis Pharma AG MMV Project Director: Dr JĂśrg MĂśhrle, MMV Development partners: Novartis Pharma AG Discovery partners: Novartis Institute for 5SPQJDBM%JTFBTFT 4JOHBQPSF5IF8FMMDPNF 5SVTU 6,4XJTT5SPQJDBMBOE1VCMJD)FBMUI *OTUJUVUF 4XJU[FSMBOE#JPNFEJDBM1SJNBUF Research Institute, the Netherlands and Genomics Institute of the Novartis Research 'PVOEBUJPO 64"

Target indication: Acute uncomplicated malaria, treatment and prevention TPP:2 Intermittent chemoprevention TCPs:3  GBTUDMFBSBODF  MPOHEVSBUJPO  & 4 (chemoprevention) Features: tIn vitro activity against liver schizonts and potential for chemoprophylaxis8 t1PUFOUJBMGPSBPOFEPTFDVSFBOE therefore improved patient adherence Project Leader: Dr Thierry Diagana, Novartis Institute for Tropical Diseases, Singapore MMV Project Director: Dr JĂśrg MĂśhrle, MMV Development partners: Novartis Institute for Tropical Diseases, Singapore Discovery partners: Genomics Institute PGUIF/PWBSUJT3FTFBSDI'PVOEBUJPO 64" Novartis Institute for Tropical Diseases, 4JOHBQPSFUIF8FMMDPNF5SVTU 6,4XJTT Tropical and Public Health Institute, SwitzerMBOE#JPNFEJDBM1SJNBUF3FTFBSDI*OTUJUVUF  the Netherlands

1

2 3 4

5

24

found in one molecule and so MMV has defined five Target Candidate Profiles (TCPs) (see last two columns of Table 1), corresponding to the necessary attributes of the TPPs. With partners, MMV has identified and is developing numerous molecules to meet these.

malERA Consultative Group on Drugs. “A research agenda for malaria eradication: drugs�. PLoS Med. 8(1):e1000402 (2011).. TPP: Target Product Profile. TCP: Target Candidate Profile. Moehrle JJ et al. “First-in-man safety and pharmacokinetics of synthetic ozonide OZ439 demonstrates an improved exposure profile relative to other peroxide antimalarials.� Br J Clin Pharmacol. 75(2):524-37 (2013). Delves M at al. “The activities of current antimalarial drugs on the life cycle stages of Plasmodium: a comparative study with human and rodent parasites.� PLoS Med. 9(2):e1001169 (2012).

6

7

8

Rottmann M et al. “Spiroindolones, a potent compound class for the treatment of malaria.� Science. 329(5996):1175-80 (2010). van Pelt-Koops JC et al. “The spiroindolone drug candidate NITD609 potently inhibits gametocytogenesis and blocks Plasmodium falciparum transmission to anopheles mosquito vector.� Antimicrob Agents Chemother. 56(7):3544-8 (2012). Meister S et al. “Imaging of Plasmodium liver stages to drive next-generation antimalarial drug discovery.� Science. 334(6061):1372-7 (2011).


Table 1

Prevention

Treatment

TPP and d attributes tt ib t

K Key actions ti

TCP and d lifecycle lif l stage t

SERCaP (Single Exposure Radical Cure and Prophylaxis) D Single dose D Radical cure – kills parasite at all lifecycle stages D Treatment for all five species to infect humans D High barrier to resistance D Post-treatment prophylaxis

Control of resistant blood-stage parasites Fast clearance Æ Long duration of action/ Æ Post-treatment prophylaxis

SEC (Single Exposure Chemoprotection) D Single dose D Suitable for mass administration D Chemoprevention for all fives species to infect humans D Different mechanism of action to treatment

Chemoprevention

Relapse prevention Æ Transmission blocking Æ

Æ

TCP1 TCP2

ĂŒ Blood stage ĂŒ Blood stage

TCP3a TCP3b

ĂŒ Hypnozoites ĂŒ Gametocytes

TCP4

ĂŒ Liver schizonts ĂŒ Blood stage (slow-onset activity)

DSM265

MMV390048

(+)-SJ557733

DDD107498

Human volunteers

Human volunteers

Preclinical

Preclinical

Target indication: Acute uncomplicated malaria TCPs:3 2 (long duration) & 4 (chemoprevention) Features: t/PWFMNFDIBOJTNPGBDUJPOBOE highly selective for the parasite with the potential to treat artemisininresistant strains of malaria t1PUFOUJBMGPSBPOFEPTFDVSFBOE therefore improved patient adherence t-POHEVSBUJPOPGBDUJPOBOEQPUFOUJBM for causal and post-treatment prophylaxis Project Leader: Dr Thomas RĂźckle, MMV Partners: 6OJWFSTJUZPG5FYBT4PVUIXFTUFSO 64"6OJWFSTJUZPG8BTIJOHUPO  64".POBTI6OJWFSTJUZ "VTUSBMJB

Target indication: Acute uncomplicated malaria TCPs:3  MPOHEVSBUJPO C USBOTNJTTJPO blocking) & 4 (chemoprevention) Features: t)JHIMZQPUFOUBHBJOTUP. falciparum blood stage t(PPEQSPQIZMBDUJDBDUJWJUZBHBJOTU P. cynomolgi (surrogate for P. vivax) in vivo after single dose Project Leader: Dr Cristina Donini, MMV Partners: 6OJWFSTJUZPG$BQF5PXO  South Africa

Target indication: Acute uncomplicated malaria TCPs:3 1 (fast clearance) & 3b (transmission blocking) Features: t/PWFMDIFNPUZQFBOEWBMJEBUFE pathway t3BQJEQBSBTJUFDMFBSBODF t1PUFOUJBMGPSBPOFEPTFDVSFBOE therefore improved patient adherence t1PUFOUJBMUPCMPDLUSBOTNJTTJPO Project Leader: Dr David Floyd, 3VUHFST6OJWFSTJUZ /+ 64"%S3,JQ Guy, Department of Chemical Biology and Therapeutics, St Jude Children’s 3FTFBSDI)PTQJUBM $" 64" MMV Project Director: %S-JEJZB Bebrevska

Target indication: Acute uncomplicated malaria TCPs:3  MPOHEVSBUJPO C USBOTNJTsion blocking) & 4 (chemoprevention) Features: t/PWFMNFDIBOJTNPGBDUJPO t$PNQBSBCMFBDUJWJUZBDSPTTNVMUJQMF stages of the malaria parasite lifecycle including inhibition of development of all liver stages and outstanding transmission blocking potential Project Leader: Prof. Ian Gilbert and %S,FWJO3FBE %SVH%JTDPWFSZ6OJU  6OJWFSTJUZPG%VOEFF 6, MMV Project Director: %S-JEJZB Bebrevska

25


5 | New medicines to drive elimination and eradication

Developing a single-dose malaria cure ISSUE

SOLUTION

ACTION

Current treatments must be taken over 3 days and so patient adherence cannot be guaranteed. This can lead to incomplete cure and exacerbate the development of drug resistance.

Develop antimalarials that are easier to take and can assure patient adherence.

MMV and partners identify and develop molecules that are fastacting and have a long duration of action for combination into a single-dose cure and first-generation Single Exposure Radical Cure and Prophylaxis (SERCaP).1

I

n 2014, we saw the progress of several compounds able to meet the requirements of our TCPs with single-dose potential and therefore able to form the building blocks of a firstgeneration SERCaP.1

The most advanced compound, the aromatic trioxolane OZ439, is a molecule that MMV has taken from discovery right up to Phase  IIB, where its efficacy in patients will now be determined. This will be the first time malaria patients will receive treatment with OZ439 in combination with a partner drug.

Dr Marc Adamy MMV Director, Product Development for our front-runner compound, OZ439, explains the development plans to speed its progress to patients. 1

2 3

SERCaP: a medicine able to cure patients (targeting the blood stage) and eliminate the human reservoir of parasites (targeting the sexual stages). In addition, for radical cure of Plasmodium vivax malaria, the medicine would need to eliminate all blood-stage forms as well as hypnozoites in the liver. Finally, it would need to prevent reinfection of the treated individual for at least 1 month. Witkowski B et al., unpublished data. World Health Organization. “Status report on artemisinin resistance.” Jan 2014: www.who.int/ malaria/publications/ atoz/status_ rep_artemisinin_ resistance_jan2014. pdf?ua=1

Given the emergence of artemisinin resistance and now treatment failures with ACT3, next-generation antimalarials are urgently needed. What strategies have been employed to accelerate the development of OZ439? In drug development, patient safety must be a top priority and so the process is highly regulated. With that in mind, the team is looking at innovative strategies to

Q

Encouragingly, in vitro data from the first artemisinin-resistance assay indicates the compound is active against resistant strains at clinically relevant concentrations.2 Meanwhile, a spiroindolone, KAE609, and an imidazolopiperazine, KAF156, are in Phase IIA clinical trials to identify suitable dosages to take forward. DSM265 – a triazolopyrimidine-based highly selective inhibitor of Plasmodium falciparum’s enzyme, dihydroorotate dehydrogenase (DHODH), is in Phase I to determine its safety in man. MMV390048, the first antimalarial

speed things up. For example, the typical route to drug development is to gather all the evidence in adults at least up to Phase II and then to start the paediatric development. Given the huge burden of malaria in children, we will combine adults and children within the same Phase IIB programme. By adopting a staggered approach, starting first with adults, we will have safety results before moving to younger age groups and overall, will be able to expedite the process. Given the high level of unmet need presented by drug resistance and that OZ439 has demonstrated ex vivo efficacy against resistant parasites, the US Food and Drug Administration might consider it for fast track and/or breakthrough

Blood stages in the lifecycle of P. falciparum. Source: Benedict Campbell, Wellcome Images

26

compound to be researched on African soil, has potent activity against multiple stages of the malaria parasite’s lifecycle, and the potential to block malaria transmission is set to enter Phase I in 2014. (+)-SJ557733, a completely novel molecule, was identified as a drug candidate in 2013 and is undergoing preclinical development. DDD107498, a compound from Dundee University has activity across multiple stages of the parasite’s lifecycle affording potent in vitro transmission-blocking activity and was approved for preclinical development in 2013.

medicine designation. Either of these FDA statuses would help to bring an OZ439 combination therapy to patients in less time.

Q

What are the next steps for the development of an OZ439 combination therapy? The next step is to run two Phase IIB trials together, where we will test the OZ439/4-aminoquinoline combination. We will investigate the safety and efficacy of OZ/PQP and OZ/FQ in typical doseranging studies to select the optimal dose for Phase III. The trial should be complete around mid-2015. Phase III is scheduled to begin in 2016. z


New tools to accelerate drug development ISSUE

SOLUTION

ACTION

Drug resistance is emerging to current first-line artemisinin-based combination therapies (ACTs), both to artemisinin and the partner drug and in some cases leading to treatment failure.1

Drug resistance monitoring and containment efforts are underway, greatly supported by the recent identification of a molecular marker for artemisinin resistance.2 At the same time, we must be prepared with alternative antimalarials that are easier to take and effective against resistant strains of the parasite.

Draw on innovative new tools to accelerate the development of a Single Exposure Radical Cure and Prophylaxis (SERCaP).

T

modelling, we are able to take raw data, such as that generated in the Challenge Model, to determine relationships between concentration and efficacy.

o help expedite the development of promising compounds, MMV is employing innovative new tools such as the Challenge Model and pharmacokinetic/pharmacodynamic (PK/PD) modelling. The Challenge Model enables us to test candidate medicines in volunteers inoculated with a small dose of malaria in a tightly controlled environment. Using PK/PD

“ MMV’s strength

Taken together, these approaches have provided a granularity of data that was previously inaccessible, enabling us to understand quickly and affordably whether a compound will work in man

Prof. James McCarthy

is its strong relationships and flexibility.”

Queensland Institute of Medical Research, Berghofer Medical Research Institute, explains how the Challenge Model is helping to accelerate antimalarial drug development. What are the advantages of the Challenge Model? First, it has the potential to reduce the size of Phase IIA clinical trials in malariaendemic countries, which can be very difficult and time consuming to conduct. The second thing is that when you test an experimental antimalarial drug there is always a risk that if the drug doesn’t work people could come to harm. In the Challenge Model, patients have very low levels of parasites in their blood so we know that they won’t be harmed.

Q

1

2

World Health Organization. “Status report on artemisinin resistance.” Jan 2014: www.who.int/ malaria/publications/ atoz/status_ rep_artemisinin_ resistance_jan2014. pdf?ua=1 Ariey F et al. “A molecular marker of artemisininresistant Plasmodium falciparum malaria.” Nature. 505(7481): 50-5 (2014).

and provide guidance on dose selection for subsequent studies. For example, with DSM265, we have been able to link safety, efficacy and dose together in 6 months to determine the optimal dose; versus the 2 years it would take using using conventional Phase I and Phase II trials.

Q

What has it been like to work with MMV on developing and using the Challenge Model? There has been continuous communication and open sharing of information. MMV’s product development partnership model is particularly suited to collaborative relationships between academia, industry and pharma. MMV’s strength is its strong relationships and flexibility. Also, its viewpoint is different from that of a pharma partner, as they are not just looking at one drug but the overall need for malaria drug development and so their strategy supports that. It’s a more holistic approach. On the other hand, MMV obviously has budgetary constraints; a big drug company can throw large amounts of money and manpower behind one drug, while MMV is more constrained by the money that’s available. z

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5 | New medicines to drive elimination and eradication

Targeting the relapse ISSUE

SOLUTION

MMV & PARTNERS ACTION

Relapsing Plasmodium vivax malaria results in around 70–80 million clinical infections each year.1 Primaquine is the only medicine available to cure it. It has been in use for 60 years, has a very long treatment regimen and potentially fatal side effects in some patients.

Discover and develop new, safe and easy-to-take medicines to stop the relapse.

MMV is working with GlaxoSmithKline to develop tafenoquine, a next-generation anti-relapse medicine (see pages 30–31), and has a drug discovery strategy in place to identify new molecules effective against P. vivax.

P. vivax is associated with appreciable mortality. Fatal cases have been reported from several endemic countries. The most common clinical manifestation is severe anaemia and this is associated with additional respiratory or diarrhoeal infection. The consequences can be disastrous. What we don’t know is how many more people are dying directly from P. vivax or indirectly from co-associated morbidities.

other countries. Sri Lanka is the latest country close to elimination. So we know we can tackle it, the question is how: through repeated blood stage treatment or expedite the process by reliably dealing with the hypnozoite.

Prof. Ric Price Menzies School of Health Research and Charles Darwin University, Darwin, Australia; and the Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, UK.

Q

Why do you consider P. vivax malaria to be a research priority? P. vivax causes a huge burden globally, and outside Africa accounts for almost 40% of the world’s malaria. In some communities, young children have bouts of P. vivax every 3 to 4 weeks leading to a huge burden of disease in individuals, families and communities. As P. falciparum malaria declines, there has been a rise in the proportion of malaria attributable to P. vivax, both relative and, at times, absolute. In many regions, P. vivax is now the predominant species; its ability to relapse from dormant liver stages makes it is much harder to eliminate.

What are the limitations of the current tools for the treatment and management of P. vivax malaria? We lack a reliable treatment for P. vivax liver stages. Primaquine has been the only available radical cure of P. vivax malaria for the last 60 years. WHO recommends a 14-day course, which is difficult to deploy, often not implemented by malaria control programmes, and rarely adhered to by patients. Also, in susceptible individuals, it can cause haemolysis, making anaemia worse. Addressing this issue is perhaps the greatest challenge in the management of P. vivax.

Q

In addition, the P. vivax parasite has become resistant to chloroquine. This was first described in Papua New Guinea in 1989, but appears to have spread across much of Asia and South America. However, chloroquine continues to be used as the first-line treatment in nearly all P. vivax endemic countries. 1

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

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Do you believe P. vivax malaria can be eradicated? Absolutely! It has already been eliminated in the UK, Italy, USA, Russia and many

Q

Q

What tools do we need to achieve P. vivax eradication? As for any major public health campaign, health systems need to be strengthened. For malaria, the priorities are vector control and access to early diagnosis and treatment. But we desperately need a safe and reliable radical cure for P. vivax. This means either rethinking how we deploy primaquine or developing alternative options. Exciting data, published at the end of last year, highlights the potential of tafenoquine, a drug under development with GSK and MMV, to provide radical cure with a single dose. If subsequent clinical trials can confirm its safety and comparative efficacy against current treatment options and it can be deployed widely, then it has potential to transform the management of P. vivax and become a major tool in the ultimate elimination of malaria. Like primaquine, however, the drug causes haemolysis in susceptible individuals and would need to be rolled out in conjunction with better diagnostics. Significant resources are now being brought to bear in tackling these issues and in the coming years we hope to be able to ensure that goals for elimination and eradication include P. vivax as well as P. falciparum.


Discovering new molecules to target the relapse

T

1

March S et al. “A microscale human liver platform that supports the hepatic stages of Plasmodium falciparum and vivax.” Cell Host Microbe. 14(1):104-15 (2013).

o identify safe, new molecules active against the dormant liver form of P.  vivax (the hypnozoite) MMV has put in place a pragmatic cascade of tests. Compounds known to be active against blood-stage parasites are screened first against a rodent malaria liver assay to test them for activity against liver-stage schizonts. Active compounds are then progressed to a primate malaria in vitro assay followed

Prof. Sangeeta Bhatia Director, Laboratory for Multiscale Regenerative Technologies, MIT, USA, explains her interest in this area of research and how the system works.

Q

As a professor of electrical engineering specializing in computer science, how did you come to be involved in malaria research? A lot of our work is about leveraging engineering tools for medicine. Many tools for computer chip manufacturing have been very useful for manipulating cells. We had been using these chips to manipulate liver cells and grow implantable livers for patients. About Fluorescent-stained 5 years ago, after the renewed call P. vivax persistent liver for malaria eradication, the Gates forms (in pink at x number of days following Foundation hosted a liver-stage meeting. They had seen our work and infection), courtesy of invited us. That’s where it all began. It S. March-Riera & S. was a combination of opportunism, Bhatia, Massachusetts experience and interest in making a Institute of Technology, global impact. 64" Day 6

Day 21

by an in vivo model to test for activity against the hypnozoites. The limitation of the current test cascade, however, is that we are not testing against parasites that infect humans (P. vivax) and so might miss some molecules. Additionally, the throughput of our current assays that look at the hypnozoite is limited. To overcome this, MMV and the Bill & Melinda Gates Foundation are

What progress has been made in the development of a P. vivax (hypnozoite) cell-based assay to identify new anti-relapse medicines? We knew it would be a big challenge to grow the hypnozoite in the lab; everyone we spoke to in the malaria field was understandably sceptical. Sanaria, a biotechnology firm, was able to provide us with cyropreserved parasites, which means we were not dependant on fresh supplies. As the project progressed, led by Sandra March, we were able to get full liver-stage maturation of P. falciparum parasites.

Q

We then started the P. vivax experiments with the help of many different groups, including Sanaria. Eventually we were able to see a sub-population of liver forms progress, while a sub-population persisted and became dormant. It is the latter population that we termed “persistent small forms”. Before we can really call them hypnozoites we need to see reactivation. The other thing we are looking at is differential drug sensitivity, which is work planned for next year. It has been really gratifying to get a glimpse at what we believe is the hypnozoite. Of course, there will be lots more to do if we can really reproduce it in this way. We’re really excited!

working with different research groups to develop a cost-effective P. vivax cell assay. In a major step towards that goal, a team led by Massachusetts Institute of Technology (MIT) researchers has now developed a system to grow liver tissue that can support the liver stage of both Plasmodium falciparum and P. vivax malaria.1

Q

How do the assays work?

The assay we have working at the moment is really for P. falciparum; for P. vivax we have only achieved feasibility. For both assays, you start with a well plate of microcultured human livers, with hepatocytes in colonies of 250 cells, on islands of collagen surrounded by feeder cells that help to support their differentiation. We then add parasites directly onto these media and essentially allow them to progress through the liver stages. First, they glide and traverse several hepatocytes and then they will choose to set up shop in one. You are then left with a well plate of infected liver cells, to which you add the drug. You then stain and count the forms that remain to determine if the drug worked.

Q

What has it been like to work in the malaria community? Once we were introduced to the community and they embraced the potential of our assay, their input was transformative. We have had access to expertise, reagents, parasites and decades of research that wouldn’t have been available to us otherwise. Credit goes to the Gates Foundation and MMV for being visionary. They really took a chance on us, a group of complete outsiders to the malaria community, and we hope to live up to their expectations. z

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5 | New medicines to drive elimination and eradication

MMV Project of the Year 2013: tafenoquine A step closer to stopping the relapse

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afenoquine, a potential nextgeneration anti-relapse medicine for P. vivax malaria, successfully completed a Phase IIB trial in 2013. In that trial, a 300 mg single dose of tafenoquine plus chloroquine provided better protection from P. vivax relapse than chloroquine alone. In addition, the US FDA granted tafenoquine Breakthrough Therapy designation – one of its newest initiatives aimed to accelerate the development and review times of drugs for serious or life-threatening diseases. Tafenoquine belongs to the same chemical family as primaquine and thus is associated with haemolytic side effects in patients who are deficient in the enzyme glucose-6-phosphate dehydrogenase (G6PD). As a result, it will need to be deployed alongside a point-of-care G6PD-deficiency diagnostic test. The tafenoquine team are working together with PATH, whose

Dr JP Kleim Project Leader, GlaxoSmithKline, UK.

Q

What was the biggest challenge you faced in the development of tafenoquine? When GSK and MMV first began working together on tafenoquine, no one had successfully developed a drug for P. vivax since primaquine in the 1950s. So there really wasn’t any recent experience to guide us. Given the nature of relapsing malaria, one of the biggest challenges was the need for a long clinical follow-up. Patients in the Phase  IIB trial were requested to come back for the last study assessment 6 months after the first study visit. For the trial to be successful, it was very important to ensure patients returned to the study centres, otherwise our primary efficacy analysis – the proportion of patients that were relapse free at 6 months – would have been jeopardized.

30

Diagnostics Group received a grant from the United Kingdom’s Department for International Development (DFID) to accelerate the development of a G6PD test to help achieve safe and effective use of medicines for radical cure of patients infected with P. vivax. Thanks to the success of the Phase IIB trial, tafenoquine entered Phase III in April 2014, taking it closer to becoming the only new medicine approved for the treatment of relapsing malaria in over 60 years. In recognition of the team’s dedicated work to advance the project this far and in view of the promise tafenoquine holds, MMV’s Expert Scientific Advisory Committee (ESAC) has nominated tafenoquine the MMV Project of the Year 2013.

Tafenoquine GlaxoSmithKline Patient confirmatory Indication:-JWFSTUBHFPGP. vivax (relapsing malaria) TPPs:1 Single dose & relapse prevention Potential advantages: Potential for a single-dose cure, and therefore better patient adherence Project Leader: Dr JP Kleim, (MBYP4NJUI,MJOF 6, MMV Project Sponsor: Dr Wiweka Kaszubska

1

TPP: Target Product Profile

Representatives of the GSK/MMV project team talk about the challenges, the partnership and what the future holds.

Q

How did you ensure patients would return for follow-up in the Phase IIB trial? By drawing on MMV’s network we were able to select appropriate clinical sites able to run the trial. GSK’s local presence ensured we had the operational support we needed. We placed a great deal of focus on the importance of patient retention and ensured everyone involved clearly understood this. Our efforts were certainly rewarded as 97% of patients returned for their 6 month visit. It was a remarkable MMV/GSK team achievement and really key to the successful completion of the Phase IIB trial.

Q

MMV and GSK have been working together for a number of years on antimalarial research projects. What makes the partnership work so well? Both GSK and MMV share the same view that malaria is one of the world’s deadliest diseases and that overcoming it requires a joint effort between the public and private sector. The partnership initially began in

2003 to work on a drug discovery “miniportfolio”. At the time, it was a unique and ground-breaking agreement and it set the tone for collaboration on many other projects, including tafenoquine. There is a lot of synergy between the partners; both bring very different skills to the table. At GSK, we have the open lab in Tres Cantos, Spain, focused on drug discovery and a clinical development group in London, UK. But it’s really MMV that oversees the entire portfolio of investigational antimalarials. MMV has established governance and oversight committees of malaria and drug development experts that simply don’t exist anywhere else. Our senior review committees at GSK always take ESAC (page 53) advice into consideration. Additionally, the expertise and network at MMV, spanning the public and private sectors as well as malaria-endemic regions, has been crucial to the progress of our efforts to tackle malaria. For tafenoquine, we look forward to continuing the successful partnership during the Phase III trial, which began in April 2014.


Dr Jörg Möhrle Head of Translational Medicine, MMV and former Project Director for tafenoquine.

Q

JP mentioned that the biggest challenge in the development of tafenoquine was ensuring patients return for follow-up. What challenges stand out for you? To help speed the development process we designed an innovative, seamless Phase IIB/Phase III protocol. This concept has been employed for cancer but never for malaria so it was challenging to explain it to some of the regulatory agencies, particularly as the historical perception of P. vivax malaria is that of a benign disease. Before starting the Phase IIB study there were only a few patients that had been treated with

a single dose of tafenoquine to eliminate P. vivax hypnozoites, so embarking on the development programme required a great deal of confidence. Another challenge was deciding where to conduct the trial. First, as we chose to treat the P. vivax blood stage with chloroquine (standard of care against chloroquine-sensitive strains of P. vivax) we could only go to countries which use chloroquine as first-line treatment. Second, different strains of P. vivax around the world, leading to different rates of relapse, would imply different follow-up times for the trial. Unfortunately, data on relapse rates from around the world are limited. We made our selection based on available data and on the advice of the investigators from the countries with the greatest burden of P. vivax disease.

Q

What is the significance of the Phase IIB results? We now know from the Phase II trial that a single dose of 300 mg of tafenoquine protected around 90% of patients from relapse. For the purpose of statistical analyses, before the trial, we decided that the efficacy of tafenoquine combined with chloroquine would have to be 30% better than chloroquine alone, in the end it was 50% better. As a consequence, the level of confidence that we will be successful in Phase III, both among the team and the wider malaria community, is much higher than before. So now, we have a huge amount of momentum and a clear pathway to complete development, and if successful, registration with a stringent regulatory authority and in endemic countries.

Dr Wiweka Kaszubska Vice President, Head of Product Development and current MMV Project Sponsor for tafenoquine. What is the significance of the US FDA Breakthrough Therapy designation? This designation offers us the possibility to get tafenoquine to patients quicker. First of all, the FDA will review the marketing application in 6 months’ time instead of the standard 10 months; and provide guidance to ensure an efficient development programme. Second, we will then be able to progress earlier with registrations in endemic countries or additional studies to support these registrations.

Q

Q

What are the next steps for tafenoquine? The Phase III trial began in April 2014 and is expected to run until the end of 2015. We will thereafter complete the submission of the regulatory dossier. In the meantime, MMV/GSK’s access and product management team are laying the groundwork for endemic-country access, where we will see the real impact of the medicine. This includes ensuring enough evidence is generated to support the inclusion of tafenoquine as well as an appropriate G6PD diagnostic test in the WHO malaria treatment guidelines. The access team is also

evaluating how to improve the supply chain in disease-endemic countries to ensure the availability of tafenoquine together with a G6PD test. While the current formulation is expected to be used by adults and adolescents, we are also progressing our plans to develop a formulation for children. z 31


5 | New medicines to drive elimination and eradication

Blocking transmission 1 World Health Organization. “Updated WHO Policy Recommendation (October 2012) Single dose Primaquine as a gametocytocide in Plasmodium falciparum malaria”: www.who.int/malaria/ pq_updated_policy_ recommendation_ en_102012.pdf 2 Howes RE et al. “G6PD deficiency prevalence and estimates of affected populations in malaria endemic countries: a geostatistical modelbased map.” PLoS Med. 9(11):e1001339. (2012). 3 Delves M et al. “The activities of current antimalarial drugs on the life cycle stages of Plasmodium: a comparative study with human and rodent parasites.” PLoS Med. 9(2):e1001169 (2012). 4 van Pelt-Koops JC et al. “The spiroindolone drug candidate NITD609 potently inhibits gametocytogenesis and blocks Plasmodium falciparum transmission to anopheles mosquito vector.” Antimicrob Agents Chemother. 56(7):3544-8 (2012).

ISSUE

SOLUTION

ACTION

To reduce the overall burden of malaria we need to be able to stop transmission from person-to-person. Primaquine is the only medicine able to do this, but few studies have been conducted to determine its efficacy and safety.

Discover and develop new, safe and easy-to-take transmissionblocking medicines that can be combined into a Single Exposure Radical Cure and Prophylaxis (SERCaP).

MMV and partners have developed and are using a test cascade to identify new and in-development molecules with transmission blocking activity.

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alternative medicines that treat patients and block transmission.

he WHO recommends a single low dose of primaquine to be taken alongside ACTs to block malaria transmission.1 This is particularly valuable in preventing transmission of drug-resistant parasites emerging in south-east Asia. However, there have been no suitably powered clinical trials to confirm the efficacy and safety of single, low-dose primaquine, though these are now in progress. Safety is of particular concern given the known haemolytic side effects in patients with glucose6-phosphate dehydrogenase (G6PD) deficiency treated with primaquine, especially since the deficiency can occur in up to 32.5% of the population in some malaria-endemic countries.2 Consequently, there is a need to identify

DS%idier Leroy Director of Drug Discovery at MMV.

Q

What has been the biggest challenge in the hunt for transmission-blocking molecules? The biggest challenge is that historically the most informative assay, known as the Standard Membrane Feeding Assay (SMFA), was pretty labour intensive. Mosquitoes feed on malaria-infected blood – with or without the addition of a test drug – and after a week we then dissect the mosquito to see whether or not the parasite developed in its midgut. Dissecting individual mosquitoes is laborious, so we were initially only able to fully characterize the activity of one or two molecules a year with this assay.

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In addition to their established bloodstage activity, OZ439 and KAE609 have both demonstrated transmissionblocking potential in the laboratory.3,4 The key now is to investigate this potential in malaria-infected people, by carefully monitoring the development of the parasite from humans to mosquitoes after patients have been treated with either OZ439 or KAE609. Working with scientists in Tanzania, MMV has established an insectary and proof-ofconcept transmission-blocking model, which is currently being used to see whether the laboratory findings are confirmed in patients.

In parallel, the hunt continues for further compounds able to cure and block the transmission of malaria. In February 2012, MMV and partners published a pioneering piece of research that brought us closer to the reality of a medicine with such multiple capabilities.4 Researchers were able to reproduce the complex biology of the malaria parasite in the laboratory through each step of its lifecycle, creating a cascade of tests (see Figure 1) to profile current medicines in development and identify promising new molecules. Today, almost 2 years since the publication of the original findings, Dr Didier Leroy, Director of Drug Discovery at MMV, explains the progress to date.

Q

Q

How did you scale-up the standard membrane feeding assay to increase the number of molecules that can be characterized? TropIQ, a spin-off company from Radboud University in the Netherlands, developed a rigorous, and reproducible approach, which enabled us to characterize the activities of more than 10 molecules in the last year. We have now been able to determine the potency of all the molecules in late-stage development and all of our preclinical candidates in the SMFA. The next step is to scale-up the assay to an industrial level, enabling around 40–50 molecules a year to be tested. In 2012, we collaborated with GSK to establish an insectary at Tres Cantos, Spain, where mosquitoes are bred. In this way, we now have an autonomous unit where molecules can be tested against falciparum gametocytes to determine their impact on transmission to the mosquitoes after feeding.

What progress has been made since the 2012 publication to identify a new transmissionblocking medicine? The most potent transmission-blocking molecule we have so far is DDD107498, (page 25) a new compound from the Drug Discovery Unit at the University of Dundee. DDD107498 is in preclinical development and is extremely potent in the standard membrane feeding assay. In addition to DDD107498 over half of our recent preclinical candidates also show some potential to block or significantly reduce transmission. z


Figure 1: Malaria transmission biology and the assays to identify compounds to block it MMV’s strategy is to identify compounds able to kill the asexual blood stages and gametocytes, thus curing the patient and blocking transmission. To do so, we have a cascade of tests in place. Blood-stage active compounds are screened against a gametocyte assay, followed by a male and female gamete formation assay followed by the Standard Membrane Feeding Assay (SMFA).

HUMAN BLOOD STAGE

MOSQUITO STAGE

9 DAYS

20 MINS

1H

12–36 H

9–12 DAYS

Oocysts

37-40°C

26°C

98.6-104°F

78.8°F

Ookinete Diploid zygote Micro-gamete Macro-gamete Sporozoites

STAGES OF GAMETOCYTES IMMATURE

1

2

MATURE

3

4

Wall of the midgut

5

Salivary glands Sporozoites

NUMBER OF PARASITES BY LIFECYCLE STAGE: ≈ 5,000 GAMETOCYTES IN A BLOOD MEAL

Ring

≈ 500 GAMETES ≈ 100 OOKINETES ≈ 5–10 OOCYSTS ≈ 103 SPOROZOITES Human blood vessel

Blood

Midgut

IN VITRO STUDY

Blood

DUAL MALE LE & FEM FEMALE GAMETE FORMATION ASSAY

STANDARD MEMBRANE FEEDING ASSAY

Gametocytes are

Late-stage gametocytes

Gametocytes in human

incubated with a

are incubated with a

blood are incubated

compound for

compound for 24–48

with a compound

24–48 hours and their

hours and their viability

for 24–48 hours.

viability assessed.

and fertility assessed.

Mosquitoes are fed on

(Oocyst Formation Assay)

the blood. Ten days

Illustration: Comstone

GAM GAMETOCYTE AM METO ETOCYT CYTE ASSAY ASS AY

later the mosquitoes are dissected to determine if there are oocyts present in their midgut.

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5 | New medicines to drive elimination and eradication

Open source drug discovery ISSUE

SOLUTION

MMV ACTION

20,000 molecules active against malaria have been identified through MMV and partners’ extensive screening campaign and released into the public domain. They now need to be followed up.

Initiate drug discovery programmes to explore the viability of these compounds.

Pioneer open source initiatives using active compounds to catalyse antimalarial and neglected disease drug discovery.

I

n 2011, MMV launched an Open Source Drug Discovery (OSDD) programme in a bid to bring as many of the world’s best scientific minds together to solve some of the complex scientific challenges posed by malaria. Working with scientists initially in Australia and then in India, it was the first attempt by a Product Development Partnership to facilitate open sharing of information, data and ideas in real time among fellow researchers. In 2013, MMV signed a memorandum of understanding with the Royal Society of Chemistry, UK, and the Drugs for Neglected Diseases initiative (DNDi), to build on the networks established through OSDD to create a global community of open source drug discovery researchers for diseases of poverty.

Prof. Mat Todd University of Sydney, who leads Open Source Malaria (OSM),1 explains how the project works and what he thinks the future holds for open science.

Q

How does open source drug discovery work? The day-to-day work is very similar to that of any research project. You have a lab book and jot down everything that is done. The critical difference is that everything is in the public domain. It sounds trivial but it’s actually a big mind shift. In addition to describing everything that has happened, the project also makes clear what is planned for the weeks ahead. The idea is that no one is behind the curve; people can provide input ahead of time.

Q

“ We must work in an

environment where the best people work on the right problems.”

What are the advantages of open source drug discovery? You open up to the possibility of working with experts even if you don’t know them. Whenever you look at a scientific problem, you think, “I want to solve this, but not if someone else already has, or if someone else is better placed to do so”. Open source is not for the faint-hearted though. It creates an extremely challenging environment: if you make a mistake it becomes

“public”; if someone is better at what you are doing they might take over. We must work in an environment where the best people work on the right problems. Open source allows you to do that.

Q

With the contribution of a new chemical series to OSM in September 2013, how is the project progressing?2 The new series, the triazolopyrazines, have already performed well in vivo. Promising new compounds are now emerging. There have been synthetic contributions to the series from Scotland and Stockholm, as well as advice and informatics support from various industrial and academic laboratories around the world.

Q

What is the advantage of working with MMV? It’s amazing to have funders who have the courage to support an initiative that has never been attempted before. One of the main advantages is scientific expertise. Working with Paul Willis has been sensational. He is extremely knowledgeable about medicinal chemistry and so his contributions drive the project forward. He is also happy to accept scientific questions live over the internet, something many scientists would be far more reticent to do. z

1 2

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Open Source Malaria: http://opensourcemalaria.org/ OpenSourceMalaria: Triazolopyrazine (TP) Series: http://openwetware.org/wiki/alaria:Triazolopyrazine_%28TP%29_Series


The Malaria Box and Pathogen Box

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he Malaria Box was launched in December 2011, in response to the need for scientists to have access to physical samples of molecules to initiate drug discovery programmes for malaria and neglected diseases.1,2 The Malaria Box contains 400 diverse molecules active against blood stage

Dr Thomas Spangenberg MMV Research Scientist, tells us how the Malaria Box is being used today and what’s in store for the Pathogen Box. 1

2

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The Malaria Box website: www.mmv.org/ malariabox Spangenberg T et al. “The open access malaria box: a drug discovery catalyst for neglected diseases.” PLoS One. 8(6):e62906 (2013). The Pathogen Box website: www.pathogenbox.org The Pathogen Box will contain compounds active against the following neglected diseases: ascariasis, Buruli ulcer, Chagas disease, cryptosporidiosis, hookworm, human African trypanosomiasis (HAT, sleeping sickness), leishmaniasis (kala-azar), lymphatic filariasis (elephantiasis), malaria, onchocerciasis (river blindness), schistosomiasis (bilharzia), trichuriasis and tuberculosis. Bessoff K et al. “Identification of Cryptosporidium parvum active chemical series by repurposing the Open Access Malaria Box.” Antimicrob Agents Chemother. Feb 24 (2014). [Epub ahead of print]. Ingram-Sieber K et al. “Orally Active Antischistosomal Early Leads Identified from the Open Access Malaria Box.” PLoS Negl Trop Dis. 8(1): e2610 (2014). ChEMBL Malaria Data website: www.ebi.ac.uk/ chembl/malaria/

Q

More than 160 Malaria Boxes have been distributed, how are they being used today? Two thirds of the Malaria Boxes distributed are being used for malaria research and the other third on neglected diseases, such as sleeping sickness and Chagas disease. For malaria, the focus is on understanding the mechanisms of action of the molecules. While those working on other diseases are looking to test the molecules for activity against their organisms of choice.

Q

How successful has the Malaria Box been so far? There have been many exciting findings already and this is just the beginning. For example, researchers from the University of Vermont tested the Malaria Box compounds against Cryptosporidium, a parasite that causes diarrhoea and is from the same family as Plasmodium. They identified three active molecules, which led to a publication5 and funding to begin a medicinal

P. falciparum malaria, available free of charge on request. To date, more than 160 boxes have been despatched to 27 countries catalysing numerous drug discovery programmes. Based on the success of the Malaria Box, MMV was awarded a grant from

chemistry programme. There are similar stories for schistosomiasis6 with the Swiss Tropical and Public Health Institute (TPH) and the London School of Hygiene & Tropical Medicine; and collaboration between the University of Antwerp, Swiss TPH and DNDi on human African trypanosomiasis.

Q

Why do you believe it has been successful? It is the first initiative of its kind, where a set of bioactive chemicals are given away for free to catalyse neglected disease drug discovery. More than that, the Malaria Box bridges the worlds of biology and chemistry to initiate new drug discovery programmes. The box breaks down the financial and technical barriers of accessing the most promising molecules.

Q

What were the most valuable lessons you learnt from the Malaria Box project that you will apply to the Pathogen Box? The main thing we learnt is that there is a huge need for molecules to be made available for neglected disease research. Researchers are eager to test molecules and eager to receive advice. Once biologists have screened the compounds, they need to be able to come back and seek medicinal

the Bill & Melinda Gates Foundation in 2013 for a follow-on project, the Pathogen Box.3 This new box will also contain up to 400 molecules for distribution to scientists, but this time they will be active not just against malaria, but also against one of a range of neglected diseases.4

chemistry advice. The other crucial component is for researchers to share their findings and data within the community in a reasonable time frame to encourage the research community to collaborate to help drive the research forward. To respond to this need, we worked together with ChEMBL,7 creating a one-stop shop for all malaria data.

Q

What are the next steps for the Malaria Box and the Pathogen Box? For the Malaria Box we are focused on gathering, mining and encouraging recipients to share their data and initiate new programmes. For the Pathogen Box we are in the process of determining which molecules to select. This is where we need input from the whole neglected diseases community, as MMV’s experience is of course focused on malaria. We aim to launch the Pathogen Box in 2015. z

35


6

Financial view Financial year to 31 December 2013

M

Switzerland to MMV of up to Swiss Francs (CHF) one million per annum.

As a not-for-profit Swiss foundation set up under statutes dated 15 November 1999, MMV is exempt from cantonal and federal taxes and is the equivalent of an exempt organization within the meaning of 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 – representing an estimated additional contribution from

Portfolio funding The prolonged effects of the global economic downturn continued to have an impact on financial operations throughout 2013. It was a challenging and eventful year where prudent financial management involved careful negotiation of contractual agreements and increased in-kind contributions from partners. In 2013, our two largest donors, namely the Bill & Melinda Gates Foundation and the UK Department for International Development (UK DFID), renewed their significant commitments to MMV. In addition, we entered into new grant agreements with a number of new donors: Global Health Innovative Technology Fund (GHIT), UNITAID, Australian Government Department of Foreign Affairs and Trade (DFAT), Norwegian Agency for Development Cooperation (Norad) and MerckSerono. Moreover, thanks to dynamic scientific and financial management coupled with proactive fundraising, healthy progress was ensured for the full R&D portfolio.

edicines for Malaria Venture (MMV) receives funding and support from government agencies, private foundations, international organizations, corporate foundations and private individuals (Figure  1). 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 specific, targeted access and product management (APM) interventions to help ensure that vulnerable populations in malaria-endemic countries can access new malaria medicines.

Figure 1.

Total funding received/pledged from 1999 to 2018 – USD 796.5 million at December 2013

Bill & Melinda Gates Foundation 62.87% 6OJUFE,JOHEPNT%FQBSUNFOUGPS*OUFSOBUJPOBM%FWFMPQNFOU %'*%  15.99% Wellcome Trust 3.66% 6OJUFE4UBUFT"HFODZGPS*OUFSOBUJPOBM%FWFMPQNFOU 64"*%  2.93% Netherlands Minister for Development Cooperation 2.21% Irish Aid 2.14% Swiss Government SDC 2.13% National Institutes of Health (NIH) 1.48% Spanish Agency for International Development 1.36% World Bank 0.96% Rockefeller Foundation 0.72% ExxonMobil Foundation 0.72% World Health Organization/Roll Back Malaria (WHO/RBM) 0.67% Global Health Innovative Technology Fund (GHIT) 0.46% 6/*5"*% 0.43% /FXDSFTU.JOJOH-JNJUFE 0.41% Norwegian Agency for Development Cooperation (Norad) 0.35% Australian Government Department of Foreign Affairs and Trade (DFAT) 0.30% BHP Billiton 0.09% MerckSerono 0.06% Individual donors 0.05% &6$3*."-%%* 0.01%

36

36

MMV’s total expenditure decreased from USD 74.9 million in 2012 to USD 65.2 million in 2013, (a reduction of USD 9.6 million or 13%). More specifically, MMV’s R&D expenditure decreased from USD 60.8 million in 2012 to USD 50.2 million in 2013 (it should be noted that in 2012 MMV received a one-off R&D supplemental grant of USD 9.7 million from UK DFID), while MMV’s APM expenditure increased from USD 4.9 million in 2012 to USD 6.1 million in 2013. Since its foundation in 1999, MMV has spent USD 561 million to build the world’s largest R&D portfolio of new and innovative antimalarial medicines: four of these have already been launched. Our business plan estimates needing a minimum of USD 329 million over the 2014–2018 period to sustain this work. With approximately USD 100 million now in hand (cash brought forward to 2014 and outstanding committed pledges for 2014), progress has been made. Even so, there is currently a shortfall from the end of 2015 onwards. MMV has several pending proposals to donors and is increasingly active in resource mobilization and advocacy activities.


Financial year to 31 December 2013 Details

Income of MMV 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 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

Project-Related R&D Access & Product Management External Relations & Advocacy Governance & Stakeholders Management & Administration

77.0% 9.4% 4.1% 0.2% 9.3%

Figure 2. MMV expenditure 2013 Total: USD 65.2 million

Management and auditing Auditing of MMV’s accounts is conducted annually by KPMG. 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.

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 2013.

Reporting standards The 2013, Financial Statements were prepared for the first time in compliance with Swiss GAAP FER. In the past, MMV has followed International Financial Reporting Standards (IFRS). The transition to Swiss GAAP FER did not alter the transparency and disclosure in any significant way. The organization’s operating procedures are constantly updated in line with evolving requirements.

Donations and pledges 2013 (see Note 6, page 45, Donations) Cash donations received in the bank amounted to a total of USD 64,892,745 with income recognized in the previous year (2012) of USD 375,419, income deferred from the previous year (2012) of USD 1,550,716 and income deferred to the following year (2014) of USD 4,113,282. Current 2013 income, to be received in early 2014 amounted to USD 452,567. Income of USD 19,350 was recognized through MMV North America Inc.

Evolving for success In 2013, MMV’s financial infrastructure continued to evolve to meet the needs of the organization by: Æ Upgrading the ‘Navision’ enterprise resource planning system Æ Revising the internal budgeting procedures, to directly involve each of the different departments in the organization Æ Improving the internal procurement procedures, supported by a new ‘Navision’-based module (operative since February 2014)

Management and administration Management and administration cost increases were kept in check during 2013. MMV’s staff headcount remained unchanged at 54. The ratio of management and administration expenditure to overall spending was 9.3% of total expenditure (9.5% if Board and Stakeholders expenses are included).

37

37


6 | Financial view

New pledges received in 2013 of antimalarial drugs designed specifically to meet that goal.

DONOR

Amount (in millions)

Period

Bill & Melinda Gates Foundation Bill & Melinda Gates Foundation Global Health Innovative Technology Fund (GHIT) UNITAID UK Department for International Development (DFID) Australian Government Department of Foreign Affairs and Trade (DFAT) Norwegian Agency for Development Cooperation (Norad) MerckSerono

USD 160.4 USD 4.6 Yen 297.5 (USD 2.8) USD 34.0 £25.0 (USD 38.0) AUD 2.5 (USD 2.4) NOK 15 (USD 2.8) Euro 0.2 (USD 0.3)

2013–2018 2013–2016 2013–2014 2013–2016 2013–2018 2013 2013–2015 2013–2014

Total (USD equivalent)

245.3

Fundraising In addition to previous pledges, MMV received several new pledges in 2013 as fundraising continued to progress (see table above). MMV is grateful for these and previous commitments from its many donors. Financial year ahead to December 2014 MMV operates in a complex multi-currency environment. The bulk of donations are received in US Dollars and UK Pounds Sterling, although other currencies are sometimes involved. 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 Swiss Francs (CHF). The resulting exposure or exchange risk is hedged, according to the budget in January 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 longterm 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, the portfolio, cash flow and new potential fundraising opportunities must be managed dynamically. Focus on sustainability: R&D and APM In 2013, MMV continued to prepare scale-up and launch activities to ensure market access to medicines emerging from its pipeline. These activities enable a ‘downstream’ extension of the public–private partnership model underpinning MMV’s overarching goal to achieve major health impact from its medicines. Moreover, in the new context of malaria elimination/ eradication, a second and critical series of investments are now urgently needed to spur on R&D for the next generation

Although fundraising remains successful and significant additional funds were sourced in 2013, major fundraising efforts will be required in 2014 and even more in 2015 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 to 2018 and pending proposals to donors, future R&D and APM activities will remain substantially underfunded (see Figure 3). The long-term financial projections for future MMV overall spending over 2014–2018 is USD 329 million. This figure represents a mixture 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/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 (May 2014). Financial tables The financial tables and notes that follow are extracted from the Swiss GAAP FER compliant accounts.

USD in millions

Figure 3. MMV income and expenditure to date and scenario 2014–2018 100

Carried forward from previous year 90

Total income for the year 80

Total expenditure for the year 70

60

50

40

30

20

10

0 2000

38

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

2016

2017

2018


MMV CONSOLIDATED STATEMENT OF FINANCIAL POSITION

ASSETS CURRENT ASSETS

31 Dec 2013 USD

31 Dec 2012 Restated USD

32 954 528 452 567 5 710 26 225 5 302 347 425 275 831 2 063 686

28 412 564 375 419 1 525 50 473 39 484 609 996 1 755 076 461 627

36 131 274

31 706 164

191 361 229 686

184 608 311 431

421 047

496 039

36 552 321

32 202 203

6 765 293 548 034 4 127 882 771 267 2 888 107 439 291

4 224 660 252 936 1 550 716 543 106 1 890 845 413 241

15 539 874

8 875 504

4 000 000 9 487 037 7 525 410

4 000 000 17 679 889 1 646 810

21 012 447

23 326 699

36 552 321

32 202 203

Notes Cash and Cash Equivalents Donations Receivable Project Reimbursements Receivable Accounts Receivable Tax Receivable Prepaids Prepaid R&D Commitments Prepaid APM Commitments

3 6

7 7

TOTAL CURRENT ASSETS LONG-TERM ASSETS Guarantees Fixed Assets, Net

15 4

TOTAL LONG-TERM ASSETS TOTAL ASSETS LIABILITIES AND CAPITAL & RESERVES CURRENT LIABILITIES Accrued R&D Commitments Accrued APM Commitments Deferred Income Other APM Creditors Accrued Expenses Short-Term Provisions TOTAL CURRENT LIABILITIES

7 7 6

5

CAPITAL & RESERVES Foundation Capital Unrestricted Operating Funds Restricted Operating Funds

TOTAL CAPITAL & RESERVES TOTAL LIABILITIES AND CAPITAL & RESERVES



39


6 | Financial view

MMV CONSOLIDATED STATEMENT OF COMPREHENSIVE INCOME

Continuing operations INCOME

31 Dec 2013 USD

31 Dec 2012 Restated USD

36 806 795 3 420 000 21 419 227 761 305

31 712 484 – 24 519 306 1 388 851

Notes

DONATION REVENUES Private Foundations & Individual Donors UN Agencies Government Agencies Corporates & Corporate Foundations TOTAL DONATIONS REVENUES

6

62 407 327

57 620 641

OTHER INCOME

9

215 095

363 554

62 622 422

57 984 195

36 818 961 12 833 182 513 669

48 406 607 11 881 862 468 060

50 165 812

60 756 529

4 021 164 2 002 626 95 836

3 056 423 1 779 486 79 956

6 119 626

4 915 865

2 444 371 49 437 206 745

2 501 376 227 532 242 703

2 700 553

2 971 611

13

158 789

373 634

8 11

3 888 772 1 270 448 39 965 111 533 37 332 323 932 94 818 293 263

3 596 570 1 189 424 55 642 294 851 67 562 397 866 113 070 127 109

6 060 063

5 842 094

27 947

14 879

TOTAL EXPENDITURE

65 232 790

74 874 612

RESULT FROM OPERATING ACTIVITIES

(2 610 368)

(16 890 417)

157 656 (37 099) 175 559 296 116

294 167 (35 353) 116 608 375 422

(2 314 252)

(16 514 995)

8 192 852 (5 878 600) 2 314 252

18 161 805 (1 646 810) 16 514 995

TOTAL INCOME EXPENDITURE RESEARCH & DEVELOPMENT EXPENDITURE Project Grants Project-Related Variable Expenditure Expert Scientific Advisory Council Expenses

7 7

TOTAL RESEARCH & DEVELOPMENT EXPENDITURE ACCESS & PRODUCT MANAGEMENT EXPENDITURE Project Expenditure Access-Related Variable Expenditure Access & Product Management Advisory Committee

7

TOTAL ACCESS EXPENDITURE EXTERNAL RELATIONS AND ADVOCACY EXPENDITURE ER&A-Related Variable Expenditure Fundraising Communications TOTAL EXTERNAL RELATIONS & ADVOCACY EXPENDITURE FOUNDATION BOARD & STAKEHOLDER EXPENSES GENERAL & ADMINISTRATION EXPENSES Staff-Related Benefits/Compensation Office and Occupancy Travel Expenses Professional and Legal Fees Training, Education and Journals IT Expenses Depreciation Other

4

TOTAL GENERAL & ADMINISTRATION EXPENSES OTHER EXPENSES

Interest Income Financial Expenses Foreign currency translation differences Net Financial Income (LOSS)/SURPLUS FOR THE PERIOD ALLOCATIONS Transfer (To)/From Operations Reserve Transfer (To)/From Donor Restricted Reserve

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10


MMV CONSOLIDATED STATEMENT OF CASH FLOW

2013 USD

2012 Restated USD

(2 314 252)

(16 514 995)

26 050 94 818

12 057 113 070 189 027

(2 193 383)

(16 200 841)

(77 148) (4 185) 24 248 33 607 (122 815) 262 571 2 540 633 295 098 2 591 766 227 620 1 006 372 243 240 7 021 009

(347 341) 372 941 (16 577) (10 139) (514 105) (355 396) 121 837 (683 662) (1 344 848) 7 089 291 058 (30 455) (2 509 598)

(11 700) (13 075) (24 774)

(47 612) (296 361) (343 973)

4 802 851

(19 054 412)

28 412 564 (260 887) 32 954 528

47 424 120 42 856 28 412 564

Notes (LOSS)/SURPLUS FOR THE YEAR Adjustments for: Increase/(Decrease) in Provisions Depreciation Release of pension asset

5 4

OPERATING RESULT BEFORE WORKING CAPITAL CHANGES CASH FLOW FOM OPERATING ACTIVITY (Increase) in Donations Receivable Decrease/(Increase) in Project Balance Reimbursements (Increase)/Decrease in Accounts Receivable (Increase)/Decrease in Tax Receivable (Increase) in Project-related Prepaid Expenses (Increase)/Decrease in Prepaid Expenses Increase in Accrued R&D Commitments (Decrease)/Increase in Accrued APM Commitments (Decrease)/Increase in Deferred Income Increase in Other Creditors Increase in Accrued Expenses Unrealized foreign currency (gain)/loss CASH FLOW RESULTING FROM OPERATING ACTIVITY

7 7 7 6

CASH FLOW FROM INVESTMENT ACTIVITY Increase in Guarantees Increase in Fixed Assets CASH FLOW RESULTING FROM INVESTMENT ACTIVITY

4

NET (DECREASE)/INCREASE OF CASH AND CASH EQUIVALENTS Cash & cash equivalents at beginning of year Effect of exchange rate fluctuations on cash held Cash & cash equivalents at end of year

MMV CONSOLIDATED STATEMENT OF CHANGES IN EQUITY

Foundation Capital USD

Unrestricted operating funds USD

Restricted operating funds USD

Total Capital and Reserves USD

4 000 000

36 005 569

40 005 569

(Loss)/Gain for the period

(16 514 995)

(16 514 995)

Restatement as per Swiss GAAP FER

(1 810 685)

1 646 810

(163 875)

BALANCE AT 31 DECEMBER 2012

4 000 000

17 679 889

1 646 810

23 326 699

(8 192 852)

5 878 600

(2 314 252)

4 000 000

9 487 037

7 525 410

21 012 447

BALANCE AT 1 JANUARY 2012 TOTAL COMPREHENSIVE INCOME FOR THE PERIOD

TOTAL COMPREHENSIVE INCOME FOR THE PERIOD (Loss)/Gain for the period BALANCE AT 31 DECEMBER 2013

41


6 | Financial view

NOTES TO THE CONSOLIDATED FINANCIAL STATEMENTS AS OF 31 DECEMBER 2013 1. ORGANIZATION MEDICINES FOR MALARIA VENTURE (MMV) is a

The two main impacts from this transition from

basis of making the judgements about carrying

IFRS to Swiss GAAP FER for the organization are

values of assets and liabilities that are not readily

the following:

apparent from other sources. Actual results may

Swiss Foundation, established as a not-for-profit

differ from these estimates. If in the future such The Swiss GAAP FER recommends the

estimates and assumptions, which are based on

dated 15 November 1999. It is managed by a

application of a static method to present the

management’s best judgement at the date of the

foundation council, a chief executive officer and

impact of pension funds on the organization,

consolidated financial statements, deviate from

six senior managers.

while IFRS recommends using a dynamic

the actual circumstances, the original estimates

method. The impact on the financial

and assumptions will be modified as appropriate

With its head office in Geneva, the aim of MMV

statements of the organization was the

in the year in which the circumstances change.

is to bring public and private sector partners

dissolution of the Employee Benefits asset.

together to fund, and provide managerial and

The net financial impact on the Statement of

Judgements made by management in the appli-

logistical support, for the discovery and devel-

Comprehensive Income and the Cash Flow

cation of Swiss GAAP FER that have significant

opment of new medicines for the treatment and

is of USD 163,875.

effect on the consolidated financial statements

Swiss GAAP FER 21 requires a separation

and estimates with a significant risk of material

fordable and appropriate for use by populations

between the retained earnings from core

adjustment in the next year are discussed below.

in developing countries.

grant and those from funds earmarked for

legal entity, registered in Geneva under statutes

prevention of malaria. The products should be af-

Æ

Æ

specific activities. The net financial impact

Foreign currency transactions

As with all Swiss foundations, Medicines for

on the Statement of Financial Position is

Transactions in foreign currencies are translated

Malaria Venture is monitored by the Swiss Federal

USD 1,646,810.

at the foreign exchange rate ruling at the date of

Supervisory Board for Foundations.

the transaction. Monetary assets and liabilities Donations from governments are not being ad-

denominated in foreign currencies at the Consol-

dressed in the Swiss GAAP FER 21; the organiza-

idated Statement of Financial Position date are

tion has decided to retain the accounting treatment

translated to USD at the foreign exchange rate

prescribed by International Accounting Standards

ruling at that date. Foreign exchange differences

(IAS) 20, namely to recognize income up to the level

arising on translation are recognized in the Con-

The significant accounting policies adopted

of expenditure allocated by government, the differ-

solidated Statement of Comprehensive Income.

by MMV in the preparation of the consolidated

ence being recognized as deferred income.

Non-monetary assets and liabilities that are

2. SIGNIFICANT ACCOUNTING POLICIES

financial statements are set out below.

measured in terms of historical cost in a foreign The consolidated financial statements have been

currency are translated using the exchange rate

Statement of compliance

prepared on the historical cost basis, except where

at the date of the transaction.

The consolidated financial statements for the year

a standard requires a different measurement basis.

ending 31 December 2013 were approved for issue by the MMV board on 27 March 2014.

The following exchange rates were used at year The consolidated financial statements give a true

end:

and fair view of the organization’s financial position; The consolidated financial statements have been

the results of its operation; and its cash flows.

2013 1 CHF

=

USD

poration of MMV, the applicable provisions of the

Basis of preparation

Æ

1 EUR

=

USD

1.3780

Swiss Code of Obligations and the Swiss Generally

The consolidated financial statements are pre-

Æ

1 GBP

=

USD

1.6562

Accepted Accounting Principles (Swiss GAAP FER).

sented in US dollars (USD), since the majority of

Æ

1 AUD

=

USD

0.8947

1.0925

prepared in accordance with the articles of incor-

Æ

1.1244

MMV’s activities are conducted in this currency As of 1 January 2013 MMV changed the financial

(group functional and presentation currency).

2012 Æ

1 CHF

=

USD

preparation of its consolidated financial state-

Fair value is the amount for which a financial as-

Æ

1 EUR

=

USD

1.3184

ments, from the International Financial Report-

set, liability or instrument could be exchanged

Æ

1 GBP

=

USD

1.6254

ing Standards (IFRS) to the Swiss GAAP FER.

between knowledgeable and willing parties in an

Æ

1 AUD

=

USD

1.0382

The comparative figures for the year ending 31

arm’s length transaction.

reporting standards, used as a reference for the

December 2012 have been restated accordingly. The preparation of consolidated financial state-

Cash and cash equivalents

Due to the increased complexity of the detailed

ments in conformity with Swiss GAAP FER

Cash and cash equivalents comprise cash

rules and disclosure requirements of IFRS, the

requires management to make judgements,

balances and short-term money market depos-

foundation council decided to move from the IFRS

estimates and assumptions that affect the ap-

its with original maturities of three months or less.

to the Swiss GAAP FER, which suits the size, na-

plication of policies and reported amounts of

ture and complexity of the organization’s opera-

assets and liabilities, income and expenditure.

Fixed or tangible assets

tions better. MMV is nevertheless committed to

The estimates and associated assumptions are

Fixed assets are stated at cost less accumulated

continue publishing high quality, transparent, true

based on historical experience and various other

depreciation. Depreciation is charged to the Con-

and fair financial statements with its new account-

factors that are believed to be reasonable under

solidated Statement of Comprehensive Income

ing and reporting framework.

the circumstances, the results of which form the

on a straight line basis over the estimated useful

42


lives of the assets. The estimated useful lives of

as a contingent asset as disclosed in Note 12.

Income tax and status

assets are as follows:

They are considered as unrestricted funds,

MMV received exoneration from income tax from

unless the donor stipulates a specific restric-

the Geneva cantonal and Swiss federal authorities

tion. A reconciliation between donations re-

from the year 2000 for an indeterminate period.

Æ Office furniture

5 years > CHF 1,000

Æ Fixtures

and installations

3 years > CHF 1,000

ceived in cash and income recognized in the

3 years > CHF 5,000

Income is shown in Note 6.

Æ Computers

and equipment

Consolidated

Statement

of

Comprehensive

A further agreement was signed on 8 December 2010 with the Swiss Federal Council under new provisions of the recently promulgated Swiss Host

Impairment

Government grants are recognized as income

State Act, to grant MMV certain privileges and im-

The carrying amounts of MMV’s assets are re-

for the allowable expenses incurred in the cur-

munities – effective as of 1 January 2011.

viewed at each Consolidated Statement of Fi-

rent year. At year end, the difference between

nancial Position date to determine whether there

the income recognized and the cumulative ex-

The principal advantages for MMV as a Swiss

is an indication of impairment. If any such indi-

penses incurred is accounted for as deferred

Foundation with ‘Other International Organization’

cation exists, the asset’s recoverable amount is

income.

status are the following:

the Consolidated Statement of Comprehensive

When the donor wishes to see a donation allo-

Æ

Income whenever the carrying amount of an

cated to a specific cause, the donation is con-

federal, cantonal and communal taxes

asset exceeds its recoverable amount.

sidered to be an allocated fund. Allocated funds

(this was originally acquired by decree with

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

the Geneva cantonal and Swiss federal

The recoverable amount of an asset is the great-

presented in a separate section of the Statement

authorities, but now formalized directly with

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

of Financial Position.

estimated. An impairment loss is recognized in

to sell. In assessing value in use, the estimated

the Swiss government within the accord). Æ

future cash flows are discounted to their present

Contributions in kind

value using a pre-tax discount rate that reflects

Occasionally MMV receives donations in kind,

current market assessments of time-value of

primarily in the form of free use of goods or ser-

money and the risks specific to the asset.

vices or preferential discounts. These contribu-

Exoneration from all direct and indirect

Exoneration from VAT on all goods and services acquired for the sole use of the foundation within Switzerland and abroad.

Æ

Unrestricted access to work permits for non-Swiss, non-EU nationals.

tions in kind are not stated in the Statement of Provisions

Comprehensive Income as this type of contribu-

MMV will deal directly with the Swiss Mission in

A provision is recognized in the Consolidated

tion is difficult to valorize.

Geneva for all such issues.

a present legal or constructive obligation as a

Operations reserve

Basis of consolidation

result of a past event, and it is probable that an

The accumulated Operations Reserve represents

MMV has established a Special Purpose Entity

outflow of economic benefits will be required to

excess of income over expenditure since the in-

(SPE) for fundraising in North America (MMV,

settle the obligation.

ception of MMV and is available to be utilized for

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

future operation and project funding costs as the

direct or indirect shareholdings in this entity.

Statement of Financial Position when MMV has

Foundation capital

rapidly evolving research and development (R&D)

Foundation capital is fully subscribed at USD

project pipeline dictates

An SPE is consolidated if, based on an evaluation of the substance of its relationship

4,000,000 as stipulated under the original legal statutes. Under normal circumstances, foun-

Interest income and financial expense

with MMV and the SPE’s risks and rewards,

dation capital may be used during the year

Interest income and financial expense comprise

MMV concludes it controls the SPE. The SPE is

to meet cash flow shortfalls, but should

interest on funds invested and bank charges.

not fully controlled by MMV, but was established under such terms and conditions that it imposes

be replenished before closing at year end. Foundation capital together with the residu-

Research and development expenditure

strict limitations on the decision-making powers

al operations reserve serves to maintain the

Expenditure and grants allocated for R&D activi-

of the SPE’s management with the result that

viability of the organization, for 6 months,

ties undertaken with the prospect of gaining new

MMV receives the majority of the benefits

until other funding sources can be found.

scientific or technical knowledge and under-

related to the SPE’s operations and net assets

standing are recorded on the basis of contracts

while being exposed to the majority of risks

Revenue recognition

with grantees. In the event that a portion of a

incident to the SPE’s activities, and retaining

An unconditional grant is recognized as rev-

grant is unpaid at the year end, it is included un-

the majority of the residual or ownership risks

enue in the Consolidated Statement of Com-

der current liabilities. Expenses paid before year

related to the SPE or its assets. MMV appoints

prehensive Income when the grant becomes

end for the following period are recorded as Pre-

the board members of the SPE.

receivable. Any other grant which has perfor-

paid R&D Commitments in current assets and as

mance, timing or other conditions is recognized

Prepaid in Note 7.

In accordance with Swiss GAAP FER 30 and based on the facts above, MMV North America

in the Consolidated Statement of Financial Position as revenue once the foundation has

Regulatory and other uncertainties inherent in

Inc. has been fully consolidated in these

complied with the stipulated conditions. If the

the development of new products in this sector

consolidated financial statements on a line by

conditions have not yet been fully complied

preclude MMV from capitalizing development

line basis since 2011.

with, then this grant component is reported

costs.

43


6 | Financial view

List of organizations consolidated in 2013:

Revenue recognition – MMV enters into complex

are formalized by contracts and agreements that

grant contracts that contain numerous provisions

outline the requested services and development

related to performance, reporting and spending.

effort. Progress against expectations is difficult

These criteria are monitored by both the scientific

to measure, and measurement criteria are

programme and finance teams to assess progress

generally not defined in grant agreements. We

according to grant milestones and objectives. The

review research plans and activities regularly

Transactions eliminated on consolidation

evaluation of progress requires judgement, as it is

to adjust annual funding levels prospectively.

All intra-group balances and transactions, and

based on subjective evaluations and discussions

Additionally, actual research and development

any unrealized gains and losses arising from

with programme participants and sponsors.

timing and execution are often different from the

Country Name and domicile Functional currency

United States of America MMV, North America, Inc. Delaware USD

intra-group transactions, are eliminated in preparing the consolidated financial statements.

original plans. These factors lead to subjectivity Research

and

Development

Expenditure

MMV’s R&D expenditure is generally not direct Accounting estimates and judgements

expenditure, but is in the form of grants and

Certain critical accounting judgements in applying

contracts with external parties who perform

MMV accounting policies are described below.

certain tasks at their request. These requests

in the timing and recognition of research and development expenditure.

3. CASH AND CASH EQUIVALENTS 31 December 2013 USD 6 632 30 947 896 2 000 000 32 954 528

Cash Bank Balances Money Market Deposits (Maturity Less Than 3 Months) TOTAL CASH AND CASH EQUIVALENTS

31 December 2012 USD 2 570 26 409 994 2 000 000 28 412 564

The effective rates on deposits have moved within the following ranges: 2013

2012

Low % 0.00 0.03 0.00 0.05 0.00

High % 0.20 0.05 0.00 0.05 0.00

Low % 0.00 0.05 0.00 0.05 0.00

High % 0.20 0.15 0.20 0.25 3.60

Fixtures & Installations USD

Office Furniture USD

Computers & Equipment USD

Total

COST At 1 January 2013 Additions Disposals AT 31 DECEMBER 2013

493 873 – (1 362) 492 511

408 534 – (13 072) 395 462

756 014 13 075 (241 848) 527 241

1 658 421 13 075 (256 282) 1 415 214

ACCUMULATED DEPRECIATION At 1 January 2013 Charge for the year Disposals AT 31 DECEMBER 2013

326 031 38 040 (1 362) 362 709

335 063 21 435 (13 072) 343 426

685 896 35 344 (241 847) 479 393

1 346 990 94 819 (256 281) 1 185 528

NET BOOK VALUE AT 31 DECEMBER 2013

129 802

52 036

47 848

229 686

US Dollar (USD) Swiss Franc (CHF) British Pound (GBP) Euro (EUR) Australian Dollar (AUD)

4. FIXED ASSETS 2013

The fire insurance value of the tangible fixed assets is USD 1,822,000.

44

USD


5. PROVISIONS MMV Statement of Movement in PROVISIONS at 31 December 2013 Unused Vacation Reserve USD

Bad Debt Provision USD

Total Provisions USD

401 184

401 184

(401 184) 398 362

– 14 879

(401 184) 413 241

398 362

14 879

413 241

(398 362) 439 291

(14 879) –

(413 241) 439 291

439 291

439 291

BALANCE AT 1 JANUARY 2012 Use/release 2012 Allocation for the year BALANCE AT 31 DECEMBER 2012 Use/release 2013 Allocation for the year BALANCE AT 31 DECEMBER 2013

6. DONATIONS Below is a summary of donations received or committed during 2013:

Bill & Melinda Gates Foundation Bill & Melinda Gates Foundation (Pathogen Box) Wellcome Trust Global Health Innovative Technology Fund (GHIT) Swiss Government SDC United Kingdom’s Department for International Development (DFID) United States Agency for International Development (USAID) Irish Aid Australian Government Department of Foreign Affairs and Trade (DFAT) Norwegian Agency for Development Cooperation (Norad) National Institutes of Health (NIH) UNITAID Newcrest Mining Limited Merck KGaA Individual donors TOTAL RECEIVED

Cash Received 2013

Income Recognized During Previous Year

Income Deferred from Previous Year

Income Deferred to Following Year

Current Year Income to be Received

USD

USD

USD

USD

USD

Total Income as per Statement of Comprehensive Income USD

30 372 520 1 923 006 1 600 000 2 891 607

– – – –

– – – –

– – – –

– – – –

30 372 520 1 923 006 1 600 000 2 891 607

1 785 193 16 023 677

– –

– –

– (1 118 420)

– –

1 785 193 14 905 257

597 721

(259 565)

338 156

1 363 400 2 369 020

– –

1 318 400 –

(1 363 400) (1 371 897)

– –

1 318 400 997 123

815 594 832 996 3 420 000 753 620 130 730 13 661 64 892 745

– – – (371 419) – (4 000) (375 419)

– 232 316 – – – – 1 550 716

– – – – – – (4 113 282)

– 194 193 – 209 924 34 450 14 000 452 567

815 594 1 259 505 3 420 000 592 125 165 180 23 661 62 407 327

Of the total donations recognized in the Consolidated Statement of Comprehensive Income, USD 19,350 have been received through MMV, North America, Inc.

45


46

Novartis (miniportfolio 2)

Sanofi Aventis (miniportfolio 4)

High Through-put Blood-Stage Screens

GHIT Screening Program

AstraZeneca (miniportfolio 5)

2

3

4

5

6

Eurartesim® (Dihydroartemisinin-Piperaquine) Pregnancy and Safety Registries

Safety/Efficacy of Retreatment with ACTs (Wanecam study)

39

2 041 732

224 575 409 536

Coarsucam (Artesunate-amodiaquine) Implementation study

38

2 675 843

873 200

Phase IIIB/IV

Pyramax® (Pyronaridine-Artesunate) Adult Registration

83 600

37

36

OZ439 Piperaquine Development

35

1 190 356

8 628 951

873 200

OZ439 Ferroquine Development

34

91 533 9 902 908

Phase III

OZ439

33

Phase II/POC

Intrarectal Artesunate

91 533

Phase I

32

113 535

21A092

31

58 719

2 314 108

DSM265-DHODH inhibitors

ELQ-300

29

2 486 362

63 502

42 400

152 169

42 437

82 148

300 800

300 509

38 603

26 250

42 873

88 946

113 513

151 986

53 477

126 834

47 423

481 279

1 320 614

86 328

30

Preclinical Development

Compound Management

Lead Optimization

28

Challenge Grants

21

Scynexis NTD Screening

Long Duration Heterocycles

20

27

Evaluate Dengue and Anti-inflammatory Activity of Malaria Box Compounds

19

Outsourcing Budget

Malaria Box ADMET

18

26

Indian Antimalarials (Chembiotech)

17

Tetraoxane (S. Ward )

Open Source Drug Discovery in Australia

16

25

Master Malaria Box

15

PfNDH2 (S. Ward LOI)

Nauclea

14

24

Argemone Mexicana

13

Anacor Oxaboroles

Nebraska Antimalarials

12

Dihydroorotate Dehydrogenase (DHODH) Inhibitor (Texas Back-up)

P. falciparum Erythrocytic Stage Inhibitors Dundee

11

23

983 964

St Jude/Rutgers/USF Antimalarials (NIH funding )

10

22

413 038

Antimalarial Pyrazoles (ex Myosin motor project)

9

86 725

Long Duration Heterocycles – Brazil Antimalarial Project

285 516

DPI UCT H2L (aminopyridine)

8

3 363 403

450 000

131 731

5 000

430 700

839 875

2 160 328

4 017 634

Awarded 2013 (USD)

7

Individual Discovery Projects

GSK (miniportfolio 1)

1

Discovery Mini Portfolios and Screens etc

7. PROJECT GRANTS

2 041 732

409 536

224 575

2 675 843

855 972

855 972

83 600

1 190 356

8 628 951

9 902 908

91 533

91 533

113 535

58 719

2 314 108

2 486 362

63 502

42 400

152 169

42 437

82 148

300 800

300 509

983 964

413 038

38 603

26 250

42 873

88 946

113 513

151 986

53 477

126 834

47 423

481 279

1 320 614

86 328

56 895

285 516

3 333 573

450 000

131 731

5 000

284 450

839 875

2 160 328

3 871 384

Final Allocation 2013 (USD)

2 235 060

819 072

224 575

3 278 707

884 783

884 783

84 688

2 208 884

10 540 241

12 833 813

104 793

104 793

113 535

69 747

2 934 526

3 117 807

66 185

42 400

213 928

83 778

82 148

300 800

300 509

1 089 748

413 038

38 603

26 250

42 873

88 946

133 396

168 183

53 477

126 834

47 423

481 279

1 737 862

86 328

56 895

285 516

3 786 901

450 000

263 462

5 000

284 450

839 875

2 160 328

4 003 115

Paid 2013 (USD)

(193 328)

(409 536)

(602 864)

(28 810)

(28 810)

(1 088)

(1 018 528)

(1 911 290)

(2 930 906)

(13 260)

(13 260)

(11 028)

(620 417)

(631 445)

(2 683)

(61 760)

(41 341)

(105 784)

(19 883)

(16 198)

(417 248)

(453 328)

(131 731)

(131 731)

Related to 2013 paid in 2014 (USD)

17 228

17 228

29 829

29 829

146 250

146 250

Prepaid 2013 for 2014 (USD)

Malaria Research and Training Center, University of Bamako

Sigma-Tau Industrie Farmaceutiche Riunite, Italy

Sanofi

Shin Poong Pharmaceutical Co. Ltd., University of Iowa

Medicines for Malaria Venture

Sanofi

Medicines for Malaria Venture, (Monash University, Swiss TPH, University of Nebraska)

Medicines for Malaria Venture

Medicines for Malaria Venture

Medicines for Malaria Venture

Medicines for Malaria Venture (University of Texas Southwestern Medical Center, Monash University)

SPECS

Scynexis

Medicines for Malaria Venture

University of Liverpool

University of Liverpool

Anacor

University of Texas Southwestern Medical Center, Monash University, University of Washington

Medicines for Malaria Venture

Queensland Institute of Medical Research

Medicines for Malaria Venture

Medicines for Malaria Venture

TCG Lifesciences Ltd.

University of Sydney

Medicines for Malaria Venture

University of Antwerp

University of Geneva

University of Nebraska

University of Dundee

Rutgers University, St Jude Children’s Research Hospital, University of South Florida, (NIH funding)

Drexel University

University of Campinas

University of Cape Town, Monash University, Swiss-TPH

AstraZeneca India

Eskitis Institute for Cell and Molecular Therapies, Griffith University, University of California San Diego

Eskitis Institute for Cell and Molecular Therapies, Griffith University

Sanofi

Novartis Institute for Tropical Diseases Pte. Ltd.

GlaxoSmithKline plc.

Project Partners

6 | Financial view


47

Development of a P. berghei uHTS Liver-Stage Assay and Screening of Biofocus Library

61

Swiss Tropical and Public Health Institute (Swiss TPH)

Monash CDCO

CRO Chemistry (Syngene)

PK Analytical Chemistry

The Pilot Human Malaria Challenge Study

Field Isolates Resistance

Human SMFA Clinical Setting (Tanzania)

Indonesian Capacity Building

Syngene Parasitology

Artemisinin – Resistance in vitro

Other diseases – Screening Activities

63

64

65

66

67

68

69

70

71

72

73

(+) Mefloquine

Kinase Programme

B-Haematin Screening

Intravenous Artesunate – 2nd provider (IPCA)

Intrarectal Artesunate (Huang – Guilin)

75

76

77

78

79

TOTAL R&D (including ESAC + Project Management)

Dacart CDA

74

Terminated projects

GSK Translational Pharmacology Group

62

Enabling technologies

Testing of Compounds on P. berghei Liver-Stage Assay in vitro

60

High Through-put Blood-stage Screens

54

ChEMBL

In vivo Assay of Compounds with Hemolytic Liabilities

53

59

Development of a Liver Stage P. vivax in vitro Assay

52

South African Transmission Blocking Research Consortium (SAMI)

P. vivax in vitro Resistance Testing

51

58

Testing of Compounds for Anti-Relapse Effect in P. cynomolgi in vivo Model

50

Drug Assay Platform for Inhibition of P. falciparum Transmission Stages

P. vivax Culture Systems and Assays Development

49

57

GSK Insectory

48

Malaria Lab Resistance Mutants Fidock

MMV390048 (Preclinical & Initiate Phase I)

47

Gametocyte Assay Development and Screen (Stage Specific)

Clinical Relapse Human POC

46

55

Pyramax® Primaquine Interaction study in Human Volunteers

45

56

Tafenoquine for P. vivax Relapse Prevention

44

37 094 793

2 109

1 650

756

44 183

2 153

23 965

74 817

160 704

51 900

122 504

398 258

353 816

45 780

1 081 628

32 489

234 000

435 179

620 506

664 760

4 201 523

244 298

50 354

52 095

50 000

230 000

315 000

250 000

215 000

150 000

189 770

15 452

171 721

270 000

304 458

1 810 331

509 723

7 813

1 474 528

469 235 839 574

Eurartesim® (Dihydroartemisinin-Piperaquine) New Paediatric Formulation

Pyramax® (pyronaridine-artesunate) New Paediatric Formulation

42

304 256

Coartem® Dispersible (Arthemeter-Lumefantrine) Safety/efficacy in children <5kgs

41

43

500 000

8 423 606

Chloroquine and Azithromycin for Prophylaxis in Pregnant Women

Elimination/Eradication

40

36 818 961

2 109

1 650

756

44 183

2 153

23 965

74 817

160 704

51 900

122 504

398 258

353 816

45 780

1 081 628

32 489

234 000

435 179

620 141

664 760

4 201 158

244 298

39 715

52 095

50 000

230 000

43 584 255

2 109

1 650

756

44 183

4 306

47 931

100 935

160 704

51 900

125 668

398 258

353 816

46 100

1 403 303

35 862

234 000

562 516

620 141

664 760

4 657 028

431 109

39 715

78 828

50 000

280 000

261 616

250 000

250 000 261 616

215 000

137 442

354 604

15 452

171 721

290 000

304 458

2 155 541

504 145

7 813

2 033 464

862 582

478 881

304 256

500 000

9 726 625

215 000

137 442

189 770

15 452

171 721

270 000

304 458

1 810 331

504 145

7 813

1 474 528

839 574

469 235

304 256

500 000

8 341 447

(6 765 293)

(2 153)

(23 965)

(26 118)

(3 164)

(320)

(321 675)

(3 373)

(127 337)

(455 869)

(186 811)

(26 733)

(50 000)

(164 834)

(20 000)

(345 209)

(558 936)

(23 008)

(9 646)

(1 385 178)

275 831

365

365

10 639

53 384

12 558

5 578

82 159

Medicines for Malaria Venture

Medicines for Malaria Venture

University of Cape Town, University of Vanderbilt

Monash University, SynMedChem

Treague Limited

GlaxoSmithKline plc.

DNDi, TB Alliance

Institut Pasteur, Cambodia

Syngene

Ejkman Institute,University of Indonesia, ALERTAsia

Ifakara Health Institute

Medicines for Malaria Venture, Swiss TPH, Centre Suisse de Recherche Scientifique en Côte d’Ivoire

Queensland Institute of Medical Research

Swiss Bioquant

Syngene

Monash University

Swiss TPH

GlaxoSmithKline plc.

UC San Diego, School of Medicine

UC San Diego, School of Medicine

chEMBL

Council for Scientific and Industrial Research

TropIQ, the Netherlands

Imperial College London

University of Columbia

Eskitis Institute for Cell and Molecular Therapies, Griffith University, Queensland Institute of Medical Research

SUNY Upstate Medical University

UC San Diego, School of Medicine

Menzies, School of Medical Research

AFRIMS, Bangkok, Thailand

University of Notre Dame

GlaxoSmithKline plc.

University of Cape Town

Ejkman Institute, Indonesian Army

Mahidol-Oxford University Tropical Medicine Research Unit

GlaxoSmithKline plc.

Shin Poong Pharmaceutical Co. Ltd., University of Iowa

Sigma-Tau Industrie Farmaceutiche Riunite, Italy

Novartis Pharma AG

Pfizer Limited, London School of Hygiene & Tropical Medicine, Queensland Institute of Medical Research


6 | Financial view

7. PROJECT GRANTS (CONTINUED) Awarded 2013 (USD)

Introduction of New Product/ Oversee Launched Product

Final Allocation 2013 (USD)

Paid 2013 (USD)

Related to 2013 Paid in 2014 (USD)

3 768 107

2 126 087

1 881 175

244 912

218 772

218 772

211 957

6 815

28 056

28 056

27 299

757

1

Policy Revision

2

Eurartesim®

3

Pyramax®

188

188

188

4

Injectable Artesunate – General

121 280

121 280

121 229

52

5

Injectable Artesunate – Public Sector

819 210

698 892

660 780

38 113

6

AZ-CQ

181 649

181 649

15 871

165 778

7

Seasonal Malaria Chemoprevention

115 461

115 461

84 004

31 457

8

Product Readiness – Packaging and Communications Materials

10 364

10 364

10 364

9

Prepaid 2013 for 2014 (USD)

1 642 020 Medicines for Malaria Venture Imperial College London, Sigma-Tau Industrie Farmaceutiche Riunite, Italy Medicines for Malaria Venture Medicines for Malaria Venture 120 317

West Africa Roll Back Malaria Network (WARN) Medicines for Malaria Venture

Improving Severe Malaria Outcomes

2 273 127

751 424

749 483

1 941

1 521 703

1 008 028

588 862

461 315

127 547

419 166

40 565

40 565

40 565

10

Vivax – Market Research to Support Tafenoqine

11

Vivax – Strategy Development

681 261

270 764

169 064

101 700

410 497

12

India Comprehensive Case Management Pilot

286 201

277 532

251 685

25 847

8 669

Gather & Generate Information

346 068

346 068

305 366

40 702

Market Intelligence – General

189 638

189 638

149 876

39 762

14

Market Volumes (Market Size & Segmentation)

156 430

156 430

155 490

940

New projects/pilots

684 874

684 874

585 130

99 744

979

979

979

77 510

77 510

74 155

3 355 96 389

16

Oilsearch

17

Newcrest Alliance

264 723

264 723

168 334

18

SMS for Life – Tanzania

341 662

341 662

341 662

Access Events & Misc. Project Costs

277 773

275 273

240 144

19

Events and Conferences

20

Miscellaneous TOTAL

India National Institute of Malaria Research, NVBDCP Odisha

Government of Zambia, IMS Health

Medicines for Malaria Venture Oil Search Health Foundation Newcrest Mining Limited Government of Tanzania 35 129

2 500

56 302

56 302

56 084

218

218 972

184 060

34 912

2 500

6 084 850

4 021 164

3 473 130

548 034

2 063 686

Medicines for Malaria Venture

8. PERSONNEL EXPENSES

ects as specified above, directly managed and supervised by MMV.

World Health Organization

Medicines for Malaria Venture

221 472

Project grants represent the awards to the proj-

Clinton Health Access Initiative, Malaria Consortium GlaxoSmithKline Services

13

Interactive Map Tool – WHO GMP

Clinton Health Access Initiative, Swiss TPH London School of Hygiene & Tropical Medicine, Pfizer

Input to R&D

15

Project Partners

PNG Industry Malaria Initiative (PIMI), World Health Organization

The occupational benefits are provided by a collective foundation, Profond, according to a defined

There were 54 employees at 31 December 2013

contribution benefit plan: investment yield has no

(2012: 54), excluding temporary staff members.

impact on premiums; the employer does not guar-

Project-related variable expenditures include all

antee the benefit amount. The plan is funded by

legal advice/services for contract negotiations

The pension plan covers all employees for death

(IPR), organization and travel for project meet-

and disability benefits. Cover for retirement bene-

ings/reviews, MMV scientific personnel compen-

fits begins in the year following each employee’s

sation and various scientific project consultan-

24th birthday. The retirement pension is based on

cies. Expenditure for this MMV support totalled

the level of the retirement credits, the interest rate

USD 12,894,036 and USD 11,881,862 in 2013

to be credited and the conversion rate to be ap-

and 2012, respectively.

plied at retirement age. Risk benefits are related

the contribution of MMV and the employees.

to pensionable salary. Project reimbursements receivable Pension Plan Statistics 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.

48

Capital Ratio (%) Economic Part of the Entity as of 1 January 2013 Economic Part of the Entity as of 31 December 2013 Occupational Benefits Included in Personnel Expenditures Pension Fund Liability

2013 USD 104.7 – – 1 902 906 2 821

2012 USD 97.5 – – 1 876 741 3 330


9. OTHER INCOME AND OTHER EXPENSES OTHER INCOME Project reimbursements (see Note 7) Other OTHER INCOME OTHER EXPENSES Allocation to bad debt provision OTHER EXPENSES

2013 USD 315 214 781 215 096

2012 USD 11 597 351 957 363 554

2013 USD (27 947) (27 947)

2012 USD (14 879) (14 879)

10. FOREIGN CURRENCY TRANSLATION DIFFERENCES FOR FOREIGN OPERATIONS FOREIGN EXCHANGE GAIN/(LOSS) Exchange gain/(loss) from CHF Exchange gain from EUR Exchange gain from GBP Exchange gain/(loss) from UGX Exchange gain/(loss) from AUD FOREIGN EXCHANGE GAIN

2013 USD 51 363 9 466 237 992 3 (123 265) 175 559

2012 USD (4 622) 33 881 87 262 (33) 120 116 608

2013 USD 846 666 2 900 918 – 3 747 584

2012 USD 798 129 3 165 703 378 551 4 342 383

11. LEASES Non-cancellable operating lease rentals are payable as follows:

Less than 1 year Between 1 and 5 years More than 5 years TOTAL

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 2013, USD 831,881 were recognized as an expense in the Consolidated Statement of Comprehensive Income in respect of operating leases (2012: USD 813,192).

12. CONTINGENT ASSETS As per current contractual agreements, and depending on satisfactory reporting to donors, contingent assets related to donations are as follows:

Less than 1 year Between 1 and 5 years More than 5 years TOTAL

2013 USD 66 715 000 189 524 000 – 256 239 000

2012 USD 35 408 000 34,077 000 – 69 485 000

49


6 | Financial view

13. RELATED PARTIES

be considered as related parties. However, MMV

15. GUARANTEES

management considers that their presence in the MMV has a related party relationship with its

foundation council does not affect the nature of

Guarantees concern office rental only and are re-

board members, executive officers and MMV

the relation between MMV and these donors.

coverable on vacating the premises subject to the

North America Inc.

Therefore, all MMV donors have been considered

prevailing contracts.

third parties. These figures represent amounts effectively paid

14. FINANCIAL RISK MANAGEMENT

16. CAPITAL COMMITMENTS AND CONTINGENCIES

Expenditure, External Relations and Advoca-

The foundation council has overall responsibility

MMV encounters certain risks and uncertainties

cy-Related Variable Expenditure and Staff-Relat-

for organizing and supervising risk management.

in conducting its affairs. These risks and uncer-

ed Benefits/Compensation in the Consolidated

The Audit Committee monitors managementâ&#x20AC;&#x2122;s

tainties have financial statement implications. In

Statement of Comprehensive Income.

approach to risk management in compliance

all instances, these have been considered in the

with

and

consolidated financial statements, despite the

Board members serve on a voluntary basis and

procedures and verifies that risks are managed

fact that the outcomes of these uncertainties

receive no remuneration. They are compensated

appropriately in light of the current risks faced by

cannot be predicted with absolute certainty. Man-

for travel and accommodation for participation in

the organization. Based on a risk identification

agement has concluded that provisions for these

board meetings and receive a per diem allowance

carried out periodically, MMVâ&#x20AC;&#x2122;s essential risks

risks are appropriate, and any adverse resolution

to cover incidental expenses during these events.

are assessed in respect of likelihood and impact

of these uncertainties will not have a material

and documented in a risk analysis report. The

impact on the financial position or results of the

management has the responsibility to monitor

foundation.

to related parties in 2013 and 2012. Total remuneration expense is included in Project-Related Variable Expenditure, Access-Related Variable

BOARD MEMBERS Board members and meetings

2013

2012

USD

USD

158 789

373 634

the

organizationâ&#x20AC;&#x2122;s

principles

and supervise the substantial risks. For risks related to accounting principles and

17. SUBSEQUENT EVENTS

There were no loans to directors or executive of-

financial reporting, a risk analysis was carried

ficers for the years ended 31 December 2013 and

out in 2013. Controls in line with the Internal

No events have occurred between balance date

31 December 2012.

Control System have been defined and measures

and the date of this report that require adjustment

resulting from this have been implemented in

to, or disclosure in, these financial statements.

Some donors are represented on the foundation

order to minimize the risks related to accounting

council. Given the foregoing, these donors could

principles and financial reporting.

50


REPORT OF THE AUDITORS TO THE BOARD OF MMV

51


7

Behind the scenes MMV Board Column 1

Column 2

Mr Ray Chambers Chairman of MMV Board; Special Envoy for Financing of the HealthRelated Millennium Development Goals; Co-Founder of Malaria No More

Dr Fatoumata Nafo-TraorĂŠ Executive Director, Roll Back Malaria Partnership, Switzerland

Dr Pedro Alonso Director, Barcelona Institute for Global Health (ISGlobal), Hospital Clinic-University of Barcelona, Spain

Dr David Brandling-Bennett Senior Advisor, Malaria, Bill & Melinda Gates Foundation, USA

Dr Ernest Darkoh Chairman & Founding Partner, BroadReach Healthcare, South Africa

Prof. Michael Ferguson Dean of Research and Professor of Molecular Parasitology, University of Dundee, Scotland

Dr Robert Newman Managing Director, Policy & Performance, GAVI Alliance, Switzerland

Dr David Reddy CEO, MMV, Switzerland

Dr Dennis Schmatz Former Vice President, Head of Tsukuba Research Institute, Merck-Banyu Research Laboratories, Japan; President of the Board of North America Inc.; Co-Chairman MMV ESAC (Discovery)

Mr Per Wold-Olsen Former President of Human Health Intercontinental Region, Merck & Co., Inc.; former Member of Merckâ&#x20AC;&#x2122;s Management Committee, Denmark

Dr Winston Gutteridge Former Chief, Product R&D, Special Programme for Research and Training in Tropical Diseases, World Health Organization, Switzerland

MMV North America Inc. Board Dr Dennis Schmatz, President of the Board of North America Inc.; Co-Chairman, MMV ESAC (Discovery); former Vice-President, Head of Tsukuba Research Institute, Merck-Banyu Research Laboratories, Japan

52

Dr David Bowen, Independent Advisor, USA Mr Ray Chambers, Chairman of MMV Board; Special Envoy for Financing of the HealthRelated Millennium Development Goals; Co-Founder of Malaria No More

Dr David Reddy, CEO, MMV, Switzerland Ms Wendy Taylor, Director, Center for Accelerating Innovation and Impact at USAID, USA


Expert Scientific Advisory Committee (ESAC) Dr David McGibney, Co-Chairman MMV ESAC (Development); Pharmaceutical Research and Development Expert; Consultant Pharmaceutical Physician Dr Dennis Schmatz, Co-Chairman MMV ESAC (Discovery); former Vice President, Head of Tsukuba Research Institute, MerckBanyu Research Laboratories, Japan Dr Salim Abdullah, Director, Ifakara Health Institute, Tanzania Dr Aileen Allsop Dr Simon Campbell, Chemist; former Senior Vice President, Worldwide Discovery and Medicinal R&D, Europe, Pfizer; (founding Chairman of ESAC 1999–2003) Prof. Kelly Chibale, Founder and Director, University of Cape Town, Drug Discovery and Development Centre (H3-D), South Africa Dr Robert Clay, Vice President Regulatory Affairs, Oncology and Infection, AstraZeneca, UK Prof. Simon Croft, Professor of Parasitology and Head of the Department of Infectious and Tropical Diseases, LSHTM, UK Prof. Umberto D’Alessandro, Theme Leader Disease Control and Elimination, Medical Research Council, Gambia Prof. Ogobara Doumbo, Director, Malaria Research and Training Center, Bamako, Mali

Dr Michael Dunne, Chief Medical Officer, Durata Therapeutics, USA Dr R Kip Guy, Department of Chemical Biology and Therapeutics, St Jude Children’s Research Hospital, USA Dr Kasturi Haldar, Rev. Julius Nieuwland, C.S.C. Professor of Biological Sciences, Director of Center for Rare and Neglected Diseases, University of Notre Dame, USA Dr Tran Tinh Hien, Deputy Director, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam Dr Trevor Laird, Managing Director/Owner, Scientific Update, UK Prof. John Lambert, Chief Medical Officer, Global Head Medical Affairs and Consulting, PAREXEL International, UK Dr Michael Makanga, Director South–South Cooperation and Head of Africa Office, European and Developing Countries Clinical Trials Partnership, South Africa Dr Christine Manyando, Head of Public Health Department, Tropical Diseases Research Centre, Ndola, Zambia Dr George K Mooney, KGM Pharma Consulting LLC, USA Prof. François Nosten, MD; Director, Shoklo Malaria Research Unit, part of the Wellcome Trust–Mahidol–Oxford University Tropical Medicine Research Programme, Thailand

Dr Bernhards Ogutu, Researcher, Kenya Medical Research Institute, Kenya Dr Paul Reider, Pharmaceutical Specialist and Lecturer, Department of Chemistry, Princeton Universtiy, USA Dr David Roberts, Independent Scientific Consultant, Congleton, UK Dr Peter Siegl, Director, Siegl Pharma Consulting LLC, USA Dr Per Sjoberg, Partner, Eureda, Sweden Prof. Dennis Smith, Former Vice President, PGRD, Pfizer, UK Prof. Terrie Taylor, MD and Distinguished Professor, University of Michigan, USA Dr Neena Valecha, MD; Director, National Institute of Malaria Research, New Delhi, India Prof. Steve Ward, Walter Myers Professor of Parasitology, Liverpool School of Tropical Medicine, UK Dr Thomas Wellems, Chief, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, USA Dr Mike Witty, Chairman, Global Alliance for Livestock Veterinary Medicines, UK 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; MD; Director, National Institute of Malaria Research, New Delhi, India Ms Valentina Buj, Health Specialist (Malaria Partnerships), UNICEF, USA Dr Elizabeth Chizema, Head of Research, Ministry of Health, Zambia Dr Graciela Diap, Associate Staff of DNDi and FACT Medical Coordinator, Spain Dr Alexander Dodoo, Head, Centre for Tropical Clinical Pharmacology & Therapeutics (CTCPT), Ghana

Dr Gunther Faber, Chairman, One Family Health, UK Dr Douglas Lungu, Hospital Director, Daeyang Luke Hospital, Malawi Dr David McGibney, Pharmaceutical Research and Development Expert; Consultant Pharmaceutical Physician; Co-Chairman MMV ESAC (Development) Prof. Ric Price, Associate Professor, Menzies School of Health Research, Darwin, Australia Ms Melanie Renshaw, Chief Technical Advisor, African Leader’s Malaria Alliance, Kenya Dr Claude Emile Rwagacondo, Coordinator of West Africa Roll Back Malaria Network (WARN), Senegal

Dr G S Sonal, Additional Director and Head of Malaria Division of the National Vector Borne Disease Control Programme (NVBDCP), India Dr Richard Steketee, MD, MPH, 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, Coordinator of Market Dynamics at UNITAID, Switzerland Dr Hashim Yusufu, Deputy Director, National Agency for Food and Drug Administration, Nigeria

Sir Colin Dollery, Senior Consultant, GlaxoSmithKline Research and Development, UK Dr Neil Garbet, Independent Consultant Pharmaceutical Physician and Consulting Partner to Kinapse Ltd, UK

Dr David McGibney, Pharmaceutical research and development expert; Consultant Pharmaceutical Physician; Co-Chairman MMV ESAC (Development)

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

53


7 | Behind the scenes

MMV staff at the end of February 2014

Marc Adamy Director, Product Development

Andrea Buscaglia Chief Financial Officer

Christina do Paço External Relations Officer

Nada Araeipour Business Development Manager

Brice Campo Associate Director, Drug Discovery

Matthew Doherty Manager, Donor and Stakeholder Relations

Adam Aspinall Director, Product Strategy and Management

Stéphanie Cherbuin Product Development Coordinator and Archivist

Cristina Donini Director, Translational Medicine

Mark Baker Associate Director, Translational Medicine Jaya Banerji Director, Advocacy and Communications Lidiya Bebrevska Associate Director, Translational Medicine Soazig Bertrand Accounting and Finance Officer Grégory Bonnaud Finance Director Isabelle Borghini-Fuhrer Director, Product Development Emilie Burlot Project Coordinator, Drug Discovery Jeremy Burrows Vice President, Head of Drug Discovery

54

Marion Colombani Senior Legal Officer Marie-Ange Coustets Roustan Finance Assistant Maud Couturier Strategic Meetings Officer Gelavizh Daghigh Office Administrator

Stephan Duparc Chief Medical Officer Mélanie Dupuy Junior Financial Controller Sylvie Fonteilles-Drabek Executive Vice President, Head of Legal Sandrine Friedli Cela Senior Legal Officer

Youcef Dahmane IT Support Technician

Penny Grewal Daumerie Director, Access and Delivery Asia & Latin America

Helen Demarest Associate Director, Clinical Operations

Roberto Hanania Senior Legal Officer

Xavier Ding Research Scientist

Joan Herbert Director, Business Development

Heidi Divecha R&D Administrative Officer

Pierre Hugo Director, Access and Delivery Africa


Defeating Malaria Together

George Jagoe Executive Vice President, Access & Product Management

Maud Majeres Lugand Project Officer, Access & Product Management

Sonia Kabuguza Administrative Assistant

Neil McCarthy Director, External Relations

Alexis Kamdjou Country and Procurement Liaison Manager

Aleksandra Misiorowska Associate Director, Product Management

Franziska Karyabwite Vice President, Head of Human Resources

Jörg Möhrle Head of Translational Medicine

Wiweka Kaszubska Vice President, Head of Product Development

Claude Oeuvray Director, Portfolio Management

Sophie Kilisky Human Resources Generalist

Alicja Poczatenko Legal Officer

Coline Legrand Project Coordinator, Drug Discovery

Elizabeth Poll Editor and Publications Officer

Didier Leroy Director, Drug Discovery

Anya Ramalho Vice President, Head of Business Development

Andrea Lucard Executive Vice President, External Relations Adrienne MacDonald Online Communications Officer Fiona Macintyre Director, Clinical Development

Elena Ramos Human Resources Coordinator David Reddy Chief Executive Officer (CEO) Mélanie Rouillier Project Coordinator, Drug Discovery

Thomas Rückle Director, Translational Medicine Binetou Sané External Relations Coordinator Thomas Spangenberg Research Scientist Ricarda Steele Junior Event Coordinator Tareq Sunderji Legal Coordinator Yuko Takase Finance Officer Philippe Terbois Travel Coordinator Simona Valigova Junior Legal Officer David Waterson Director, Drug Discovery Helen Weir Personal Assistant to the CEO Tim Wells Chief Scientific Officer (CSO) Paul Willis Director, Drug Discovery

55


MMV is grateful for the support in 2013 from the following institutional donors:

National Institutes of Health (NIH/NIAID)

MMV is also grateful for the support received from private individuals

Editors Designer Printer Lithograph Photographs

Elizabeth Poll & Jaya Banerji, MMV ComStone - Pierre Chassany, Geneva, Switzerland Atar Roto Presse SA, Geneva, Switzerland Catherine Vogt, Carouge, Switzerland Anna Wang* (p. 7), Ben Moldenhauer (pp. 12 & 17), Benedict Campbell, Wellcome Images (p. 26b), BMC St Jude (p. 24), Christine Manyando (p. 19 b & c), Creative commons, Manta Ray Media (p. 21b), David Greyo* (p. 10), Fabian Biasio* (pp. 14b & 21a), Feliciano Monti* (p. 4), General Reference Hospital, Kimpese district, DRC (p. 16), Jaya Banerji (p. 15a), Kathleen Monroe* (p. 37), Konstantin Ikonomidis* (p. 22), Madleina Zilaba* (p. 20), Massachusetts Institute of Technology (p. 29a, b, c), Menzies School of Health Research and Charles Darwin University (p. 28a), Merck Serono (p. 6), Ministry of Health & Family Welfare, Odisha (p. 15b), MMV (pp. 5, 19, 26a, 31a, 31b, 32 & 35), National Malaria Control Programme, Ghana (p. 13), Neil Palmer/CIAT for CIFOR used under a Creative Commons license © 2011 (CC BY-NC-ND 2.0) (p. 31c), Nicolas Spuhler (pp. 54 & 55), Olga Zavialova* (p. 28b), QIMR Berghofer (p. 27), Roll Back Malaria (p. 10), Sandipan Majumdar* (p. 49), Sarah Hoibak* (front cover), Sumon Yusuf* (p. 18), Tejeda Pedro* (p. 2), Todd Jennings* (back cover), University of Science, Techniques and Technologies of Bamako, Mali, (p. 14a) & University of Sydney (p. 34). * Photograph from Swiss Malaria Group photo contest 2013 ‘Malaria: The BIG Picture’

International Centre Cointrin Route de Pré-Bois 20 PO Box 1826 1215 Geneva 15 Switzerland

W NE

Tel. +41 22 555 03 00 Fax +41 22 555 03 69 info@mmv.org www.mmv.org


MMV Annual Report 2013  

The report includes interviews with MMV's partners and scientists about our work to research and deliver new medicines to support the long w...

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