Research and Development inPediatric Neglected Diseases

Isabela Ribeiro

First Latin American Workshop in Pediatric Pharmacology Research

Buenos Aires, Argentina October 28, 2011

Bes

t Sci

ence

for t

he M

ost N

egle

cted

World pharmaceutical market$837 bn in 2009*

Neglected Diseases

Most Neglected Diseases

Global Diseases

Neglected Diseases: - primarily affect developing countries

- lie outside the world market

*Source: IMS Health, 20.04.2010

Bes

t Sci

ence

for t

he M

ost N

egle

cted

~ 139 Million

Bes

t Sci

ence

for t

he M

ost N

egle

cted

What’s Needed to Combat NTDs?

Hotez P, Pecoul B. "Manifesto" for Advancing the Control and Elimination of Neglected Tropical Diseases, PLoS NTDs, May 2010, Vol 4, 5, e718

Bes

t Sci

ence

for t

he M

ost N

egle

cted

Source: Chirac P, Torreele E. Lancet. 2006 May 12; 1560-1561.

15 years ago –a fatal imbalance and virtual standstill

Tropical diseases:18 new drugs(incl. 8 for malaria)

Tuberculosis: 3 new drugs

1.3% 21 new drugs for neglected

diseases98.7% 1,535 new drugs

for other diseases

(1975-2004)

Tropical diseases (including malaria) and tuberculosis account for:•12% of the global disease burden•Only 1.3% of new drugs developed

6

• Poorest of the poor• Living in remote

areas• Socioeconomic

burden on family and community

• Marginalised & voiceless patients

Among the mostneglected…

7

Neglected Diseases: Current Treatment Limitations

We Need Safe, Effective, Easy-to-Use, Adapted Treatments

Melarsoprol Eflornithine

• Ineffective (resistance)• Toxic• Expensive• Painful when delivered• Difficult to use• Not registered in

endemic regions• No paediatric

formulations or dosage forms

• Pediatric regimens extrapolated from adults

• Restricted by patents

Bes

t Sci

ence

for t

he M

ost N

egle

cted

Millennium Development Goals

Child Health

Bes

t Sci

ence

for t

he M

ost N

egle

cted

Neglected Diseases and Pediatrics

• Often the population with the highest prevalence and incidence

• Severity of disease: – Increased mortality– Increased likelihood of complications, impact on growth and

intellectual development

• Several examples: dengue, rabies, trachoma, buruli ulcer, Chagas disease, African Trypanosomiasis, echinococcus, etc

• No adapted formulations • Doses extrapolated from adults

Bes

t Sci

ence

for t

he M

ost N

egle

cted

Pediatric R&D• A change in momentum over recent years• Requirements of pediatric development plan

in the US and EU• Guidances on pediatric development,

selection of dosage form and pharmacokinetic studies

• Evaluation in children should start as early as possible. Initial studies can/should be carried in children if it represents the population most severely affected

Bes

t Sci

ence

for t

he M

ost N

egle

cted

Neglected Diseases –Special Issues

• Often small population size, challenges for study design and feasibility

• Regulatory consultation• Considerations on access from early in

development– Involvement of control programs– Affordability– Stable in conditions of use

Bes

t Sci

ence

for t

he M

ost N

egle

cted

Brazil

India

KenyaMalaysia

USA

DRC

Japan

Geneva CoordinationTeam + consultants

7 Founding Partners

• Indian Council for Medical Research (ICMR)

• Kenya Medical Research Institute (KEMRI)

• Malaysian MOH• Oswaldo Cruz Foundation

Brazil• Medecins Sans Frontieres

(MSF)• Institut Pasteur France• WHO/TDR (permanent

observer)

7 worldwide offices

• Non-profit drug research & development (R&D) organization founded in 2003

• Addressing the needs of the most neglected patients• Harnessing resources from public institutions, private industry and

philanthropic entities

DNDi: An innovative R&D model

Bes

t Sci

ence

for t

he M

ost N

egle

cted

DNDi’s Main Objectives

• Deliver 6 - 8 new treatments by 2014 for sleeping sickness, Chagas disease, leishmaniasis and malaria

• Establish a robust pipeline for future needs• Use and strengthen existing capacity in disease-

endemic countries• Raise awareness and advocate for increased

public responsibility

Bes

t Sci

ence

for t

he M

ost N

egle

cted

Innovative partnership with sanofi-aventis• Registered in 2007, prequalified

by WHO in 2008

• Registered in 30 sub-Saharan countries + India

• Over 80 million treatments distributed in 21 countries

• Only FDC with a 3 year shelf life

• Ambitious risk management plan (Pharmacovigilance)

India:• Registered in 2009

• Clinical studies with high efficacy results

• Easy to Use• Affordable• Field-Adapted• Non-Patented

© MSF

Available ASAQOver 80 million treatments distributed in Africa

Co-blistered non-fixed AS+AQArtesunate-amodiaquine

AS: 50 mg; AQ 153 mg

AS: 100 mgAQ: 270 mg

AS: 100 mgAQ: 270 mg

AS: 50 mgAQ: 135 mg

AS: 25 mgAQ: 67.5 mg

NEW Fixed-dose ASAQArtesunate/amodiaquine

3 dosage strengths available

Simplified 3-Day Dose Regimen of “ASAQ”

Adults (≥36 kg)

Children (17-35 kg)

Young Children (8-17 kg)

Infants (4.5-8 kg)

Available

Bes

t Sci

ence

for t

he M

ost N

egle

cted

ASMQFrom Brazil to Asia and Africa

• Registered by Farmanguinhos in Brazil in 2008 and implemented by the Brazilian national programme

• Successful technology transfer to Cipla (India)

• Cipla filing to WHO pre-qualification and Indian/ASEAN registration

• Positioning ASMQ:

• Clinical studies completed: Latin America (Brazil), Asia (India, Myanmar)

• Clinical studies on going: Africa (Tanzania, Burkina Faso, Kenya), Asia (Malaysia)

Available

Bes

t Sci

ence

for t

he M

ost N

egle

cted

ASMQSmall Tablets-Paediatric Strengths & Easy to use

Day 1

Day 2

Day 3

Once a day

INFANT DOSE< 1 YEAR Once a day

New FACT ASMQ

AS: 100mgMQ(salt): 220mg

NON-FIXEDAS and MQ

AS: 50mgMQ(salt): 250mg

Available

Bes

t Sci

ence

for t

he M

ost N

egle

cted

Current ways to administer to administer Benznidazole

Macerated tablet

Ressuspended em 10 mL

de água

Dose Equivalent in

Volume given with syringe

Oral administration

Oral administrationPowder with equivalent

dosage weigthted => capsules

Reconstituition of content from

capsules

Pediatric Benznidazole - The need

. 100 mg tablet fractionation in ½ (50mg), ¼ (25mg), etc

• Registration by Roche in 1971, now licensed to Lafepe • Supplied in 100 mg tablets, twice daily for 60 days

Bes

t Sci

ence

for t

he M

ost N

egle

cted

Selection of Dosage Form Pediatric Formulation

Bes

t Sci

ence

for t

he M

ost N

egle

cted

0

50

100

150

200

250

300

Perc

entu

al q

uant

ifica

do

BZN (1/8) BZN (1/4) 1 cp/10mL 1 cpmac/10 mL

1 cpmac/20mL

1 cp mac/100 mL

cp mac/env

Avaliação de formulações extemporâneas de benznidazol

Mínimo Máximo

cv = 23,82%

cv = 2,38%

cv =30,97%

cv =13,83%

cv =27,27%

cv =7,70%cv =2,75%

Pediatric Benznidazole - The needExtemporaneous formulations of benznidazole

Bes

t Sci

ence

for t

he M

ost N

egle

cted

Pediatric Benznidazole

Objective: An affordable, age-adapted, easy to use, pediatric formulation for Chagas disease

Definition of Tablet Strength and Formulation:

Target: 12.5 mg dispersible tablets for <20 kg children

12,5 mg1/8 = 12,5 mg100 mg 12,5 mg1/8 = 12,5 mg100 mg

Bes

t Sci

ence

for t

he M

ost N

egle

cted

Principal Investigator: Dr. Jaime AltchehHospital de Niños Ricardo Gutierrez, Buenos Aires, ArgentinaStudy sites: Buenos Aires, Santiago del Estero, Salta and JujuyPrimary objective: To describe the population pharmacokinetic parameters of benznidazole in children with acute or early chronic indeterminate form of Chagas Disease.

Target Recruitment: 80 patientsStudy status:

– FPFV: June 2011 (total of 29 patients recruited)

“Population Pharmacokinetics of Benznidazole in Children with CD”

Bes

t Sci

ence

for t

he M

ost N

egle

cted

Bes

t Sci

ence

for t

he M

ost N

egle

cted

Bes

t Sci

ence

for t

he M

ost N

egle

cted

Bes

t Sci

ence

for t

he M

ost N

egle

cted

Bes

t Sci

ence

for t

he M

ost N

egle

cted

Thank you!