2 0 1 MMV ANNUAL REPORT

Transcription

2
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MMV ANNUAL REPORT
Medicines for Malaria Venture is a not-for-profit foundation dedicated to
reducing the burden of malaria in disease endemic countries by discovering,
developing and delivering new affordable anti-malarials through effective
public-private partnerships.
CONTENTS
1
Joint Statement by the Chair of the Board
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and the Chief Executive
2
The Maturation of Medicines for Malaria within
the Global Context
3
Building MMV’s Portfolio for Future Expansion
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4
Drug Discovery and
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Drug Development Projects
5
The Organisation
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6
Financial Information
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Our vision is a world in which affordable drugs will help eliminate the
devastating effects of malaria and help protect the children, pregnant
women, and vulnerable workers of developing countries from this
terrible disease.
1
JOINT STATEMENT
BY THE CHAIR OF
THE BOARD AND THE
CHIEF EXECUTIVE
In our report last year we focused
anti-malarial medicines. We also
on the burden of malaria on the
recognise that even where relevant
lives of people living in developing
commercial R&D occurs, for example
countries and on MMV’s vision:
for the modestly sized travellers’
a world in which affordable drugs
market, little from its output
will help eliminate this scourge and
eventually goes to the poor in
protect children, pregnant women,
endemic countries. The reality is
and vulnerable migrant workers.
that both the R&D value-chain and
Integral to this vision is the under-
subsequent so-called “access” issues
standing that success in combating a
can be very complex and intimidating.
disease as complex and multi-faceted
It would be as foolish to pretend
as malaria requires many coordinated
that the problem has been fully
public health interventions, in addition
addressed through public-private
to safe and effective drugs.
partnerships, as it is to point a finger
of blame at any one sector.
We are also well aware of the history
of over-promise and under-delivery
These caveats notwithstanding, what
associated with some malaria control
can be said even after only a short
programmes in the past. Bearing
period of MMV’s existence, is that
this history in mind, we are neither
the central partnership concept that
tempted to promise more than is
sustains MMV’s operations does work
the spider against malaria.
possible nor to overstate our
better than most expected. Our
Often applied as a plaster,
achievements. What then have been
experience is that we have success-
the achievements in MMV’s first
fully configured the rather imprecise
full year of operation?
though widely accepted wisdom,
“In Western England up until
well into the 19th century
many people continued to believe
in the curative powers of
the spiders were also sometimes
ingested alive in a pat of butter
of the benefits of public-private
or submerged in a spoonful
of English treacle.”
We have always been passionate
partnerships into a specific template
advocates of public-private partner-
that actually functions to significantly
ships as a strategy to counter the
stimulate leading edge drug R&D.
lack of commercial R&D for new
This achievement is very clear from
4
the scientific section of this report.
it against a detailed business plan
programmes from developing and
size, decrease the percentage spent
Critical to this achievement is the
and completed the first part of the
particularly from malaria endemic
on Geneva-based operations and at
fact that we have real pharmaceutical
plan successfully, we are now focusing
countries.
the same time increase our operational
partners – several are at the top of
on fine-tuning and scaling-up the
the big Pharma R&D productivity
operation. This will involve in the first
Our newly established “International
with the close involvement and
rankings. They are real net contribu-
instance a major updating of the
Operations” office in Delhi will thus
counsel from our donors, stakeholders
tors to the complex set of human
business plan, which is targeted for
focus on engaging the science base
and professional advisors.
skills and technological resources
completion in Q3/4 2002.
and the industry of these countries
that need to be marshalled for state
5
reserves. All of this has been possible
– but only where these resources
Fundraising is always part of the
of the art pharmaceutical R&D to
Many enterprises falter at this
already exist and can contribute
landscape of not-for-profit organisa-
be possible. The size of the anti-
crucial “mezzanine” stage of their
to our vision without the need for
tions like MMV. We believe that for
malarial portfolio we now manage
development. Early success can lead
priming investments. It is in this
the process to be effective – and it
is the largest assembled since the
to overconfidence with a subsequent
context that we recently signed a
will have to be for us to reach the
Second World War. It is also the first
overcommitment of human and
Memorandum of Understanding
targets outlined in our business plan
ever specifically targeted at the poor
financial resources that cannot
with the Indian Council for Scientific
– it will require the participation not
living in the approximately ninety
in the end be sustained. We will be
and Industrial Research (CSIR),
only of MMV management but of all
disease endemic countries. MMV’s
very careful not to do this.
one of the world’s largest R&D
stakeholders and donors.
contractual relationships with our
Nevertheless, it is clear that we
organisations with a long history
pharmaceutical and academic
must now begin to scale-up in order
of interest in malaria R&D. We
In concluding our statement last
partners are structured as creative
to achieve the critical mass and
are also particularly delighted that
year we made the point that our
win-win agreements. Although each
portfolio size that will allow us to
Dr. R A Mashelkar FRS, the Director
primary goal during the next several
is unique, MMV always gets free and
deliver our target of registering one
General of CSIR, has agreed to join
years was to create an organisation
unfettered access to the key research
new anti-malarial drug every five
MMV’s Board of Directors.
capable of delivering MMV’s vision in
outputs, including rights to intellectual
years. Scaling-up for us involves not
property within our field of interest.
only a desire to increase the quantity
Finally, scaling-up also involves
goal has not changed but in reviewing
and quality of the R&D we support;
an increased focus over the next
the detail of this report we feel that
What is particularly pleasing in
we hope over the next several years
several years on efficient financial
the goal is not only achievable but
reporting these achievements is that
to approximately double the size
management and on effective
well on track.
they are beginning to be widely
of our portfolio and to apply tried
fundraising. As is clear from the
recognised. Even erstwhile critics of
and tested portfolio management
financial section of this report, we
the partnership concept who imag-
techniques to it. It also implies some
have in 2001 both managed to
ined that there were irreconcilable
qualitative changes including a
increase our R&D spend and portfolio
differences between our public-health
broadening of the malaria indications
remit and the needs of our pharma-
we hope to target. Additionally our
ceutical partners are largely
current portfolio, perhaps not
conceding that we must be doing
surprisingly, originates mainly from
something right. Indeed many are
developed countries where relevant
now seeking to work with us or
R&D is largely focused and where
Dame Bridget Ogilvie
Dr. Christopher Hentschel
to replicate the template we have
most of our partners are located. We
Chair
Chief Executive Officer
developed for other neglected
now hope, without compromise to
Medicines for Malaria Venture
diseases. Having established the
quality, to broaden the provenance
template, committed to executing
and scope of this R&D to include
a sustainable manner. That strategic
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“ Malaria research outlays are perhaps $ 100 million, or $2.20 per
DALY (disability-adjusted life years). Thus, the malaria R& D per DALY
is around one-twentieth of the global average. It is notable and disturbing
that the premier public-private partnership for developing new malaria
drugs, the Medicines for Malaria Venture ( MMV ), currently disburses
less than $ 10 million per year in funding, and is so limited in funding
that it currently aims for only $30 million per year by 2004.”
( p.79, “ The Macroeconomic Report on Health” , WHO, 2002 ).
2
THE MATURATION OF
MEDICINES FOR MALARIA
WITHIN THE GLOBAL
CONTEXT
Malaria : The Ignored Killer
The year 2001 ended with global
community to support health inter-
attention becoming increasingly
ventions, including R&D that targets
receptive to the problem of neglected
the very poor. The Commission
diseases in developing countries
argues: “With globalization on trial
and culminated in the creation of the
as never before, the world must
Geneva-based Global Fund to fight
succeed in achieving its solemn
AIDS, tuberculosis and malaria. The
commitments to reduce poverty and
concept for such a fund was initially
improve health. The resources
raised at the G8 Summit in Okinawa
– human, scientific, and financial –
in 2000. It was then endorsed at the
exist to succeed, but must now be
UN General Assembly Special
mobilized. As the world embarks on
Session on HIV/AIDS in June 2001
a heightened struggle against the
and again at the G8 Summit in
evils of terrorism, it is all the more
Genoa in July 2001.
important that the world simultaneously commit itself to sustaining
2001 also saw the relationship
millions of lives through peaceful
between global health and economic
means as well, using the best of
ever developed, was late to be
growth highlighted in the report of
modern science and technology and
accepted because it was long
the Commission on Macroeconomics
the enormous wealth of the rich
considered too toxic. It finally
and Health entitled “Macroeconomics
countries. This would be an effort
became recognised as an effective
and Health: Investing in Health
that would inspire and unite peoples
treatment when it was adopted as
for Economic Development”. The
all over the world”.
“Chloroquine, one of the most
effective synthetic anti-malarials
a standard anti-malarial for
report, authored by a group of
the United States Army.”
eminent economists headed by
Harvard’s Professor Jeffrey Sachs,
provides detailed analysis and
economic arguments as to why it
is in the interest of the global
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3
BUILDING MMV’S
PORTFOLIO FOR
FUTURE EXPANSION
In last year’s annual report, MMV’s
This consolidation has taken
Robert Ridley
first, the scientific section focused
several aspects:
Chief Scientific Officer
on the medical need for anti-malarial
• The formal review by MMV’s
Solomon Nwaka
drugs, the scientific opportunity that
Expert Scientific Advisory
Scientific Officer (Drug Discovery)
exists for these needs to be met, and
Committee of the three projects
Lise Riopel
the portfolio building process that
already operational
Scientific Officer (Clinical Development)
was under way at MMV to deliver on
• The establishment of agreed
its mission. At that time, three pro-
project plans for the newly
jects had been initiated and could be
selected projects
described in detail, all of them dis-
“It has been suggested that
officers to provide project
many of them at the developmental
management support to MMV
stage, had been selected for funding,
projects
• The initiation of a third round
these projects into the portfolio
of project selection, to be
represents a major advance in the
completed by early 2003, and
level of MMV’s scientific operations
the identification of potential
and its chances of future success.
new projects for consideration
in that process.
Oliver Cromwell, who died of malaria
in 1658, could have been saved
The past year has essentially been
one of portfolio consolidation, rather
The progress within the project
tree however none of his physicians
than growth and further project
portfolio itself is illustrated next page.
dared prescribe it. The bark from the
selection. MMV has had to work
by the powder from the cinchona
hard to put in place both personnel
Some remarkable advances within
and procedures to manage what
individual projects occurred in 2001
is already perhaps the largest
– particularly noteworthy are :
time were suspicious of this
anti-malarial drug development
The University of Nebraska/Monash
“popish powder” and considered it
portfolio ever assembled by one
University/ Swiss Tropical Institute/
organisation.
Roche Synthetic Peroxide project
Peruvian cinchona tree had been
introduced to Europe by the Jesuits
and therefore most English at that
to be part of a larger plot to
spread Catholicism.”
Scientific Officer (Non-clinical Development)
• The hiring of three scientific
covery projects. Eight other projects,
but were not operational. Combining
David Ubben
(see page 17)
10
Exploratory
Projects
Discovery lead
identification
Discovery lead
optimisation
Dihydrofolate
Reductase
Lactate
Dehydrogenase
Inhibition
Cysteine
Proteinase
Inhibition
Transition
Phase 0
(preclinical)
Early
Stage Dev- Mid Stage
elopment Development
Late Stage
Development
Synthetic
peroxide
Dihydrofolate
Dehydrogenase
Heme
Polymerisation
Fatty acid
Biosynthesis
Inhibition
Protein Farnesyl
Transferase
Inhibition
product, or a single agent related
The pre-clinical data currently being
to the artemisinins, either as a
obtained in the MMV projects, for
semi-synthetic, or fully synthetic,
example in reproductive toxicology,
compound. This class of agents has
and the subsequent good clinical
received tremendous scientific
practice associated with MMV clinical
Semi-synthetic peroxide
Chlorproguanil / Dapsone /
Artesunate Combination
interest and validation over the last
regulatory studies, will also greatly
Improved Quinoline
Pyronaridine / Artesunate
Combination
decade and the science was ripe
assist in this process.
Improved antifolate
combination
for further exploitation. Increased
use of artemisinin derivatives to
Although the artemisinin related
treat malaria, often in poorly
projects have been highlighted this
financed healthcare systems, has
year, it should be stressed that MMV
led to an increased and urgent need
is significantly invested in other
to better understand and characterise
approaches including entirely novel
these drugs. In particular it is
molecular targets and we envisage
important to more fully define their
that these will start to play a larger
The GSK/University of Liverpool/
safety profile. Improved pharma-
role in our portfolio focus in the
compounds with enhanced longer
WHO project on the chlorproguanil
covigilance with currently used
coming years.
lasting activity than artemisinin
– dapsone – artesunate combination
therapies will help address this issue.
derivatives. These compounds could
has proceeded very well with
deliver improved drugs with shorter
pre-clinical safety studies almost
treatment times than those required
complete (see page 32)
for the artemisinin derivatives
• Assuming there are no untoward
Intravenous artemisinin
Projects initiated and under contract
Projects initiated, some funds disbursed and close to contract
Projects under contractual discussion
• The design and identification of
toxicity results this product should
There has been a quantum increase
page is taken. Moving in a clockwise
patent application, with ownership
also enter Phase I clinical trials
in our level of understanding of
direction around the figure, MMV’s
and rights to all anti-malarial
in 2003.
malaria biology in recent years. This
projects cover many of the areas
is the result of increased investment
highlighted in the figure:
• The submission of MMV’s first
applications residing with MMV.
A further patent application is
The Korea SP Pharm Inc./WHO
from many national and regional
likely within the year.
project on the pyronaridine –
scientific research agencies and
Projects on cytosolic drug targets
artesunate combination (see page 30)
research foundations, such as US
include : Antifolate inhibition,
• Rapid advancement into pre-clinical
National Institutes of Health,
including inhibitors of dihydrofolate
Wellcome Trust, Burroughs-Wellcome
reductase
Fund, and the European Union.
• Chlorproguanil-dapsone-artesunate
The Bayer Project on Artemisone, a
semi-synthetic artemisinin derivative
with improved efficacy and reduced
studies, especially toxicology
• The establishment of appropriate
neurotoxicity characteristics com-
outsourced activities in both
Evidence of this is perhaps best
development project with GSK:
pared to the artemisinin derivatives
South Korea and elsewhere
illustrated by the revolution in malaria
chlorproguanil inhibits dihydrofolate
genomics – the completed genome
reductase; dapsone inhibits a folate
toxicity results this product should
will be published later in 2002.
pathway enzyme called dihy-
has been initiated within three
also enter Phase I studies by
An excellent overview of the current
dropteroate synthase (see page 32)
months of project selection
early 2003.
status of malaria research activities
(see page 27)
• A full scale pre-clinical programme
• Assuming there are no untoward
can be found in the recent Nature
• Phase I clinical studies are envisaged
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Scientific Opportunities for New Chemotherapeutic Approaches
th
• Dihydrofolate reductase inhibition
exploratory project with the
in 2003 if all goes well with
It is perhaps no accident that all the
Insight (Nature, February 7 , 2002
National Science and Technology
toxicological assessment.
highlighted projects this year involve
issue) which was co-sponsored by
Development Agency, Thailand
an artemisinin derivative combination
MMV and from which the figure next
(see page 25).
12
Cytosol
Lysosomal food vacuole
Drugs
Antifolates
New targets
Glycolysis (e.g. lactate
dehydrogenase)
Nucleotide biosynthesis
Drugs
Quinolines interact with
haem/haemozoin
Peroxides oxidoreductively
generate free radicals
•
•
•
•
Projects on apicoplast metabolism
drug discovery and development are
New targets
include : Inhibition of Type 2 Fatty
many-fold. They include the extensive
• Plasmepsin aspartic proteases
• Falcipain cysteine protease
Acid Biosynthesis
rise of drug resistance to many of the
• Enoyl-acyl-carrier protein reductase
commonly used anti-malarial drugs,
inhibition discovery project with
safety issues associated with some
Texas A & M University, Howard
drugs and difficulty in ensuring
•
Hughes Medical Institute and Jacobus
compliance for drugs that have a
•
•
Pharmaceuticals (see page 19).
more complicated dosage regimen.
•
Parasite plasma
membrane
New targets
Glusose
transport
Nutrient uptake
Na+/H+ antiport
Apicoplast
Mitochondrion
Drugs
Antibiotics inhibiting protein translation
(e.g. tetracycline and doxycycline)
New targets
Plastid DNA replication and transcription
Type 2 fatty acid biosynthesis
Non-mevalonate isoprenyl biosynthesis
(link to protein prenylation)
Drugs
Atovasquone inhibition of
cyt c reductase
New targets
•
•
•
•
•
In addition, the cost of certain drugs
Inhibition of protein isoprenylation
greatly risks their inclusion in
• Protein farnesyltransferase
national policies, especially in
inhibition discovery project with
Sub-Saharan Africa. The safety issues
University of Washington and
are of particular significance given
Yale University (see page 22).
the poor infrastructure of many
• (Dihydroorotate
healthcare systems in which malaria
dehydrogenase)
As stressed in last year’s report, the
is endemic and the resultant lack
medical needs driving anti-malarial
of supervision of drug use. This is of
Sites of drug action and new drug targets
Diagram of P. falciparum trophozoite residing in erythrocyte. Major organelles associated with
drug targets are highlighted, drawing attention both to sites of current anti-malarial drug
Drug
Main limitations
• Chloroquine
• Quinine
• Amodiaquine
• Mefloquine
• Halofantrine
• Resistance
• Compliance, safety, resistance
• Safety, resistance
• Artemisinins
• Compliance, (safety), (GMP), (cost)
action and new targets that are under investigation (taken from Ridley (2000) “Medical
need, scientific opportunity and the drive for anti-malarial drugs”, Nature 415, 686-693 and
reproduced with permission from Nature).
Glycolysis inhibition
Isoquine is an analogue of chloro-
• Lactate dehydrogenase inhibition
quine which interferes with
discovery project with GSK,
University of Bristol and London
heaemozoin formation (see page 31)
• Cysteine proteinase inhibition
School of Hygiene and Tropical
discovery project with GSK and
Medicine (see page 20).
University of California,
(arthemether, arteether, artesunate)
(safety), resistance, (cost)
• Safety, resistance, cost
Overview of current
anti-malarials
Drugs currently in use as anti-malarials
have many attributes, but also contain
certain liabilities that could be improved
• Sulphadoxine-pyrimethamine
• Resistance
• Atovasquone-proguanil
• Resistance potential, cost
• Lumefantrine-artemether
• (compliance), resistance potential, (cost)
upon by further drug discovery and
development.
San Francisco (see page 23).
Projects relating to the lysosomal
food vacuole include all the
Projects on mitochondrion related
particular concern for the two most
Uncomplicated malaria, where the
artemisinin projects already
metabolism include:
“at risk” groups of patients, namely
main issues relate to:
mentioned including the synthetic
Interference in nucleotide
very young children and pregnant
• Overcoming drug resistance
peroxides. In addition they include:
biosynthesis
women (see figure above).
• Ensuring a drug dosing regimen
Interference with hemoglobin
• Dihydroorotate dehydrogenase
degradation and haemozoin
exploratory project with University
It is helpful to divide malaria into
formation
of Leeds (see page 26).
several major sub-indications and to
• Isoquine development project with
13
that encourages good compliance
GSK and University of Liverpool.
• Low cost.
acknowledge that a different set of
Complicated or severe malaria
issues exists for each of these.
where the main issues relate to:
14
• Appropriate, stable formulations
MMV is making every effort to
there is a danger of generating
last resort and may be inappropriately
(intramuscular, intravenous or
address the issues of safety in
resistance to the few remaining
used under poor supervision. The
intra-rectal)
pregnancy early on in development.
drugs.
dilemma posed by this “balance“
• Rapidly acting drugs to bring
This is especially important as the
can be reduced significantly if new
current drug of choice for intermittent
Thus today, it may be inappropriate
drugs are developed that are config-
treatment in pregnancy is sulfadoxine-
to make certain drugs too easily
ured for easy and safe use and with
Plasmodium vivax malaria, for
pyrimethamine against which there is
available in an environment where
dosing regimens that ensure good
which drugs are needed that are
substantial resistance development.
the drugs are effectively drugs of
compliance.
active against both the blood and
There is an urgent need to address
liver stages of the disease, and
the current lack of effective
where the main issues relate to:
treatments for this indication.
about rapid recovery from coma.
Early diagnosis and prompt
treatment
• Overcoming drug resistance for
the blood stage of the disease
The MMV portfolio is already quite
• Superiority in safety to the only
comprehensive. However, it should
drug currently available to treat
be stressed that many projects are
the liver stage of the disease,
reaching the most risky stages of
primaquine.
the drug R&D process. That is, they
Goal:
Equity, reduce morbidity
and mortality
toxicological evaluation and an
main issues relate to:
assessment of their ability to generate
• Safety, especially a defined lack of
useable drug formulations. Several
Goal:
Reduce delay
resistance
Broad access to anti-malarials
Restrictive access to drugs
Emphasis on community and
household management
Emphasis on regulation and
control of drug use
Requires high sensibility
are about to engage in extensive
Malaria in pregnancy where the
Reduce evolution of drug
resistance
Requires high specificity
Malaria control
any foetal toxicity
• A profile that facilitates intermittent
may not survive the rigorous tests
ahead and we calculate that we still
treatment during pregnancy to
need to double our project portfolio
prevent women from contracting
to deliver on our mission to generate
serious disease.
one new anti-malarial every five years.
A balance has to be struck by malaria control programmes in locations where health
infrastructure is weak and a great amount of self-purchase and treatment of malaria occurs.
On the one hand there is a desire to encourage wide distribution of drugs for ease of access.
On the other there is a desire to ensure drugs are used only when needed and that they are
used appropriately to avoid the generation of drug resistance. The more options there
are for malaria treatment, the less acute this dilemma becomes and one can promote
For many of the sub-indications
Nevertheless, progress to date has
mentioned above, it is very difficult
been far better than we could have
to define how appropriate projects
predicted. With luck we hope that
are until they have progressed
this portfolio could indeed change
far into the drug discovery process,
the face of anti-malarial drug use in
or even have entered pre-clinical
the coming decades.
widespread use without fear that this will result in no malaria treatment being available
downstream.
or clinical development. It is
15
therefore not easy at the moment
The figure on the following page,
to state the specific relevance of
kindly provided by Tom Sukwa of
our projects for these indications.
WHO/AFRO, illustrates the issues
However, as more and more
facing those charged with malaria
projects are subjected to rigorous
control. On the one hand there is an
toxicological evaluation,
urgent need to make drugs widely
their potential will become more
available to ensure ease of access to
apparent.
treatment. However, if this is done
16
4
DRUG DISCOVERY
AND DRUG DEVELOPMENT
PROJECTS
DISCOVERY PROJECT 1
Synthetic Peroxide
Project description provided by Prof. Jonathan L. Vennerstrom
The objective of this project is
inexpensive, has high oral activity,
to identify an orally active low cost
and is devoid of neurotoxicity.
anti-malarial synthetic peroxide
more potent than any of the currently
At the outset of the project,
available semisynthetic artemisinins
we began with peroxides that had
with a treatment regimen of no more
excellent intrinsic potency against
than three days to ensure good
P. falciparum. Thus, our emphasis
compliance.
has been on identification
of peroxides with a combination of
“An old South Indian remedy
for malarial fever
was to embrace a bald-headed
Brahmin widow at dawn,
The suitability of the compounds
high oral activity in the P. berghei-
for non-oral formulations and their
infected malaria mouse model and
potential for prophylactic use will
a good pharmacokinetic/metabolic
be important secondary, but not
profile. Throughout this process,
essential, criteria. Our aim is to
we have explored structure activity
generate sufficient data by 2003
relationship (SAR) in sufficient
to allow for selection of a compound
detail to provide strong patent
to enter development.
protection.
Many synthetic anti-malarial
There have been a number of key
peroxides have been prepared, but
results and achievements to report
most suffer from low oral activity,
in 2001:
a defect shared in part by the semi-
• Several key synthetic peroxidic
imagining that one would thus
transfer the disease to her.”
synthetic artemisinins. Therefore,
intermediates were prepared on
a need exists to identify a new
a 100 mmol scale and subjected
peroxide anti-malarial agent, espe-
to further transformations that
cially one that is easily synthesised,
are to obtain target compounds
18
difficult or, in some cases, impossi-
and intravenous pharmacokinetic
DISCOVERY PROJECT 2
ble to obtain directly by our
studies in rats.
Anti-malarial drug development focused on inhibition of Plasmodium
standard peroxide-bond forming
• As shown in the figure below, one
peroxide development candidate
reaction.
structure activity of this class of
of action, but unlike artesunate,
This project proposes the develop-
inhibitor complexes, which will
compounds has been defined.
a long lasting anti-malarial effect.
ment of anti-malarial compounds
help develop the structure-activity
that target P. falciparum enoyl ACP
relationships of the compound series.
• In an exploratory toxicity study,
• Lead optimisation efforts have
Dr. Solomon Nwaka,
involved prospective estimation
rats were treated with doses of
reductase (ENR), a key enzyme in
P. falciparum and Mycobacterium
e-mail :
of log P and polar surface area
artesunate and three peroxides
the Fatty Acid Synthase II system
smegmatis will serve to assess
[email protected]
values for compounds, and this
up to 300 mg/kg/day for five
(FAS II).
whether resistance can be readily
has been effective in decreasing
consecutive days. Clinical laboratory
the previously limiting lipophilicity
investigations revealed minimal
Three chemical hits against this
of the peroxides. Furthermore,
and essentially reversible changes.
enzyme have been identified, two
Optimised leads will be subjected to
rapid metabolism screening of
In summary, at this stage there
of them from a high-throughput
pharmacokinetic and safety analyses
active peroxides using human, rat,
are no adverse toxicological
combinatorial library screen and
to screen for compounds suitable for
and mouse liver microsomes has
findings.
the third being triclosan, a known
pre-clinical and clinical evaluation.
successfully screened out
bacterial ENR inhibitor. These chemical
The absence of FASII in humans
compounds with high metabolic
structures provide the basis for lead
and the identification of specific
conversion rates. Those compounds
optimisation, with the most effective
inhibitors validate this pathway as
successfully passing the metabolism
inhibitors identified through a
an outstanding target for the
screen hurdle have been
combination of three screens.
development of new anti-malarial
DISCOVERY PROJECT 1
Synthetic peroxide
Principal Investigators and
Affiliations :
• Prof. Jonathan L. Vennerstrom
University of Nebraska
Medical Center, U.S.A.
• Dr. Yuxiang Dong
University of Nebraska
Medical Center, U.S.A.
• Dr. Reto Brun
drugs.
Swiss Tropical Institute,
Switzerland
100
• Prof. William N. Charman
Monash University,
Australia
5.8 days
17.8/18.5 days
MMV 1
artesunate
control
80
• Dr. Susan A. Charman
9.6 days
Monash University,
Australia
chloroquine
• Dr. Heinrich Urwyler
F. Hoffmann-LaRoche,
Switzerland
Funds allocated in 2001 :
Parasitemia (%)
F. Hoffmann-LaRoche,
Switzerland
60
DISCOVERY PROJECT 2
Anti-malarial drug development
focused on inhibition of
Plasmodium falciparum fatty
acid biosynthesis
Principal Investigators &
Affiliations :
• Dr. Jim Sacchettini
Texas A & M University, U.S.A.
• Dr. David Jacobus
Jacobus Phramaceuticals,
Princeton, New Jersey, U.S.A.
• Dr. William Jacobs
Optimisation has already begun
• Dr. Bernard Scorneaux
• Dr. Hugues Matile
selected in vitro.
progressed to oral bioavailability
Swiss Tropical Institute,
Switzerland
Albert Einstein College of
Medicine & Howard Hughes
Medical Institute,
New York, U.S.A.
with the synthesis of over twenty
In addition to investigating
triclosan analogs. Synthesised
P. falciparum enoyl ACP reductase,
compounds are being screened
significant progress has also been
using assays with purified and active
made on characterising other
P. falciparum ENR, whole-cell assays
enzymes in the fatty acid synthase
Albert Einstein College
of Medicine,
New York, U.S.A.
against P. falciparum asexual blood
type-II pathway (whose activities lie
Contract under negotiation
stage parasites propagated in vitro,
upstream of that of PfENR, also
and in vivo assays against P. berghei
known as fabI). The genes fabF, fabG
in mice. The P. berghei screen will
and fabH have been subcloned from
employ a recombinant parasite line
RT-PCR products and we are
in which the P. berghei gene encod-
now crystallizing recombinant,
ing ENR is being replaced by the
purified fabF.
• Dr. David Fidock
Contact at MMV:
40
22 days
mefloquine
20
MMV 2 >60 days
rigorous in vitro/in vivo relationship.
0
0
5
10
15
Time post infection (days)
infection
treatment
20
Dr. Solomon Nwaka
e-mail :
[email protected]
P. falciparum homolog, to establish a
$ 1’079’110
19
Project description provided by Dr. Jim Sacchettini
has, like artesunate, a rapid onset
• A clearer understanding of the
Contact at MMV:
falciparum fatty acid biosynthesis
The interest in this project is
to test whether other enzymes
25
Our lead optimisation process
represent valid chemotherapy
benefits from parallel elucidation
targets. The project is made
of the crystal structures of enzyme-
feasible by the combination of the
20
requisite chemical, biochemical,
this coordinated academic and
an inhibitor that specifically inhibits
sites and generate a pharmacophore
pharmaceutical, molecular
pharmaceutical effort.
plasmodia LDH alone. Fortunately,
– a generalised representation of the
we have obtained crystal structures
compound based on one-dimensional
of both human and Plasmodium
(physical and biological), two-dimen-
falciparum LDH and they demonstrate
sional (substructures) and three –
significant structural differences,
dimensional (charged groups,
implying the development of highly
hydrophobic groups, hydrogen bond
selective inhibitors should be feasible.
acceptors and donors) properties.
Initial identification of possible leads
Once the pharmacophore has been
has utilised a combined approach
assembled, compounds in the
incorporating high-throughput
database with similar properties
screening of over half a million
can be identified. This state of the
compounds, in silico screening on
art technique uses many weeks
millions more and structure-based
of computer time, but has enabled
design. From these studies we
the project team to identify
have identified several classes of
compounds that not only bind to the
compounds that selectively inhibit
enzyme, but also inhibit the growth
plasmodial LDH in preference to
of the parasite. Once lead compounds
human forms of the enzyme.
have been identified, the comple-
Crystallographic studies are being
mentary range of skills that are
used to visualise precisely how these
available across the three sites are
compounds bind within the active
brought into play to fully characterise
site of the target enzyme, and hence
the molecules: the activity against
direct further chemical modifications
the parasite is determined by the
of these molecules. These studies
parasitologists at LSHTM while
are, of course, complemented by
the crystallographers at Bristol
both in vitro and in vivo studies at
attempt to obtain the structure of
the London School of Hygiene and
the inhibitory complex formed with
Tropical Medicine using both normal
the target enzyme. This information
and drug resistant strains of
is then used by the bio-molecular
Plasmodia. In order to expand the
modellers to direct the design of
repertoire of possible inhibitory
new compounds that are synthesised
structures, we are also using com-
by the chemists at GSK. Central to
puters to interrogate a database
these studies is the availability of
containing the three dimensional
structural data describing the intimate
structures of over nine million
interactions of inhibitors with the
drug-like compounds.
target enzyme. The combination
and parasitological expertise in
PfENR with bound Triclosan
DISCOVERY PROJECT 3
Inhibitors of Plasmodium falciparum lactate dehydrogenase
as novel anti-malarials
Project description provided by Dr. Gus Cameron
This project team is developing
synthesis of ATP is driven by both
inhibitors of Plasmodium falciparum
glycolysis and the enzymes of the
Lactate Dehydrogenase as potential
citric acid cycle, Plasmodia instead
drugs for the treatment of uncompli-
rely on simple, fermentation-coupled
cated malaria. The aim is to identify
glycolysis. The key enzyme in this
compounds with efficacy against
process is lactate dehydrogenase
MDR Plasmodium, suitable for oral
(LDH), and compounds that inhibit
administration and well tolerated,
this enzyme have been shown to kill
fast acting and inexpensive.
the parasite. This enzyme forms the
target for this project. Humans also
ATP is the fundamental energy
have several forms of LDH
“currency” in most living organisms,
- although we do not rely so heavily
and needs to be constantly regener-
on their activity for our survival –
ated for growth and survival.
so one of the challenges the project
Whereas in most higher organisms
team must overcome is to develop
DISCOVERY PROJECT 3
Inhibitors of Plasmodium
falciparum lactate
dehydrogenase as novel
anti-malarials
Affiliations :
• Dr. Leo Brady
Principal Investigator,
Bristol University, U.K.
• Dr. F. Gómez de las Heras
Research Director,
GSK, U.K.
• Dr. Simon Croft
Principal Investigator,
London School of Hygiene
and Tropical Medicine, U.K.
• Dr. Gus Cameron
Project Manager,
Bristol University, U.K.
$ 289’825
Contact at MMV:
Dr. Solomon Nwaka
e-mail :
[email protected]
of complementary skills across the
21
These calculations use the known
project team has enabled us to make
structures of lead compounds that
good progress within a relatively
Photomicograph of infected erythrocytes labelled with mepacrine.
have been co-crystallised in the
short period of time.
C : cytoplasm, F: food vacuole
active site of LDH to identify contact
22
DISCOVERY PROJECT 4
P. falciparum Protein
Farnesyltransferase Inhibitors
as Drugs Against Malaria
Affiliations :
•
•
Prof. Wesley C. Van Voorhis
University of Washington,
Seattle WA, U.S.A.
Prof. Michael Gelb
University of Washington,
Seattle WA, U.S.A.
•
Prof. Andrew Hamilton
Yale University, U.S.A.
•
Schering Plough
Research Institute
DISCOVERY PROJECT 4
assistance of Christophe Verlinde
P. falciparum Protein Farnesyltransferase Inhibitors as
and Wim Hol (University of
promising compounds. Enzyme
Drugs Against Malaria
Washington) combined with parallel
inhibition studies will be comple-
Project description provided by Prof. Wesley C. Van Voorhis
organic synthesis for rapid
mented by evaluation of compound
preparation of lead compound
activities in the erythrocyte-based
• We hope to screen at least 500
The long-term objective of this
for structure determination. PFT
derivatives in the Gelb and Hamilton
culture assay and the P. berghei
research is to develop inhibitors
is a heterodimeric protein with
laboratories with attention to
malaria model in mice. If appropriate,
of P. falciparum protein
· and ‚ subunits. We have found
optimisation of pharmacokinetic
follow-up studies in a primate
farnesyltransferase (PfPFT) as
that the native PfPFT · and ‚ genes
properties of lead compounds
P. falciparum model (laboratories
drugs against malaria.
would not express in either E. coli
measured in the laboratory of
of Wesley Van Voorhis and
or in insect cells using baculovirus
S. Sebti (University of South
Fred Bruckner) and toxicology
PfPFT is an excellent candidate drug
constructs, probably because of
Florida).
studies will be initiated.
target for a number of reasons:
the high AT nature of plasmodium
• Inhibition of PFT is predicted to be
DNA and the resulting codon bias.
lethal to P. falciparum because
We have constructed completely
P. falciparum probably lacks an
synthetic PfPFT · and ‚ genes
enzyme called PGGT-1 that rescues
with optimal codon usage for
PFT-inhibited mammalian cells.
baculovirus and are in the midst
Consistent with this hypothesis,
of constructing baculoviruses for
preliminary evidence demonstrates
expression of these synthetic genes.
Protein Prenylation
that PFT inhibitors kill P. falciparum
rather than being cytostatic.
• The genes for PfPFT have been
identified.
• Discovery of lead PfPFT inhibitors
Proteins containing a C-terminal CaaX are first prenylated on the cysteine group. This is
followed by endoproteolytic removal of aaX tripeptide and methylation of ·-carboxyl group
of the prenylated cysteine. Shown on the left is the cysteine-attached 15-carbon farnesyl
group. Some proteins contain the 20-carbon geranylgeranyl group (right).
by screening compounds prepared
by medicinal chemists at BristolMyers Squibb and Schering Plough
• PfPFT is transcribed in erythrocytic
Research Institute as part of their
DISCOVERY PROJECT 5
forms of P. falciparum, and is thus
efforts to develop mammalian PFT
Development of falcipain inhibitors as anti-malarial drugs
Bristol-Myers Squibb
likely synthesised in the life cycle
inhibitors as anticancer drugs. We
Project description provided by Dr. Philip J. Rosenthal
stage that is the target of therapy.
will also test compounds prepared
•
• There is a good correlation with
in the labs of Profs. Andrew
Malaria parasites reside within red
cysteine protease inhibitors cured
some inhbitors of PfPFT between
Hamilton (Yale University) and
blood cells during the portion of
mice of otherwise lethal malaria
enzyme inhibition and P. falciparum
Michael Gelb (University of
their life cycle that is responsible for
infections. Thus, the falcipains offer
growth inhibition.
Washington). Some of these
clinical malaria. While inhabiting red
a validated drug target.
compounds show activity against
cells, the parasites take up and
of PfPFT can be found, and
P. falciparum infected red blood
degrade human hemoglobin as a key
An important current goal is
selective PfPFT inhibitors may
cells with an IC50 of <100 nM.
source of amino acids. A number of
the identification of safe and
increase the therapeutic window
Some of these compounds have
proteases participate in hemoglobin
effective falcipain inhibitors for
of PFT inhibitors for malaria
a >20-fold selectivity in growth
degradation, including cysteine-class
rigorous testing as potential
therapy.
inhibition of P. falciparum
proteases known as falcipains.
new anti-malarial drugs.
compared with mammalian cells.
Inhibitors of cysteine proteases
Contact at MMV:
Dr. Solomon Nwaka
• It is likely that selective inhibitors
e-mail :
[email protected]
Our goals for the first 2 years are:
• To express recombinant PfPFT for
23
screening potential inhibitors and
• Optimisation of lead compounds
blocked hemoglobin degradation and
Important progress since our
using computer-assisted structure-
development by cultured malaria
original application has included
based drug design with the
parasites. In addition, peptide
the following:
24
throughput screen is evaluating the
DISCOVERY PROJECT 6
orthologs from other species
activity of the entire GSK cysteine
Synthesis and Selection of Inhibitors of
were identified, enabling us to
protease inhibitor collection against
Malarial Dihydrofolate Reductase
better plan our activities for drug
recombinant falcipain-2, falcipain-3,
Project description provided by Prof. Yongyuth Yuthavong
discovery against cysteine proteases
and vinckepain-2. The full screen
would be more complex than
will be completed and data from it
The overall plan of the project is to
A major achievement in obtaining
initially anticipated.
analysed in the near future. At that
prepare recombinant P. falciparum
crystals of the enzyme, both in the
point, effective compounds will
dihydrofolate reductase (DHFR),
wild-type and double mutant
falcipain-2 and falcipain-3 were
be identified and collected, and
both in wild-type and mutant forms
(C59R+S108N) forms are available
expressed in a heterologous
they will then be evaluated for
responsible for drug resistance, to
of sufficient size and quality for X-ray
system, purified, and extensively
in vitro anti-malarial activity and
crystallize and obtain the structure
diffraction studies. As for active-site
characterised.
for pharmacokinetic properties.
of the enzyme through X-ray
inhibitors, we have designed and
Data from in vitro and pharmacoki-
diffraction and to design and screen
screened a number of compounds
and production of crystals of this
netic analyses will guide SAR
compounds likely to be effective
against the two types of mutants:
enzyme were achieved.
determinations and optimisation of
inhibitors for further development
one is the A16V+S108T and another
the inhibitors for activity against
as anti-malarials. We have achieved
comprises mutants containing S108N,
P. vinckei and P. berghei were
falcipains and cultured P. falciparum
the expression and purification of
single, double (C59R+S108N), triple
expressed, purified, and
parasites, and for pharmacokinetic
the wild-type, single (S108N), double
(N51I+ C59R+S108N or C59R+S108N
Principal Investigator and
Affiliation :
biochemically characterised,
properties.
(S108N+C59R and A16V+S108T),
+I164L) or quadruple (N51I+C59R+
• Prof. Yongyuth Yuthavong
triple (N51I+C59R+S108N and
S108N+I164L).
• Three falcipains and multiple
• The key P. falciparum targets
• High yield expression of falcipain-2
DISCOVERY PROJECT 5
Development of
falcipain inhibitors as
anti-malarial drugs
Affiliations :
•
•
•
Dr. Philip J. Rosenthal
University of California,
San Francisco, USA
Dr. Scott Thompson
GlaxoSmithKline,
King of Prussia, PA, USA
Dr. Frederico Gómez de las Heras
GlaxoSmithKline,
Tres Cantos, Spain
• Falcipain-2 orthologs from
and key differences between
C59R+S108N+I164L) and quadruple
were identified.
coming year include:
(N51I+C59R+S108N+I164L) mutant
These compounds have significant
• Optimisation of expression,
forms of P. falciparum DHFR through
anti-malarial activity and the stage
$ 50’000
• Partial screening of the GSK
the use of both natural and our
is set for the design of even more
collection against falcipain-2 has
of falcipains and orthologs from
synthetic genes.
potent compounds which avoid the
Funding allocated in 2001 :
resulted in the identification of
other plasmodial species.
$ 1’458’694
potent and selective inhibitors,
• Complete screening of the GSK
resistance effects enabled by
The enzymes, expressed both as
some of which have demonstrated
cysteine protease inhibitor
DHFR domain only and as DHFR-TS,
potent in vitro anti-malarial activity
collection against recombinant
constitute the most important
Contact at MMV:
against chloroquine sensitive and
falcipains.
mutants responsible for antifolate
Dr. Solomon Nwaka
resistent P. falciparum strains.
• The GSK cysteine protease
inhibitor collection was extensively
enlarged, and available biochemical
and biological data for components
was expanded.
• Screening of active GSK inhibitors
prepared and purified for both
parasites.
screening and crystallization
• Pharmacokinetic analysis of
lead GSK inhibitors in rodents.
• Crystallization and initial
structure determination for
reorganising chemistry efforts to
falcipains.
mutations at various sites.
Contact at MMV:
Dr. Solomon Nwaka
e-mail :
[email protected]
resistance, are now routinely
against cultured P. falciparum
A major effort has gone into
incorporate the Tres Cantos site,
25
BIOTEC,
Thailand’s National Science
and Technology
Development Agency
Major project objectives for the
purification, and characterisation
[email protected]
Synthesis and Selection of
Inhibitors of Malarial
Dihydrofolate Reductase
these enzymes and falcipain-2
cysteine protease inhibitor
e-mail :
DISCOVERY PROJECT 6
purposes. This represents the first
time that P. falciparum DHFR crystal
structures have been available to
assist in drug discovery efforts.
• Synthesis of new candidate
which in 2001 was dedicated entirely
falcipain inhibitors based on
to research targeted at developing
results of initial screens and SAR
world diseases. Currently, a high
determinations.
26
DISCOVERY PROJECT 7
DEVELOPMENT PROJECT 1
Dihydroorotate dehydrogenase inhibition
Development of an Improved Semisynthetic Artemisinin Derivative
Project description provided by Dr. Glen McConkey
Project description provided by Dr. Burkhard Fugmann
This year this project has advanced
Over 60 compounds based on
Bayer AG, Germany, has a successful
Dr. Gabrielle Schmuck at Bayer devel-
greatly with the discovery of new
prototype dihydroorotate dehydro-
history in developing drugs against
oped novel in vitro assays to test for
compounds that inhibit the targeted
genase inhibitors were synthesised
tropical infectious diseases. As far
neurotoxic potential. This proved
enzyme dihydroorotate dehydroge-
at the University of Hull (A. Boa).
back as 1934, Bayer discovered
extremely valuable in the selection
nase. The targeted enzyme catalyzes
The most potent inhibitors were
chloroquine (ResochinR) which in
of compounds to take forward as
an intermediate step in synthesis of
tested in parasite assays and found
subsequent decades was developed
potential development candidates.
pyrimidines, building blocks of the
to inhibit growth at low concentrations.
to become the most effective
medicine for prevention and therapy
By the end of the year 2000 several
Current efforts are characterising
of malaria. In 1995, in the context
C-10 aminoalkylartemisinin derivatives
Unlike animals, malaria parasites
the mechanism of inhibition.
of growing chloroquine resistance,
had been identified, that met the
must derive their pyrimidines from
Understanding how the compounds
Bayer Central Research department
selected criteria for entry into
synthesis and cannot salvage
inhibit the enzyme will guide the
started collaboration with Professor
development; high activity in rodent
pyrimidines. Related studies this
synthesis of a second generation
Richard K. Haynes of the Hong Kong
malaria, lack of neurotoxicity both
year have demonstrated that this
of compounds to search for more
University of Science and Technology
in vitro and in vivo, as well as easy
Affiliations :
enzyme is essential for growth of
potent inhibitors. The kinetics of
(HKUST), an internationally renowned
chemical access and scalability. The
• Dr. Burkhard Fugmann
Plasmodium falciparum . This validates
inhibition and X-ray crystallography
authority on the study of Artemisinin.
final development selection was
our rationale for targeting this
with co-crystals of the enzyme
enzyme. In the first year of the study,
and inhibitor will elucidate the
The goal of the “Bayer-HKUST
Australian Army Malaria Institute
we developed an in vitro assay for
interactions. Based on these findings
Anti-malarial Project” was to discover
in Brisbane. Plasmodium falciparum
testing compounds based on
libraries of derivatives will be
and develop improved artemisinin
naive Aotus trivirgatus monkeys were
expression of recombinant enzyme
synthesised in a full drug discovery
derivatives for the treatment of
infected with a multi-drug-resistant
from malaria parasites and humans.
program.
uncomplicated, non-severe malaria
Plasmodium strain. Parasitemia
via oral and suppository formulations.
developed over 6-9 days after inocu-
This year we have adapted the assay
Design features would also seek to
lation up to a level of 10%. The best
for screening series of compounds.
ensure suitability for intravenous
compound, later given the proposed
Several “hits” identified from
treatment of severe malaria, for
name “Artemisone“, when applied
the screening have been tested and
which the only current therapy is
as a single dose of 10mg/kg p.o.
found to inhibit parasite growth.
intravenous quinine.
reduced parasite density to zero
genetic material RNA and DNA.
DISCOVERY PROJECT 7
Dihydroorotate
dehydrogenase inhibition
Affiliation :
• Dr. Glen McConkey
University of Leeds, U.K.
1
$ 118’038
done in cooperation with the
Contact at MMV:
Dr. Solomon Nwaka
e-mail :
[email protected]
within 1 day, whereas artesunate
Development of an Improved
Semisynthetic Artemisinin
Derivative
Bayer AG,
Leverkusen, Germany
(project coordinator)
• Prof. Richard K. Haynes
Hong Kong University of
Science and Technology
Affiliates :
• Australian Army Malaria
Institute,
Brisbane, Australia
• London School of Hygiene
and Tropical Medicine, U.K.
Funds allocated in year 1 :
$ 495’000
Contact at MMV:
The existing artemisinin class of
achieved clearance from parasites
Dr. David Ubben
drugs thus had to be improved
after 4 days under the same condi-
e-mail :
regarding efficacy, neurotoxicity,
tions. Artemisone is in fact 10-30
stability and pharmacokinetic
fold more active than artesunate
behaviour. From the beginning of
based on preliminary pharmacokinetic
the cooperation, parasiticidal efficacy
and efficacy data in monkeys.
[email protected]
and the establishment of reliable
1
27
McRobert, L. and G.A. McConkey. 2002. RNA interference (RNAi) inhibits growth of
safety parameters were of equal
In 2001, MMV decided to support
Plasmodium falciparum. Mol Biochem Parasitol. 119:273-8
importance. In particular,
the accelerated development of
28
Artemisone as a new drug candidate
and pharmacokinetics. Additional
been developed as intra-muscular
In rat, a single dose study showed
against non-severe and severe
milestones have been the elaboration
and rectal formulation for severe
that only 1% of AL is cleaved to
malaria. Pre-clinical development
of a detailed pre-clinical and clinical
malaria. However, absorption from
dehydroartemisinin (DHA), indicating
is being done by Bayer Central
development plan and conclusion of
the intramuscular site is slow and
that efficacy and toxicology findings
Research under the leadership of
the chemical backup program. In
absorption from the rectum is highly
may be attributed to the parent
Dr. B. Fugmann. Clinical development
2002, the pre-clinical development
variable. Our rationale is that a better
compound rather than the metabolite.
is managed by Bayer Pharma division
will continue with a safety package,
approach which would improve cure
In contrast, 80% and 38% of a single
in cooperation with MMV staff.
further biological testing with
rates would be an intravenous
dose of AS is converted to DHA in
exploratory dose finding and combi-
formulation of artemisinins that can
man and rat, respectively. It has been
The pre-clinical development of
nation experiments, GMP synthesis
achieve reproducible peak plasma
shown that human liver microsomes
Artemisone in 2001 has focused on
optimisation and formulation
concentrations. Our plan is first to
in vitro metabolise AL into 2-hydroxy
the development of a competitive
development. Clinical phase I with
compare AL to a current formulation
artelinate. Because microsomes of
multi-kg scale synthesis as well as
healthy human volunteers is
of AS, with respect to chemistry and
rhesus monkey, but not dog, also
GLP process development and
scheduled to start in 2003.
manufacturing, pharmacology,
produce 2-hydroxy artelinate, rhesus
toxicology (including neurotoxicity),
monkey have been selected as non-
pharmacokinetics and metabolism.
rodent animal model for pre-clinical
The better of the two compounds
studies.
analytical method for toxicology
would then be synthesised under
Development of an intravenous artemisinin treatment for severe malaria
Good Manufacturing Practices (GMP)
WRAIR has developed a rat model
Project description provided by Dr. Jonathan Berman
conditions and evaluated in GLP
for severe malaria. Using an i.v.
animal studies to meet regulatory
dose of 40mg/kg/day for three
Development of an intravenous
artemisinin treatment for
severe malaria
Affiliation :
• Dr. Jonathan Berman
Walter Reed Army Institute
of Research (WRAIR), USA.
The management of severe malaria
cardiotoxicity have been attributed
Investigational New Drug (IND)
days, both AL and AS cleared
requires good medical care and the
to quinine. Artemisinins are now
requirements. Assuming that there
parasite Plasmodium berghei from
use of chemotherapy to decrease
being used in an attempt to improve
are no safety concerns, a clinical
rat. Efficacy has also been studied
parasitemia to a non life-threatening
upon quinine’s efficacy and toxicity.
development program will be designed
in Aotus monkey infected with
level. At present this is accomplished
As illustrated in the figure, oil soluble
to meet current international regula-
Plasmodium falciparum, a commonly
primarily by administering quinine
artemisinins, artemether and
tory and ethical requirements.
used animal model. Our data indicate
e-mail :
intravenously. However, this
artheeter, have a methyl and ethyl
that AL clears parasite at 8mg/kg/day
[email protected]
treatment is unsatisfactory as the
group respectively, with ether links
The project status and achievements
for three days and AS clears parasites
mortality rate reported in the late
to oxygen. In contrast the water
can be summarised as follows:
at 2mg/kg for three days. Definite
1990’s was up to 27% in South East
soluble artemisinins, artelinic acid
Asia and up to 20% in Africa.
(AL: figure left) and artesunic acid
Chemistry, Manufacturing, Control
Additionally, adverse effects such
(AS: figure right) have a polar group
(CMC): AL has been formulated in a
as cinchonism, hyperinsulinemic
attached to the oxygen. Oil-soluble
soluble salt with purity greater than
Rat and Rhesus have proven to be
hypoglycemia, and often fatal
artemisinins and artesunate have
99%. The AL salt is dissolved prior
good models to study toxicology and
use to form a stable solution suitable
toxicokinetics (drug levels in blood
for i.v. injection. The dissolved salt
associated with toxicity). These
decays over time (10% in two
studies will allow the determination
months). Other formulations with
of the non-toxic levels and the
improved stability are being studied.
appropriate therapeutic dose.
Contact at MMV:
Dr. David Ubben
efficacy studies in Rhesus monkey
model are now underway.
AS dissolves in bicabornate but
29
Artelinate
Artesunate
decays at a 10% rate in hours.
30
of 2003. Parallel registration with
Pyronaridine Artesunate
the European Agency for Evaluation
of Medicinal Products is envisaged.
Project description provided by Dr. Tom Kanyok
Pyronaridine, an acridine-type
African setting, compared to the
Mannich-base, is a water soluble blood
other artemisinin fixed dose
Development of a novel and superior 4-aminoquinoline – Isoquine
schizontocide first synthesised in
combination currently marketed
Project description provided by Prof. Steve Ward
China in 1970. Data indicate that
which needs to be administered
it is effective against chloroquine
twice a day for three days.
resistant parasites and is well
Pyronaridine Artesunate
Affiliations :
•
•
Dr. Tom Kanyok
WHO/TDR,
Switzerland
Dr. Chang Sik Shin
Korea SP Pharm Inc.,
Seoul, South Korea
$ 643’000
• Possibility of broader geographic
The 4-aminoquinoline class of
idiosyncratic adverse drug reactions,
anti-malarial, as exemplified by
a feature which has blighted the
tolerated. Artesunate is a water-
use since widespread development
chloroquine and amodiaquine, have
widespread use of the drug. Clearly
soluble semi-synthetic derivative of
of resistance to pyronaridine has
been the most successful class
there are many areas of overlap
artemisinin. Artesunate has been
not yet been reported.
of anti-malarial drugs to date. The
between these two research
success of the class is partly based
programmes.
developed in various forms by several
• The long-half-life of pyronaridine
pharmaceutical companies and is
(60-190 hrs) may increase the
on their ability to exploit features
registered for clinical use in many
interval between new infections in
of the haemoglobin degradation
Isoquine is the most promising lead
countries.
some high transmission settings.
pathway, a unique malarial parasite
compound to have emerged from
pathway. In addition to this selective
these research programmes after
Affiliations :
• Prof. Steve Ward
A pyronaridine-artesunate fixed
A Product Development team is in
mode of action these drugs are
the synthesis and evaluation of
dose combination should provide
place to manage the development
affordable, easy to use and prior to
some two hundred novel molecules.
the following advantages over
programme and has representation
the emergence of chloroquine
Isoquine is an isomeric derivative
non-artemisinin-containing drugs
from Iowa University, WHO-TDR, MMV,
resistance the drugs were highly
of amodiaquine under patent to the
already marketed:
Korea SP Pharm Inc., and other
effective.
University of Liverpool. This molecule
• Rapid onset of action translating
consultants from academic or
governmental institutions.
has been re-designed to remove
For the past fifteen years the
the metabolic alert for reactive
Tropical Pharmacology Group in
metabolite formation, a feature that
Under the leadership of Korea SP
Liverpool has attempted to establish
is central to the toxicity of the
development of resistance when
Pharm Inc., the pharmaceutical devel-
the pharmacological basis of drug
molecule. This manipulation has
compared to standard single agent
opment is well advanced with a major
action, resistance and toxicity to this
been achieved without any loss
anti-malarial regimens.
achievement realised in the form
class of drugs. Our ambition was to
of anti-malarial activity. In fact the
of a simplified route of pyronaridine
use this information in the rational
drug shows improved activity both
of malaria due to the ability of
synthesis, which will significantly
re-design of novel 4-aminoquinolines
in vitro against P. falciparum and
artemisinin derivative to prevent
reduce the final product cost.
with improved pharmacological
in vivo against a rodent model of
the development of gametocytes.
The non-clinical safety studies and
profiles. We developed two parallel
malaria after oral drug administration
the ADME programme are currently
lines of investigation: using
compared to amodiaquine or the
In addition this fixed combination
ongoing in Korea. A first stop/go
chloroquine as the lead molecule
therapeutically relevant de-ethylated
should present the following
evaluation about progression into
we focused on understanding the
metabolite of amodiaquine. The
advantages over other artemisinin
clinical programme is due by 2nd Q,
chemical basis for resistance and
chemical modification introduced
containing drugs:
2002. Assuming that there are no
using amodiaquine as our lead we
into isoquine also shifts the overall
• Once daily regimen for three days
safety concerns to move into human
tried to separate anti-malarial activity
metabolic pattern of the drug in a
will improve compliance and ease
trials, the team plans to file an IND
from the liability of this drug to
way that could have therapeutic
control program in Asian and
to the Korean FDA at the beginning
produce potentially life threatening
benefit. Importantly this new drug
into rapid fever and parasite
clearance time.
Development of a novel and
superior 4-aminoquinoline –
Isoquine
University of Liverpool, U.K.
• Prof. Kevin Park
• Dr. John Horton
GlaxoSmithKline, U.K.
Contact at MMV:
• Possible decrease in the rate of
Dr. Lise Riopel
Contact at MMV:
e-mail:
[email protected]
e-mail :
• Possible decrease in transmission
31
Dr. David Ubben
[email protected]
32
can be synthesised in three simple
process. The core members of this
advanced. Pharmaceutical develop-
at various ratios for a preliminary
steps from readily available chemical
development team have already suc-
ment of CDA is progressing within
assessment of efficacy and safety.
intermediates. As such the drug
cessfully managed the development
GSK.
should be affordable to our target
to UK registration of another new
population.
anti-malarial agent, chlorproguanil-
The ratio of CPG and DDS is fixed
influence the efficacy results of the
dapsone. The pre-clinical pharmacol-
but the ratio of these components
above Phase-II study, CDA will also
In order to develop this drug quickly
ogy study plans have just been
and artesunate is not determined.
be studied in less-immune children
we have developed a public-private
completed and mutagenicity testing
Pharmaceutical development will
populations. A clinical development
partnership between the University
should begin within the next four
proceed with a number of ratios
plan will be prepared in accordance
of Liverpool, the Liverpool School of
months following the scaled up
until the optimal ratio has been
with current ICH guidelines
Tropical Medicine and GSK pharma-
synthesis of drug. The development
finally determined by clinical trial.
and discussed with partners and
ceuticals. The product development
of our programme is structured so
team is made up of academic and
as to allow a first into man decision
A stop/go decision point to initiate
industry expertise that covers all
within two years with a product
Phase-I studies will be made shortly.
aspects of the drug development
registration within five years.
The main aim of the first Phase-I
As immunity can be expected to
appropriate regulatory authorities
prior to implementation.
study will be pharmacokinetic
interaction between CPG-DDS and
artesunate.
Chlorproguanil-dapsoneartesunate.
Affiliations :
•
Prof. Peter Winstanley
•
Dr. John Horton
GlaxoSmithKline, U.K.
•
Dr. Tom Kanyok
WHO/TDR, Switzerland
Chlorproguanil-dapsone-artesunate
Project description provided by Prof. Peter Winstanley
Following the Phase-I programme,
a dose-finding Phase-II study will be
Chlorproguanil-dapsone (Lapdap;
artemisinin compound (CDA), is now
performed to determine the optimal
CPG-DDS), is the partner component
being undertaken for the following
artesunate dose in patients with
of this artemisinin combination.
reasons:
uncomplicated malaria. Lapdap will
It is a rapidly-eliminated antifolate
• Artemisinin combination therapy
be co-administered with artesunate
drug currently submitted for regula-
(ACT) has been shown to reduce
tory approval for the treatment of
the rate at which resistance to
uncomplicated malaria. It has been
mefloquine is evolving in Thailand.
shown:
• To select less readily for resistant
Co-sponsors:
WHO/TDR
United Kingdom Department for
International Development (DFID).
• A large body of scientific opinion
believes that ACT has the potential
Contact at MMV:
parasites than sulfadoxine-pyrime-
to reduce the rate at which drug
Dr. Lise Riopel
thamine (SP).
resistance will evolve in Africa –
e-mail :
• To be safe and well tolerated.
where approximately 90% of the
• To have clinical utility in patients
deaths due to malaria occur.
[email protected]
whose prior treatment with SP
33
had failed. It is also available at a
A Product Development Team
price that is affordable in the
(PDT) has been formed to manage
context of malaria in Sub-Saharan
the CDA project. Its membership
Africa.
includes academics, an MMV Officer,
and personnel from WHO and GSK.
MMV gratefully recognizes, that all partner institutions have contributed to the projects
Further development of the product
A full pre-clinical programme has
through writing off overhead costs and through the provision of other services and gifts
with the addition of artesunate, an
been commissioned and is well
in kind.
34
5
THE ORGANISATION
The MMV Board Members
The Chair of the Board is Dame Bridget Ogilvie, a former head of the
Wellcome Trust, with a distinguished career in pharmaceutical research.
Dame Bridget is now on the faculty of University College London.
“In Italy during
the thirteenth century alone,
17 popes died of malaria.”
Prof. Trevor Jones
University College London,
Director-General,
United Kingdom.
The Association of British Pharmaceutical
Mr. David Alnwick
Industries, United Kingdom.
Project Manager,
Dr. R. A. Mashelkar
Roll Back Malaria, WHO, Switzerland.
Director General,
Dr. Enriqueta Bond
Indian Council of Scientific and
President, Burroughs Wellcome Fund,
Industrial Research, India.
USA.
Dr. Graham Mitchell
Mr. Louis Currat
Chairperson,
Executive Secretary, Global Forum for
Scientific and Technical Advisory
Health Research, Switzerland.
Committee, Special Programme for
Dr. Winston E. Gutteridge
Research and Training in Tropical
Ex-Chief, Product R&D,
Diseases (TDR), WHO, Switzerland.
Special Programme for Research and
Foursight, Australia.
Training in Tropical Diseases (TDR), WHO,
Prof. Francis Nkrumah
Switzerland.
Director, Noguchi Memorial Institute
Dr. Chris Hentschel
for Medical Research, University of Ghana,
Chief Executive Officer,
Ghana.
Medicines for Malaria Venture,
Prof. Leon Rosenberg
Switzerland.
Department of Molecular Biology,
Princeton University, USA.
(see picture next page)
36
Dr. David Roos
Dr. Thomas E. Wellems
Professor of Biology and Director,
Biologist with expertise in cell
University of Pennsylvania Genomics
and molecular biology of malaria and
Institute. Expertise in the cell biology
mechanisms of drug resistance.
of apicomplexan parasites and joint
National Institutes of Health, USA.
coordinator of the Plasmodium
Dr. David Wesche
genome database, USA.
Clinical Pharmacologist with expertise in
Dr. Dennis Schmatz
malaria from previous position with
Biologist with expertise in parasitology,
Walter Reed Army Institute of Research,
including malaria. Executive Director,
currently with Pfizer Global Research and
Human and Animal Infectious Disease
Development, Ann Arbor, USA.
1
Research, Merck Research Laboratories,
3
USA.
1. Board Members
The Medicines for Malaria Management Team and Staff
2. Expert Scientific Advisory Committee
3. Management Team and Staff
2
The Expert Scientific Advisory Committee
The Committee Chair is Dr. Simon Campbell FRS, who was formerly
Head of Global Drug Discovery for Pfizer.
Erin Kimaoui
Chief Executive Officer
Personal Assistant to
Dr. Robert Ridley
the Management Team
Chief Scientific Officer
Dr. Lise Riopel
Peter Potter-Lesage
Scientific Officer
Chief Financial Officer
Dr. David Ubben
Diana Cotran
Scientific Officer
Human Resources and
Dr. Solomon Nwaka
Administration Manager
Scientific Officer
Dr. V.P. Venugopal
Souzie Zador
Director, International Operations
Communications Officer
Dr. Simon Campbell FRS
Prof. Gilbert Kokwaro
Chemist, ex-Head of Worldwide Drug
Pharmacologist with expertise in malaria,
Discovery and Development, Europe,
University of Nairobi, Kenya.
Pfizer.
Prof. Sornchai Looareesuwan
Dr. Tanjore Balganesh
Clinician with experience in malaria, Dean
Biologist with specialist expertise in
of Faculty of Tropical Medicine, University
infectious diseases. Head of Research
of Mahidol, Thailand.
Tony Murdoch
John Sudduth
and Development, Astra-Zeneca, India.
Dr. Yves Ribeill
MBC Business Consultants
IT consultant
Dr. Simon Efange
Chemist with experience in malaria
Chemist, Professor of Medicinal
through earlier work as Head of Anti-
Chemistry, University of Minnesota, USA,
infective Chemistry Research with
and University of Buea, Cameroon.
Rhône-Poulenc Rorer France, now
Dr. Alan Hudson
President and CEO, Scynexis Chemistry
Chemist, ex-Head of Cancer Research,
and Automation Inc. USA.
MMV also uses the services of:
Wellcome plc (UK) with additional
expertise in parasitology and malaria
36
chemotherapy, United Kingdom.
(continued next page)
37
Medicines for Malaria Venture receives funding and support from
government agencies, private foundations, international organisations,
corporations and corporate foundations. These funds are used to finance
the MMV portfolio of research and development projects to provide new,
affordable medicines for the treatment and prevention of malaria. As
a not-for-profit Swiss Foundation under statutes dated 15 th November
1999, MMV is exempt from cantonal and federal taxes and is the
equivalent of an exempt organisation within the meaning of Section
501 (c) ( 3 ) of the United States Internal Revenue Code.
6
FINANCIAL INFORMATION
The financial year to 31 st December 2001
This second financial year has been
posts and more were recruited and,
one of innovation and consolidation.
most important of all, expenditure
The MMV Financial Regulations,
on malaria drug research & develop-
Investment Guidelines and Financial
ment increased dramatically.
& Accounting Rules and Procedures
were drafted and ratified. Internal
Research & Development
compliance procedures and controls
Expenditure
were formalised and a new in-house
Project-related expenditure in 2001
multi-currency, multi-lingual
was virtually 3 times the figure for
accounting system was installed
the year 2000, with USD 6’709’653
and is fully operational. We continue
as against USD 2’280’748 (note 4).
to use PricewaterhouseCoopers Ltd.
as external international auditors
Foundation Capital
and UBS, a major Swiss bank, for
The legally stipulated foundation
our global banking services such
capital of USD 4'000'000 was,
“The introduction of quinine to India
as current accounts, investments
for historic reasons, under the
indirectly led to the development of
and cash-management facilities.
custodianship of the World Health
The on-line bank-to-customer link
Organisation. At 31 December 2000
already in use was extended to
USD 1'197'619 had been received.
include electronic payment facilities.
During 2001 a further USD 2’309’741
The year was characterised by a
originating from the Netherlands
number of exceptional factors. The
Minister for Development Cooperation
capital fund which, was largely under
was transferred. At 31 December 2001
the custodianship of WHO in 2000,
the amount still outstanding amounted
is now almost fully subscribed,
to USD 492’640 (note 2g/6).
the tonic drink industry.
In 1858 a patent was granted for
“an improved aerated tonic liquid”,
today known all over the world as
Schweppes tonic water.”
considerable additional donations
and pledges were received, liabilities
Donations & Pledges
increased as new staff took up their
Donations received at bank amounted
40
to USD 12’177’850 with an additional
agreements signed with project
USD 1’000’000 expected from WHO
partners. Other operational expenses,
Roll Back Malaria on presentation of
however, are normally in Swiss
the audited Financial Statements
Francs. The resulting exposure or
and Annual Report 2001 (note 3).
exchange risk is hedged at budget
time to provide a realistic fixed
Medicines for Malaria Venture – MMV Balance Sheet at 31st December 2001
2001
2000
USD
USD
170
815’530
11’584’765
535
1’017’493
5’891’716
12’400’464
6’909’744
1’000’000
0
10’195
143’588
0
27’166
49’735
9’239
Prepaid & other Receivables
1’153’783
86’140
Prepaid R&D Commitments
0
59’000
13’554’247
7’054’884
34’030
18’084
75’221
32’968
38’956
19’371
82’849
14’338
160’303
155’514
6
13’714’550
7’210’398
2e/4
3
0
0
51’103
0
419’948
1’000’000
151’194
51’160
2f
2b
279’143
100’176
0
0
430’422
1’622’302
4’000’000
(492’640)
4’000’000
(2’802’381)
6
3’507’360
1’197’619
2h
9’776’768
4’390’477
13’714’550
7’210’398
Assets
Current Assets
Staff & General Administration
USD/CHF budget rate for the year.
The senior management team was
The accounts are kept in US dollars.
completed with the arrival of the
A sophisticated treasury management
Chief Scientific Officer and Chief
and accounting approach is therefore
Financial Officer. There were 8 new
required, matching inflows to outflows
appointments in 2001 and MMV also
by currency, and taking timely multi-
Prepaid & Receivables
financed the start-up costs of its
currency investment and foreign
permanent headquarter offices,
exchange decisions.
Donations Receivable
Prepaid Expenses
Accounts Receivable
Recoverable Withholding Tax
including furniture, I.T. and communi-
Cash
Cash in Banks
Short-term Deposits
Cash & Cash Equivalents
Our financial management is one
investment in infrastructure, general
of prudent, conservative control,
administration (non R&D) spending
including appropriate return on
is on a downward trend as a percent-
interim treasury investments. We
Fixed Assets
age of total expenditure (note 5b/c).
also seek to forecast various long-
Guarantees
Fixtures & Installations
Office Furniture
Computers & Equipment
so as to manage MMV’s growing
December 2002
R&D portfolio more effectively and
Great consideration is given to efficient
to enable us to fundraise proactively.
Total Assets
financial management at MMV,
The figure “the funding-gap scenario”
Liabilities and Capital & Reserves
which operates in a complex multi-
illustrates one such scenario and
currency environment. The bulk of
shows why effective fundraising,
92'200'000
Financial Tables
$ 90'000'000
The detailed financial tables that
$ 80'000'000
follow – Balance Sheet, Statement of
$ 70'000'000
Income & Expenditure, Cash Flow and
$ 60'000'000
Notes – represent MMV in its second full
$ 50'000'000
The funding-gap scenario
MMV funding received and pledged
against actual/forecast expenditure
2d
2c
Total Fixed Assets
Current Liabilities
Accrued R&D Commitments
Deferred Income
Other Creditors
Accrued Expenses
Provisions
Short-term Provisions
Unrealised Exchange Gain
59'700'000
Received / pledged (cumulative)
Spend (cumulative)
3
Total Current Assets
The financial year ahead to
$ 100'000'000
2a/2b
Cash & Cash Equivalents
cations. In spite of this significant
term funding and income scenarios
Notes
47'2
200'000
Total Current Liabilities
40'2
200'000
200'00
year of operation in which all the
$ 40'000'000
fundamental compliance and financial
$ 30'000'000
components of the organisation have
$ 20'000'000
been consolidated.
Capital & Reserves
33'200'00
200'000
23'200'00
200'000
$ 10'000'000
$
0
8'700'0
00'000
3'20
00'000
2000
1
31'700'
31'700'000
Foundation Capital
-subscribed
-less unpaid capital
11'500'000
2001
2002
2003
2004
2
3
4
5
Capital Fund
Operations Reserve
41
donations are received in US dollars,
probably involving several new
although other currencies are some-
donors, is now a high priority.
times involved. Outflows for projects
Without it, planned expenditure
are mostly in USD as per the various
could outstrip income in 2003.
Total Liabilities and Capital & Reserves
2g
42
Medicines for Malaria Venture - MMV Statement of Income & Expenditure at 31 st December 2001
Income
Donations received
Private Foundations
UN Agencies
Government Agencies
Corporates & Corporate Foundations
Donations received
Medicines for Malaria Venture - MMV Statement of Cashflow at 31 st December 2001
2001
2000
USD
USD
6'000'000
4'250'000
2'827'850
100'000
6'300'000
500'000
612'015
100'000
3
13'177'850
7'512'015
2b
371'441
0
10'385
76'162
18'772
0
Notes
2001
2000
Notes
USD
USD
2h
5'386'290
4'390'477
3
(1'000'000)
0
39'540
(49'735)
(134'349)
(9'239)
86'166
(86'166)
(419'948)
419'948
(1'000'000)
1'000'000
(100'091)
151'194
(51'160)
51'160
(2'579'842)
1'477'162
1'287
(19'371)
7'628
(82'849)
(18'630)
(14'338)
4'927
(38'956)
(4'788)
(155'514)
379'319
0
2'309'741
1'197'619
Cash flow resulting from financial activity
2'689'060
1'197'619
Net variation of petty cash, cash & bank deposits
5'490'720
6'909'744
6'909'744
0
12'400'464
6'909'744
5'490'720
6'909'744
2a/3
Excess of income over expenditure for the period
Operating activity
Increase/Decrease in Donations Receivable
Financial Income
Exchange Difference
Other Income
Increase/Decrease in Receivables
Increase/Decrease in Recoverable Withholding Tax
Total Income
13'559'677
7'606'949
Increase/Decrease in Prepaid Expenses
Expenditure
Increase/Decrease in Accrued R & D Commitments
2e /4
Research & Development Expenditure
Increase/Decrease in Deferred Income
Project-Related Variable Expenditure
Expert Scientific Advisory Committee Expenses
2e/4
5a
Research & Development Expenditure
Foundation Board & Stakeholder Expenses
5a
6'633'542
76'111
2'241'373
39'375
6'709'653
2'280'748
39'228
30'934
Increase/Decrease in Other Creditors
Increase/Decrease in Accrued Expenses
Cash flow resulting from operating activity
Investment activity
General Administration Expenses
Increase/Decrease in Fixtures and Installations
Staff-Related Benefits / Compensation
Recruitment / Relocation
Office Rental
General Insurance
State Emoluments
Supplies
Telecom, Internet & Postal Charges
Travel & Fundraising Expenses
Professional & Legal Fees
Training, Education & Journals
I.T. Expenses
Web Site & Advertisements
Printing & Brochures
Public Relations
Communications Consultancy
5b
5b
823'418
12'488
165'775
1'585
1'024
29'447
35'272
38'132
92'849
57'891
58'477
43'252
42'013
14'514
60'519
117'598
111'283
46'074
1'987
0
1'903
2'737
88'406
48'628
20'063
1'904
0
2'447
80'268
380'430
2c
Increase/Decrease in Office Furniture
Increase/Decrease in Computers and Equipment
Increase/Decrease in Guarantees
2d
Cash flow resulting from investment activity
Financial activity
Provisions
Foundation Capital:
2g/6
FInancial Charges
Payment received to Capital Fund
Bank Charges & Visa
Exchange difference (loss)
Depreciation on Fixed Assets
2c
General Administration Expenses
Total Expenditure
3'402
126
45'081
1'062
0
0
1'525'267
904'790
8'274'147
3'216'472
Cash & cash equivalents at beginning of period
Ancillary Activity Income
5c
100'761
0
Transfer to Operations reserve
2h
5'386'290
4'390'477
0
0
Cash & cash equivalents at end of period
Variation
Result
43
44
Notes to financial statements for the year ending 31 December 2001
the premises subject to the prevailing
Special Programme for Research &
contracts.
Training in Tropical Diseases (TDR).
The TDR funds represent earmarked
1a. Introduction
internal annual average rate
calculated on the weighted average
is a Swiss Foundation, established
of opening balances in foreign
as a non profit legal entity, registered
currencies and the exchange deals
The grants allocated are recorded on
World Bank and the Netherlands
in Geneva under statutes dated
effected to obtain sufficient balances
a contract or letter of understanding
Minister for Development
15 November 1999. It is managed by
in the currencies concerned. In 2001
basis, the expense being accounted
Cooperation prior to the foundation
a foundation council, a chief executive
the average rate for USD/CHF was
for by MMV at the moment of
of MMV. At 31 December 2000 the
officer and 3 senior managers.
1.7468 and for GBP/USD 1.41.
allocation and initial payment. In
amount of USD 2'802'381 was still
the case of any portion remaining
to be transferred from the World
e. Grants committed for projects
funding from the U.K. Department
for International Development, the
With its head-office in Geneva,
Year-end balances in other currencies
unpaid at the year-end, it is included
Health Organisation. At 31 December
the aim of MMV is to bring public
are converted at the prevailing rates
under current liabilities.
2001, the remaining balance for
and private sector partners together
of exchange at balance sheet date.
to fund, and provide managerial
The accounting rate USD/CHF used
and logistical support for the
at the 31 December 2001 balance
discovery and development of new
transfer was USD 492’640
f. Short-term provisions
(see also Note 6).
sheet closing was 1.63 and that for
These provisions represent estimated
h. Operations reserve
medicines for the treatment and
GBP/USD 1.44. The resulting
costs for certain performance-related
prevention of malaria. The products
Exchange Difference was taken to
staff payments and for audit services.
should be affordable and appropriate
Provisions as an unrealised gain and
for use by populations in developing
any unrealised loss is taken to
countries.
Income & Expenditure.
b. Accounting Standards
c. Fixed assets
The accounting standards followed
Fixed assets are stated at cost less
are those of the Swiss Code of
depreciation in three classes. The
Obligations, articles 957 to 964.
foundation applies the straight-line
This represents the excess of income
over expenditure for the period and
g. Capital
accrued. This amount is ascribed to
the Operations Reserve utilised for
The founding capital referenced in
future operation and project funding
the statutes amounted to USD
costs by MMV as its rapidly evolving
4'000'000 from WHO – Roll Back
research and development project
Malaria & UNDP/World Bank/WHO
pipeline dictates.
method for the depreciation of these
3. Donations received at bank
2. Summary of significant
assets, using rates of 20% p.a.
in addition to Foundation Capital received (see also Note 6)
accounting policies
for office furniture and 33% p.a. for
both fixtures and installations and
a. Donations received
*An additional amount of
USD 1’000’000 expected from
W.H.0. Roll Back Malaria after
During 2001 the following donations were received:
presentation of the Financial
computers and equipment.
Statements and Annual Report
Rockefeller Foundation (received in 2000 for 2001)
USD
1’000’000
for 2001 has been taken as
The donations received are recorded
Depreciation started only in the year
Bill & Melinda Gates Foundation
USD
5’000’000
income for 2001 as it
on an accruals basis.
2001 with the effective operation at
U.K. DFID
USD
2’827’850
relates to an agreement up to
the foundation's final premises.
W.H.O. Roll Back Malaria
USD
2’500’000*
31 December 2001. This explains
World Bank via Global Forum
USD
750’000
total Donations Received
d. Guarantees
Exxon Mobil
USD
100’000
of USD 13’177’850 as taken to
dollars. Receipts and expenditure in
Guarantees concern office rental
Total received at bank
USD
12’177’850*
other currencies are recorded at an
only and are recoverable on vacating
b. Foreign exchange
The accounts are denominated in US
45
Income & Expenditure.
46
4. a) Project-related variable expenditure : Grants committed +
During 2001, the foundation awarded grants to the following projects:
Project
Partners
Award
Paid
Prepayment
Accrued
Major Discovery Projects
290’825
GSK
U. Bristol
290’825
0
0
1’079’110*
1’020’1 1 0
59’000*(from 2000)
0
Roche 4
U. Nebraska 5
STI 6
U. Monash 7
Drug Discovery Project 990069
1’458’694
GSK
8
UCSF
9
Artemisone
1’458’694
grants represents an amount of
31 December 2001 to be transferred
USD 551’875 and covers legal fees
from the books of the World Health
for contracts, organisation and trans-
Organisation originates from the
port for project meetings/reviews,
following agencies:
project consultancies.
2’442’000
5. Expenses
World Bank
a) Governing Board and ESAC
WHO/TDR/Roll Back Malaria
expenses represent travel and a
per-diem.
During 2001 an amount of
b) Internal capacity building
USD 2’309’741 originating from the
advanced efficiently in 2001 with
Netherlands Minister for Development
8 staff appointments and effective
Cooperation was transferred by
operations in new, dedicated office
W.H.O. and attributed directly to
premises.
Foundation Capital.
to office space and infrastructure
Bayer 10
UK Department
c) Ancillary activity income refers
2’442’000
sub-let income, which can be offset
H.K.U. 11
Pyronaridine artesunate
Foundation Capital still pending at
for International Development
2
Cysteine protease inhibition
over and above these direct project
1
LSHTM 3
Synthetic endoperoxide
6. Foundation Capital pending
scientific staff compensation and
Lactate dehydrogenase inhibition
b) Project-related variable expenditure
against total rental, telecom and
643’000
643’000
related operational expenses.
Korea SP Pharm Inc. 12
WHO/TDR 13
Exploratory Projects
Medicines for Malaria Venture has received funding and support
Exploratory Project 990016
Heme polymerisation inhibition
U. California Berkeley
Orotate dehydrogenase inhibition
0
0
0
from the following organisations:
118’038
118’038
0
0
• Bill and Melinda Gates
Foundation
U. Leeds 15
Dihydrofolate reductase inhibition
0
14
50'000
50'000
0
0
• ExxonMobil Corporation
• Global Forum For Health
U. Mahidol 16
Research
Total USD
+
47
Grants committed mainly covered the effective
period from June 2001 to June 2002
6’081’667
1 Glaxo Smith Kline (Madrid, Spain)
2 University of Bristol, UK
3 London School of Hygiene and Tropical
Medicine, UK
4 F. Hoffmann–La Roche AG (Basel, Switzerland)
5 University of Nebraska, USA
6 Swiss Tropical Institute, Basel, Switzerland
7 Monash University, Melbourne, Australia
8 Glaxo Smith Kline (Philadelphia USA)
9 University of California San Francisco, USA
10 Bayer A.G. Leverkusen, Germany
6’022’667
59’000
1 1 Hong Kong University of Science &
Technology, Hong Kong
12 Korea SP Pharm Inc., Korea
13 UNDP/World Bank/WHO Special Program
for Research & Training in Tropical
Diseases (TDR), World Health Organisation,
Geneva, Switzerland
14 University of California Berkeley, USA
15 Leeds University, UK
16 Mahidol University, Bangkok, Thailand
• International Federation of
• Rockefeller Foundation
• Swiss Agency for Development
Cooperation
• United Kingdom Department for
International Development
• World Bank
Pharmaceutical Manufacturers
• World Health Organization
Associations
• Roll Back Malaria
• Netherlands Minister for
• TDR
Development Cooperation
48
To the Governing Board of
Geneva
As auditors, we have audited the accounting records and the financial
statements (balance sheet, income statement, cash flow and notes) of the
Medicines for Malaria Venture (MMV) for the year ended December 31, 2001.
These financial statements are the responsibility of the Foundation’s
management. Our responsibility is to express an opinion on these financial
statements based on our audit. We confirm that we meet the legal
requirements concerning professional qualification and independence.
Our audit was conducted in accordance with auditing standards promulgated
by the profession in Switzerland, which require that an audit be planned
and performed to obtain reasonable assurance about whether the financial
statements are free from material misstatement. We have examined on a
test basis evidence supporting the amounts and disclosures in the financial
statements. We have also assessed the accounting principles used, significant
estimates made and the overall financial statement presentation. We believe
that our audit provides a reasonable basis for our opinion.
In our opinion, the accounting records and financial statements comply with
the Financial Regulations of the Foundation and the accounting principles as
described in the Appendix 4 of the financial statements.
Cover Illustration
We recommend that the financial statements submitted to you be approved.
Hospital for Tropical Diseases, Mahidol University:
A 10 year old Karen boy (from the Thai/Myanmar border area),
who has severe, drug resistant malaria, in the intensive care unit,
prepares to take his artesunate tablet.
Photo courtesy of: WHO/TDR/Crump
PricewaterhouseCoopers SA
MMV logotype
The MMV logotype was designed by Rick Vermeulen of Rotterdam
in The Netherlands, winner of a worldwide design competition
held in 1999.
Photograph Credits
J.-P. Gallay
J.-A.-Ducrest
p.
2 WHO/TDR/Sawyer
p.
6 WHO/TDR/Crump
p.
8 WHO/TDR/Martel
p. 16 WHO/TDR
Geneva, March 8 th, 2002
p. 34 WHO/TDR/Reiler
p. 38 WHO/TDR
Concept and Graphic Design
Appendices
Grey Worldwide, Geneva
Photolithography
Financial statements (balance sheet, income statement, cash flow and notes)
Thiong-Toye Associés S.A., Geneva
Printing
TPC Sprint S.A., Geneva, April 2002
MMV – Medicines for Malaria Venture
P.O. Box 1826
CH - 1215 Geneva 15, Switzerland
Phone +41 22 799 4060
Fax +41 22 799 4061
info @mmv.org
www.mmv.org

2 0 1 MMV ANNUAL REPORT

Transcription

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