Transcript Best Science for the Most Neglected

Neglected Diseases – a special case
Isabela Ribeiro
VI Pan American Network for Drug Regulatory
Harmonization Conference (PANDRH)
Strengthening of the National Regulatory Authorities in the
context of Health Systems
Brasilia, Brazil, 6 to 8 July, 2011
Best Science for the Most Neglected
Neglected Diseases:
- primarily affect developing countries
- lie outside the world market
Global Diseases
Most Neglected
Diseases
Neglected Diseases
World pharmaceutical market
$837 bn in 2009*
*Source: IMS Health, 20.04.2010
~ 139 Millions
Best Science for the Most Neglected
Best Science for the Most Neglected
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
Best Science for the Most Neglected
15 years ago –
a fatal imbalance and virtual standstill
Tropical diseases (including malaria)
and tuberculosis account for:
•12% of the global disease burden
•Only 1.3% of new drugs developed
(1975-2004)
Tropical diseases:
18 new drugs
(incl. 8 for malaria)
98.7%
1,535 new drugs
for other diseases
Tuberculosis:
3 new drugs
1.3%
21 new drugs
for neglected
diseases
Source: Chirac P, Torreele E. Lancet. 2006 May 12; 1560-1561.
Best Science for the Most Neglected
Product Development Partnerships (PDPs):
Filling the Gaps in Translational Research and
Product Development
Vaccine Development Program
HHVI
Combined PDP pipeline today includes 143 candidates
104 biopharmaceutical candidates in
development...
... and 39 diagnostic & vector control
candidates
Diagnostics
Pre Clinical
59
Phase I
57%
14%
15
Phase II
Feasibility
7
26%
Test
Development
7
26%
Evaluation
12%
12
6
Demonstration
Phase III
Registration
10%
10
6
Drugs
Vaccines
Microbicides
6%
6
0
4%
Country
Adoption
2%
2
Launched
1
0
2
4
40
60
# candidates
6
8
5
IVCC
In
Development
7
0
Notes: Includes products not funded by Gates Foundation.
Biopharmaceutical candidates in development Include: IAVI, IPM, IVI, GATB, Aeras, MMV, MVI, MVP, PVS, DNDi, iOWH, PDVI, HHVI.
Source: PDPs
Slides source from:
22%
CD4
FIND
IDRI
Vector control
Early Stage
20
22%
2
4
6
8
# candidates
&
7
Countries Burdened with
Neglected Tropical Diseases
WHO, 2010
8
Responding to the Needs of Patients
Suffering from Neglected Diseases…
Malaria
Sleeping Sickness (HAT)
Visceral Leishmaniasis (VL)
Chagas Disease
9
Human African Trypanosomiasis (HAT)
or Sleeping Sickness
• 60 million at risk in sub-Saharan Africa
• Transmitted by the tsetse fly
• Difficult to diagnose; many patients go
undiagnosed until late stage of disease
• Fatal if untreated
• Needs:
• A safe, effective, and practical stage 2
treatment
• A simple stage 1 treatment
10
Visceral Leishmaniasis (VL)
• 200 million at risk worldwide (in 70
countries)
• Transmitted by the sandflies
• Symptoms: prolonged fever, enlarged
spleen & liver, substantial weight of loss,
progressive anemia
• Fatal if untreated
• Current drugs: antimonials,
Amphotericin B, AmBisome®,
miltefosine, paromomycin
• Needs:
• oral, safe, effective, low-cost and
short-course treatment
11
Chagas Disease: A Silent Killer
• 100 million at risk in Latin America
• Kills more people in region than malaria
• Patient number growing in non-endemic,
developed countries
• Transmitted by ‘kissing bug’, blood
transfusion, organ transplantation, as
congenitally or orally
• Majority of patients undiagnosed until
late stage
• Needs:
• An affordable, age-adapted, safe, and
efficacious paediatric strength
• A new drug for early chronic stage
12
Among the most
neglected…
Poorest of the poor
Living in remote
areas
Socioeconomic
burden on family
and community
Marginalised &
voiceless patients
13
Neglected Diseases:
Current Treatment Limitations
• Ineffective (resistance)
• Toxic
• Expensive
• Painful when delivered
• Difficult to use
• Not registered in
endemic regions
• Restricted by patents
Melarsoprol
Eflornithine
We Need Safe, Effective, Easy-to-Use Drugs
14
Best Science for the Most Neglected
DNDi: An innovative R&D model
•
•
•
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
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
Geneva Coordination
Team + consultants
USA
Japan
India
DRC
Malaysia
Kenya
Brazil
Best Science for the Most Neglected
Vision
A collaborative, patients’
needs-driven, virtual,
non-profit drug R&D
organisation to develop
new treatments against the
most neglected
communicable diseases
Best Science for the Most Neglected
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 diseaseendemic countries
• Raise awareness and advocate for increased
public responsibility
Best Science for the Most Neglected
DNDi Portfolio-Building Model
• Existing
chemical
libraries
• New lead
compounds
Longterm
projects
• New formulations
(fixed-dose
combinations)
• New indications of
existing drugs
Mediumterm
projects
• Completing
registration dossier
• Geographical
extension
Shortterm
projects
Project Portfolio – June 2011
Discovery
Pre-clinical
Clinical
HAT LO Consortium
- Scynexis
- Pace Univ.
Nitroimidazole backup (HAT)
Fexinidazole (HAT)
Oxaborole SCYN7158 (HAT)
New VL treatments –
Bangladesh
VL LO Consortium
- Advinus
- CDRI
Alternative formulations of
Amphotericin B (VL)
Chagas LO Consortium
- CDCO
- Epichem
- Murdoch Univ.
- FUOP
Major Collaborators:
- Sources for hit and lead
compounds:
GSK, Anacor, sanofi aventis,
Merck, Pfizer, Novartis (GNF,
NITD), TB Alliance,…
- Screening Resources:
Eskitis, Institut Pasteur
Korea, Univ. Scynexis, U.
Dundee,…
- Reference screening centres:
LSHTM, Swiss Tropical &
Public Health, University of
Antwerp
Nitroimidazole (VL)
Drug combination (Chagas)
K777 (Chagas)
Flubendazole
Macrofilaricide (Helminth)
Exploratory
a robust
pipeline
New VL treatments –
Africa
New VL treatments –
Latin America
Benznidazole
Paediatric dosage form
(Chagas)
Azoles E1224
& Biomarker (Chagas)
Paediatric HIV
(exploratory)
Exploratory
Implementation
ASAQ (Malaria)
Fixed-Dose Artesunate/
Amodiaquine
ASMQ (Malaria)
Fixed-Dose Artesunate/ Mefloquine
NECT (Stage 2 HAT)
Nifurtimox – Eflornithine
Co-administration
SSG&PM co-administration
VL in Africa
New VL treatments in Asia
(SD AmBisome®,
PM+M / A®+M / PM+ A®)
6 to 8 new
treatments
by 2014
Best Science for the Most Neglected
Five Products Making a Difference
2007
ASAQ (Malaria)
Fixed-Dose
Artesunate/
Amodiaquine
Main Partners
sanofi-aventis
(France)
2008
ASMQ (Malaria)
Fixed-Dose
Artesunate/
Mefloquine
Farmanguinhos
(Brazil)
Cipla
• Easy to Use
(India)
2009
NECT
Nifurtimox Eflornithine
Co-Administration
(HAT)
2010
Paramomycin
+ SSG
(VL)
National Control Programs
MSF / Epicentre
Bayer / sanofi-aventis
WHO
• Field-Adapted
• Non-Patented
LEAP
National Programs
iOWH
2011
New VL treatments in Asia
(SD AmBisome®,
PM+M / A®+M / PM+ A®)
• Affordable
National Programs
ICMR, iOWH, TDR
Best Science for the Most Neglected
Chagas: Consolidating our Portfolio
Discovery
Lead opt. Consortium
Preclinical
Clinical
Azoles E1224
Phase 2
Available to patients
Paediatric Benznidazole
Lafepe
Best Science for the Most Neglected
Chagas
Azoles
E1224
• License signed with the Japanese pharma
Eisai for clinical development of
Ravuconazole for treatment of Chagas
disease funded by DNDi (September 29,
2009)
– E1224, pro-drug of ravuconazole, an
anti-fungal drug discovered by Eisai
– Implementation of Phase II clinical
trial in adult patients with chronic
indeterminate Chagas disease
(Bolivia, 2 sites in 2011)
• Study initiation in June 2011
Best Science for the Most Neglected
Chagas
Biomarkers in Chagas
• PCR study: optimization of sampling
procedures in chronic Chagas Disease (n=220)
– Collaboration with MSF Spain, Bolivia Mission (MSFOCBA) and UMSS
– Study initiation – April 13th (102 patients recruited)
• RT-PCR lab optimization and validation for
clinical studies
– Collaboration with UMSS, CEADES, CONICET
• NHEPACHA network for long term evaluation
of candidate biomarkers
• Coordination of activities with different
partners
– Work towards the integration of data on candidate
markers
– Participation in PAHO/TDR PCR meeting in B. Aires
– Collaboration with Univ. of Georgia and TBRI– nonhuman primate study
Chagas
Pediatric Benznidazole
Best Science for the Most Neglected
A pediatric formulation available in 2011
Benznidazole registered by Roche in 1971,
licensed to Brazilian government in 2003
Objective:
An affordable, age-adapted, easy to use,
pediatric formulation for Chagas disease
Current ways to administer in children
• 100 mg tablet fractionated or macerated for
administration
• High risk of delivering improper dosages
• 40-160% of Target BZ content
Target: 12.5 mg tablets for <20 kg children
DNDi-Lafepe agreement in 2008 for development
of pediatric formulation
100 mg
1/8 = 12,5 mg 12,5 mg
Best Science for the Most Neglected
Chagas
Chagas Clinical Research Platform
Objectives:
• Facilitate effective and efficient trials to
deliver improved treatment for Chagas
disease
• Strengthen institutional research
capacity
• Support an environment conducive to
quality research
• Develop a critical mass of expertise
• Define priority areas for clinical
evaluation of new treatments in Chagas
disease
• Conduct periodic review and update of
Target Product Profile in Chagas Disease
• Articulate with other initiatives
7-Year Results
•
•
•
•
•
•
•
2 new malaria treatments
1 new sleeping sickness combination
1 new visceral leishmaniasis combination for Africa
1 new visceral leishmaniasis combination for Asia
Largest pipeline ever for the kinetoplastid diseases
Clinical research platforms in Africa and Latin America
On track to deliver new treatments per business plan
Best Science for the Most Neglected
Global R&D funding
for neglected diseases
Neglected Diseases
$3.2 billion (US)
Public (LMIC* and
HIC** governments)
- 95% from HIC
gov.)
66.5
20.5
Kinetoplastids
$162 million (US)
=> 5% of the total!
Philanthropic
Public (LMIC*
governments)
12.9
58.6
Private (multi.
pharmas & small
pharmas and
biotechs)
Public (HIC**
governments)
Philanthropic
5.3
Source: Moran et al., G-Finder report,
Feb. 2011 Data 2009
33
Private (multi.
pharmas & small
pharmas and
biotechs)
3.2
*LMIC= Low- and Middle-Income Countries
**HIC= High-Income Countries
Best Science for the Most Neglected
DNDi Portfolio – ~100 M spent since 2003
Discovery
Pre-clinical
Clinical
HAT LO Consortium
- Scynexis
- Pace Univ.
Nitroimidazole backup (HAT)
Fexinidazole (HAT)
Oxaborole SCYN7158 (HAT)
New VL treatments –
Bangladesh
VL LO Consortium
- Advinus
- CDRI
Alternative formulations of
Amphotericin B (VL)
Chagas LO Consortium
- CDCO
- Epichem
- Murdoch Univ.
- FUOP
Major Collaborators:
- Sources for hit and lead
compounds:
GSK, Anacor, sanofi aventis,
Merck, Pfizer, Novartis (GNF,
NITD), TB Alliance,…
- Screening Resources:
Eskitis, Institut Pasteur
Korea, Univ. Scynexis, U.
Dundee,…
- Reference screening centres:
LSHTM, Swiss Tropical &
Public Health, University of
Antwerp
Nitroimidazole (VL)
Drug combination (Chagas)
K777 (Chagas)
Flubendazole
Macrofilaricide (Helminth)
Exploratory
a robust
pipeline
New VL treatments –
Africa
New VL treatments –
Latin America
Benznidazole
Paediatric dosage form
(Chagas)
Azoles E1224
& Biomarker (Chagas)
Paediatric HIV
(exploratory)
Exploratory
Implementation
ASAQ (Malaria)
Fixed-Dose Artesunate/
Amodiaquine
ASMQ (Malaria)
Fixed-Dose Artesunate/ Mefloquine
NECT (Stage 2 HAT)
Nifurtimox – Eflornithine
Co-administration
SSG&PM co-administration
VL in Africa
New VL treatments in Asia
(SD AmBisome®,
PM+M / A®+M / PM+ A®)
6 to 8 new
treatments
by 2014
Best Science for the Most Neglected
PDP costs will likely increase in the next
years
Risks in research and
development of pharmaceutical
drugs
(Preziosi, P. 2004, Nature Reviews in Drug
Discovery 3, 521-526)
Best Science for the Most Neglected
Access
• Need to facilitate equitable access to new treatments
• Unmet medical needs == often non-existing procurement
and distribution mechanisms and lack of traditional
commercial partners
• Important to full transition, in long term, new treatments to
natural implementers, i.e., Ministry of Health, National
Control Programmes, WHO, NGOs
Access strategies: pragmatic and focused on
most pressing “actionable” access barriers
Towards a global public health & equitable
access framework for R&D
WHO Global Strategy on Public Health, Innovation and
Intellectual Property
Incentives and financing mechanisms tailored to particular
stages of R&D, types of diseases and health technologies
are necessary to address existing gaps and the unmet
needs of neglected patients
Best Science for the Most Neglected
Increasing resources for neglected
disease R&D
• Investigate innovative sustainable funding for product development and
access
• Pilot milestone prizes to stimulate discovery of new clinical candidates
Reducing the costs of R&D for neglected
diseases
• IP management, open innovation and sharing of knowledge
• Accessing compounds and annotated data
• Negotiating freedom to operate, paving the way for access
• Pushing for transparency and sharing of knowledge
• Innovative regulatory pathways to expedite access in endemic regions
and strengthening local regulatory capacity
Best Science for the Most Neglected
Regulatory
• Historically, most new drugs for neglected diseases have been
submitted to regulatory authorities such as the U.S. Food and Drug
Administration, the European Medicines Agency, or SwissMedic, either
for routine regulatory review or under specific pathways such as orphan
drug legislation or expedited approval mechanisms
This regulatory process has drawbacks:
• Potential for delays in access, if there is a two-step process with
agencies waiting for regulatory decisions in the North before
commencing action
• It puts neglected disease product decisions in the hands of regulators
who have less experience in tropical disease products, presentations,
and epidemiology, and who are not accountable for the needs and
safety of target patients
Best Science for the Most Neglected
Current Regulatory Mechanisms
New Drugs for Neglected Diseases
Standard regulatory review by stringent authorities
• Routine regulatory review
• Orphan drug designation and review process
• Expedited review
Neglected disease-specific review by stringent authorities
• European Union: Article 58
• US FDA: “Tentative approval”
• WHO drug prequalification
Best Science for the Most Neglected
Regulatory Review by
Non-Endemic Countries
• Decades of regulatory experience to bear on assessment of
the neglected disease product
but
• Delayed access for target patients
• Inability to provide clear guidance on the clinical trial
design and the data required for marketing approval
• Lack of sufficient safety and efficacy data requirements for
wider use
• Inappropriate data requirements
• Inappropriate risk-benefit assessment for wider use
Best Science for the Most Neglected
“Registering New Drugs: The African Context”
DNDi-commissioned report, by the George Institute for International
Health.
Experts involved in this study expressed that African regulators have a
crucial role to play in assessing health tools being used to respond to
specific patient needs in their countries.
Key recommendations to strengthen regulatory authorisation processes in
Africa for new drugs against neglected diseases:
• Ensure closer collaboration between developing and developed countries
by involving regulators of endemic countries in regulatory assessments
of new drugs for neglected diseases;
• Extend WHO’s role in the prequalification process of new tools against
neglected tropical diseases, in addition to HIV/ AIDS, malaria, and
tuberculosis; and
• Strengthen regulatory capacity in Africa through the creation of Regional
Centres of Excellence in each of Africa’s main sub-regions.
Best Science for the Most Neglected
Regulatory Context – Latin America
- Unique opportunity of the PARF - Pan American
initiative for harmonisation of regulatory requirements
- Identification of Reference National Authorities
- Prioritization of diseases with public health impact
and affecting neglected populations
- Key examples in the region where not for profit
development and access on neglected diseases
could be facilitated by innovative review process
Best Science for the Most Neglected
Benznidazole
- Product developed by Roche and registered in Brazil and Argentina in
the 70’s
- Licensed to LAFEPE, second largest public laboratory in Brazil
- Following technology transfer, product registered in Brazil in 2006
- Current status:
- 17 of 21 countries: Bz is listed among first line treatment for
Chagas disease
- 6 of 21 countries include it in the Essential Medicines List
- 6 of 21 countries product is currently registered
- Well-recognised bottleneck in product availability in the countries:
difficulties in importation process and distribution issues
- Adult and new pediatric presentation would benefit from concerted
review and action from regulatory authorities in the Latin American
region
Best Science for the Most Neglected
R&D of new candidate drugs for Chagas
- Challenges of the assessment of therapeutic
response in Chagas disease has hampered drug
development for many years
- No available early test of cure
- Several meetings indicate that current marker of
choice for assessment of therapeutic failures in
Chagas: PCR
- Regional mechanisms for consultation and agreement
with regulatory authorities on R&D development
strategy and definition on necessary steps for
registration of new products
By working together in a creative way, PDPs,
large and small pharma, and the public sector
can bring innovation to neglected patients!
Thank you!
www.dndi.org