Shedding light on antimalarial drug flows · 2012-06-05 · Shedding light on antimalarial drug...

Shedding light on antimalarial drug flows

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MMVreport_ 20120503_PROD3b.indd 12 04.05.12 09:50

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Better medicines for uncomplicated malaria 3

Artemisinin-based combination

therapies (ACTs) are currently

the best medicines available

to treat uncomplicated malaria but un-

fortunately many patients lack access

to them. Thanks to donor investment

in recent years ACT procurement has

steadily increased, but poor supply

chain management often leads to

stock-outs of antimalarials at points-

of-care, causing needless suffering.

Better understanding of the supply

chain can help prevent stock-outs

and enable better measurement of

access initiatives and the impact of

donor support. With these goals in

mind, MMV is working with a variety

of partners on two key initiatives. The

first, ‘Pharmaceutical market sizing’,

determines the type and volume of

medicines arriving in-country; the

second, ‘SMS for Life’, uses mobile

phones to monitor stock levels at the

other end of the supply chain, the point-

of-care. Taken together, they provide

a holistic picture of the supply and

availability of antimalarial medicines.

Pharmaceutical market sizing: the Zambian experience

To better understand the pharma-

ceuticals market in Zambia, a

collaboration between IMS Health*

and the Pharmaceutical Regulatory

Authority of Zambia has built up a

user-friendly database on the types

of products available on the Zam-

bian market. These data provide an

understanding of how the market

has changed since ACTs became

widely available, what market share

different classes of medicines have

in Zambia, and what happens when

policy changes and new drugs

become available. These data can

also be used to regulate the quality

of medicines entering the country.

This is the first systematic and

regular collection and dissemination

of pharmaceutical market sizing

information for an African ministry

of health.

Mrs Esnet Mwape

Director-General, Pharmaceutical

Regulatory Authority, Zambia,

explains how the project has helped

to better regulate the medicinal

products coming into Zambia.

What information has been

collected in Zambia to date and

how is it being used?

We have been able to collect data on

the brand, manufacturer and quan-

tity of most of the medicinal products

coming into the country since 2008.

This has enabled us to ensure that

only those products authorized by the

Pharmaceutical Regulatory Authority

actually enter. We can also corrobo-

rate the import data with the medi-

cines available in our pharmacies and

health-care facilities and follow up if

they do not correspond. Using these

data we have been able to respond

to donors wishing to track how their

funds have been spent. At the click of

a button we can find out which pro-

ducts have been imported, when and

in what quantities.

Why is this important?

We need to be sure that the medicines

coming into Zambia are of high quality

and not counterfeit or substandard.

Tackling this problem is important not

only to ensure the safety and appro-

priate treatment of patients now, but

also to prevent the emergence of drug

resistance in the future.

Having access to these data has been

like turning a light on in a dark room.

Imagine that the room is the country with

a door that allows medicines to come

in. We can now see much more clearly

what medicines are coming through

the door and therefore what needs to

be done to improve their transit to their

final destination – the patients. The next

step will be to use these data to better

manage the supply chain of medicinal

products.

Having access to these data has been like turning a light on in a dark room.

From procurement to patients

IMS Health is a leading

information provider

for the health-care

industry, covering

markets in more

than 100 countries.

*

“

”


1414

Mr Winna Shango

Acting Chief Pharmacist, Ministry

of Health and Social Welfare,

Tanzania, tells us how the SMS

for Life programme is motivating

health-care workers in Tanzania.

What has been the impact of

SMS for Life in Tanzania?

We now have a completely new pers-

pective; we have a clearer picture of

stock status in all facilities across

the country on a weekly basis. With

this information we are better able to

manage the supply of commodities.

Moreover, the weekly reporting is

helping to build a database of informa-

tion that can be used to forecast future

needs and therefore improve overall

supply chain management. The pro-

gramme has also helped to motivate

health-care workers to continue report-

ing, as they see their actions result in

stock being replenished.

What are the next steps for

SMS for Life in Tanzania?

We would like to include the reporting

of stock levels for more life-saving

medicines and other medical commo-

dities. These collated data could be

made available to all the programme

officers in the Ministry of Health and

Social Welfare working on other

diseases, to improve the supply of

medicines across the board.

In addition to financial support,

what have been the benefits of

working with MMV?

MMV provided a great deal of support

with communication on a number of

levels. They helped to coordinate with

commodity providers; it helped that

MMV knew which providers could

offer the best deal and also that they

could provide neutral advice, as MMV

doesn’t have a financial incentive.

Preventing stock-outs: SMS for Life

At the other end of the supply

chain, SMS for Life uses widely

available SMS technology to

record antimalarial stock levels

at the point-of-care. Informa-

tion is collated in a central

database and used to display

countrywide stock availability by

district and health facility. Facilities

at risk of stock-out can then be

replenished with the needed

supplies.

Following a pilot in 2009 support-

ed by Novartis and other imple-

menting partners*, SMS for Life

was scaled up in 2011 to cover

all 133 districts of Tanzania with

technical and financial support

from MMV, the Swiss Develop-

ment Corporation and a number

of other partners. By the end of

2011, health-care workers in 5,099

health facilities had been trained,

covering the whole country. Today

the national programme is led by

the Ministry of Health and Social

Welfare.

In Kenya, MMV is working with

the National Malaria Control Pro-

gramme and Kenya Medical

Research Institute (KEMRI)/the

University of Oxford, to assess how

this technology can also be used to

gather malaria case-management

information. This additional data on

the number of fever cases, the use

of rapid diagnostic tests and the

appropriate treatment of patients

with ACTs, will support better mon-

itoring of care for malaria patients

and ultimately lead to improved

health outcomes.

With this information we are better able to manage the supply of commodities.

They shared experiences with the

programme in other countries such as

Kenya. Also, they helped disseminate

information to the scientific communi-

ty at the American Society of Tropical

Medicine and Hygiene annual confer-

ence. This enabled the programme

implementers to have the opportunity

to discuss and share ideas with other

experts in the area.

Google Inc., Voda-

fone Group PLC, IBM

and the Roll Back

Malaria Partnership

*

“

”


15

Ensuring safety of new medicines

of around 10% of patients can be

followed more closely if there are any

specific concerns with the medicine.

Why is pharmacovigilance a

priority for MMV now?

Our pipeline is maturing and we now

have three co-developed ACTs that

have been stringently approved. We

must follow these new medicines to be

sure their safety is equally as valid in the

real world as it was in the clinical trials.

We do not want to put patients at risk.

What are the key pharmaco-

vigilance projects that MMV is

working on?

Sanofi, DNDi * and MMV are under-

taking a Phase IV field event cohort

monitoring study to assess the real-life

safety and effectiveness of the fixed-

dose ACT, artesunate-amodiaquine

(AS-AQ), developed by DNDi, Sanofi

and partners. The study has now re-

cruited half the necessary patients in

the health district of Agboville, Côte

d’Ivoire, where AS-AQ is used as

first-line treatment.

We are also planning a pharmaco-

vigilance study of recently approved

Eurartesim® (dihydroartemisinin-

piperaquine, DHA-PQP; see page 20)

with INESS** in four African countries:

Ghana, Tanzania, Burkina Faso and

Mozambique. The studies will begin

once registration has been obtained in

each of the countries. There are also

plans to conduct a similar study with

Pyramax® (pyronaridine-artesunate)

in the Mekong Delta region, and in

association with DNDi, with other

ACTs in northern India.

Once completed, what implica-

tions might these studies have

for the use of the medicines?

Sufficient evidence, be it positive

or negative, can have the potential

to change the recommendations stip-

ulated on the drug label and therefore

the way the medicine can be used.

Monitoring post-approval

drug safety has become

a matter of increasing

importance, as it enables us to

maximize the safe use of registered

medicines. Prior to registration, new

ACTs are evaluated in clinical trials

– like all new drugs – but trials are

typically conducted in a limited

number of patients (~2,000). Due

to strict inclusion criteria in the

selection of patients for clinical trials,

these cohorts might not fully reflect

the actual population receiving the

treatment. To overcome this, it is

necessary to collect post-approval

safety data from larger cohorts of

patients in real-life settings (pharma-

covigilance).

Dr Stephan Duparc

Chief Medical Officer, MMV,

explains what pharmacovigilance

means for MMV.

How is pharmacovigilance

usually carried out?

Post-launch safety data can be collected

either passively or actively. In an ideal

world all patients experiencing an

adverse event would report it to their

physician, who in turn would report it

to the pharmaceutical company, who

would report it to the regulatory author-

ity. This is known as passive reporting.

Unfortunately, most of the time this

process does not work optimally, par-

ticularly in malaria-endemic countries;

often patients and physicians simply

don’t report these events.

Alternatively, pharmacovigilance data

can be collected actively via Phase IV

event monitoring studies. These studies

are designed to detect adverse events

classified as ‘rare’, which occur in

between one in 3,000 and one in

5,000 patients. To detect such events,

between 10,000 and 15,000 patients

must be followed. They take the first

course of treatment at the clinic and

then go back home. A health-care

worker visits the patient at home

during the following week to see if there

are any problems. In addition, a subset

INESS: INDEPTH

Effectiveness and Safety

Studies of Anti-malarial

Drugs in Africa

DNDi: Drugs for

Neglected for Diseases

initiative

**

*


1616

Dr Fiona Macintyre

Associate Director, Translational

Medicine, MMV, tells us about

the development plan for OZ439.

To protect against the develop-

ment of drug resistance, the

World Health Organization

(WHO) recommends that every

medicine should be combined

with a partner drug. How

will this drug be selected for

OZ439?

At the moment we are considering

four drugs as potential partners. The

acid test to determine which we take

forward will be the Phase IIb combina-

tion efficacy and safety clinical studies

in malaria patients.

With four combinations to work on,

before we get to that stage there is

a tremendous amount of work to be

done. We are currently conducting

non-clinical and clinical safety stu-

dies on these drugs, both alone and

in combination with OZ439 in an at-

tempt to discriminate between them.

It is really important that we conduct

the right experiments at this point and

carry them out thoroughly, to fully un-

derstand the pros and cons of each

potential partner drug.

With such a complex develop-

ment plan ahead, how will MMV

ensure OZ439 is ready to treat

patients as quickly as possible?

By conducting several projects in

parallel, we increase the likelihood

of success. It takes a finite amount

of time to develop drug formulations

for each combination and to conduct

clinical studies. But if we conduct

these studies for each partner, as far

as possible in parallel, we can get to

the point where we can make a fully

informed decision on which combina-

tion to choose much faster than if we

were to do them sequentially. This is

why we are investing a great deal into

this project now.

How will we know if OZ439

is fully efficacious against

artemisinin-resistant strains

of malaria?

We plan to test OZ439 in patients with

potential artemisinin-resistant malaria.

Testing in these patients is the only real

way we can answer the question. The

challenge, thankfully in many ways, has

been to identify sufficient patients with

whom to conduct the study.

We have partnered with Mahidol Uni-

versity scientists in Thailand to help

identify further sites of artemisinin resis-

tance. This will then allow us to decide

the best place to conduct the study.

While ACTs are available

and access to them is

improving, MMV cannot

rest on its laurels, but must con-

tinue to innovate and develop better

medicines for uncomplicated mala-

ria. There is a real need for medi-

cines that are simpler and easier to

take, such as a single-dose cure.

Not only would such a medicine

facilitate ‘directly observed therapy’,

which would help to prevent the

emergence of drug resistance,

it would also reduce the cost of

treatment.

2011 witnessed the continued

progress of several potential anti-

malarial compounds through the

pipeline. Results of the ongoing

Phase IIa study of MMV’s synthe-

tic endoperoxide OZ439 continue

to show that the compound is not

only potent, but also has the poten-

tial to become the breakthrough

single-dose cure for Plasmodium

vivax and Plasmodium falcipa-

rum infection. Furthermore, given

the structural differences between

OZ439 and the artemisinins, there

is also hope that it will be efficacious

against artemisinin-resistant strains

of malaria. The challenge now is to

find the right partner medicine and

the right dose.

OZ439Medicines for Malaria Venture

Phase IIa

Project Leader: Dr Fiona Macintyre, MMV

All shots on goal for a single-dose cure

STI


17

Scientist at St Jude’s

Research Hospital, TN,

USA, conducting high-

throughput screening

to identify compounds

with antimalarial

activity.


1818

MMV portfolio 4th quarter 2011

MMV’s portfolio is focused on deliver-

ing new antimalarial medicines that

are affordable, accessible and ap-

propriate for use in malaria-endemic

areas. Each medicine must provide

significant benefit compared to the

current gold standard treatment and

be active against all known resistant

strains of the parasite. Our goal is to

develop products that will provide a

range of benefits including:

A one-dose cure for

uncomplicated malaria

Potential for intermittent

treatments (infants and

pregnant women)

Safety in small children

(< 6 months old)

Safety in pregnancy

Efficacy against Plasmodium

vivax (including radical cure)

Efficacy against severe malaria

Transmission-blocking

treatment


19


2020

MMV Project of the Year 2011

Eurartesim®, dihydroartemisinin-

piperaquine (DHA-PQP), the

first novel chemical entity

developed by MMV (in partnership

with Sigma-Tau) is awarded MMV

Project of the Year 2011. With the

recent European Medicines Agency

(EMA) approval, this medicine can

now be used safely and effectively,

and be deployed widely.

Eurartesim offers important advan-

tages over currently used artemisi-

nin-based combination therapies

(ACTs): it is easier to administer –

once-a-day for 3 days as opposed

to twice-a-day – and, owing to the

long half-life of piperaquine, it also

offers better and longer protec-

tion from new malaria infections.1

Additionally, formulation develop-

ments mean it has a 2-year shelf

life in disease-endemic countries.

Although DHA-PQP was already

available, it could not be pur-

chased using donor funds since it

was not registered as being deve-

loped to international standards.

This hampered its widespread use.

The EMA approval has changed

that and the drug, in the form of

Eurartesim, now has the poten-

tial to treat many more vulner-

able people in malaria-endemic

countries. It was with this goal in

mind that MMV and Sigma-Tau

joined forces back in 2004.

Dr Marco Corsi

Medical Director, Neglected

Diseases Department (R&D),

Sigma-Tau.

As an Italian pharmaceutical

company, what motivated

Sigma-Tau to embark on the

development of a medicine to

treat malaria?

Our Founder and President, Dr Claudio

Cavazza’s vision was to improve

health and quality of life for people

worldwide. He also felt it was Sigma-

Tau’s responsibility to continue Ita-

ly’s scientific contribution to malaria.

In 2003, Dr Cavazza was in touch

with the Italian Minister of Health who

suggested the idea of the initial colla-

boration between Sigma-Tau, WHO,

MMV, Hollykin and the University of

Oxford. Dr Cavazza took a keen inter-

est in the development of the drug

but unfortunately, passed away a few

weeks before Eurartesim’s approval

by the EMA. We dedicate our work on

Eurartesim to his memory.

Why did the project team work

towards regulatory approval in

Europe for a drug that will be

predominantly used in Africa

and Asia?

As a small company we knew that we

did not have the resources and the

contacts to submit a regulatory dossier

in all malaria-endemic countries. We

also didn’t want to discriminate against

European patients. Submission to

the EMA was the best option as the

agency can act as a kind of consultant

to endemic countries. As such, with

EMA approval in hand the dossier can

now be filed and accepted much more

quickly in disease-endemic countries.

What did you gain from working

in partnership with MMV?

Without MMV, donor and procurement

bodies would not have been able to

obtain what is now considered one of

the best antimalarials.

MMV and Sigma-Tau were both integral

to the project. In terms of timing and

deadlines for each stage of the project,

the extra attention from MMV was really

valuable. Together we agreed on what

to do and when, and ensured we were

ready to modify the planning if needed.

Each time there was a hurdle or issue to

discuss we were able to overcome it via

the ingenuity of the group – we always

found a way to move forward. The

experience certainly proved that two

organizations are better than one!

On a more personal note, we received

lots of support at critical moments in

the early stages of the project from

Chris Hentschel and Carl Craft (former

MMV CEO and CSO, respectively).

David Ubben (MMV Project Director)

became a superb friend as well as

partner. For me the development of

Eurartesim has been the highlight of

my professional career. Few drugs for

western diseases could be defined

as real breakthroughs. Working on

a medicine with the potential to save

and change so many lives is really the

opportunity of a lifetime.

What are the next steps to ensure

Eurartesim reaches as many

patients in need as possible?

We are looking to work with a com-

mercial partner for the distribution of

the medicine across disease-endemic

countries. We will first need to register

Eurartesim in these countries and,

Eurartesim® (dihydroartemisinin- piperaquine)

Sigma-Tau Industrie Farmaceutiche

Riunite, Italy

Approved by a stringent regulatory

authority (EMA)/Phase IV

Project Leader: Gianemilio Stern, Sigma-Tau

MMV Project Director: Dr David Ubben

Dr Marco Corsi and Dr David Ubben explain why the two organizations embarked on the Eurartesim development project, the lessons learnt and what the future holds.

Valecha N et al. “An

open-label, randomised

study of dihydroarte-

misinin-piperaquine

versus artesunate-

mefloquine for

falciparum malaria

in Asia.” PLoS One.

5(7):e11880 (2010).

1


21

Dr David Ubben

Director, Clinical Development,

MMV.

With the approval of Eurartesim,

there are now several ACTs

available for the treatment of

malaria. Why is this important?

By providing a range of therapies

to treat malaria we enable disease-

endemic countries to adapt control

strategies to their specific needs.

The use of multiple first-line therapies

against malaria potentially yields

a better clinical and public health

outcome than using a single ACT.

Using different therapies could also

delay the emergence of resistant

strains of parasite. Besides these

key benefits, having multiple choices

means better prices and supply,

driven by the performance of the

suppliers.

What was the biggest challenge

in the development and regis-

tration of this combination?

There were many challenges, but

the one that stands out for me was

answering all the questions that the

EMA had in response to the submis-

sion of the dossier. The response

necessitated three further clinical

trials to be completed in the space

of 6 months. Even for an extremely

large pharmaceutical company this

would be a challenge.

With so many questions to answer in

such a short period of time Sigma-

Tau’s response rapidly transpired into

nothing short of inspirational. They

made the decision to commit all the

resources they had to answering the

questions. People worked until mid-

night for months on end to formulate

what ended up as a 12,000-page

reply. We worked together to come up

with the very best answers and sup-

port them with sound data. Together

we were able to demonstrate Eurar-

tesim is a medicine that meets the

highest quality standards.

What do you believe has been

the secret of the Eurartesim

project’s success?

There was no secret per se; the suc-

cess of the project was down to the

fact that we had a great drug, a pas-

sion to help those who suffer from ma-

laria, and a persistent and dedicated

team.

What has the experience taught

you?

Throughout the project I certainly

came to appreciate the ingenuity

and dedication of our Italian partners.

When we received the EMA appro-

val it was a real pleasure to see this

dedication and passion rewarded with

success. But the best reward is still to

come, when the medicine treats many

patients suffering from malaria, and

saves lives.

Representatives of the Eurartesim development team at the European

Medicines Agency, London, UK. Marco Corsi (kneeling in the front row)

and David Ubben (third from the right)

Thumbnail: The late Dr Claudio Cavazza, Founder, Sigma-Tau

with the help of MMV, implement an

access and delivery plan to guarantee

the distribution of the medicine to the

remotest villages. To continue to improve

our understanding of the medicine and

potentially expand its use beyond treat-

ment to, for example prevention, post-

approval studies are important. There

are already plans to use Eurartesim in

about 20 independent studies.

Additionally, Sigma-Tau will continue

to partner with MMV for the develop-

ment of the child-friendly dispersible

tablet, with the objective of submitting

the dossier in 2014.

... the best reward

is still to come, when

the medicine treats many

patients suffering from

malaria, and saves lives. David Ubben

“

”


Shedding light on antimalarial drug flows · 2012-06-05 · Shedding light on antimalarial drug...

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