SLIDE 1
The Changing Landscape of Malaria Drug Development Ben Lin, Sarah - - PowerPoint PPT Presentation
The Changing Landscape of Malaria Drug Development Ben Lin, Sarah - - PowerPoint PPT Presentation
The Changing Landscape of Malaria Drug Development Ben Lin, Sarah Barkow, Elina Pradhan, Sameer Sabir, Ruth Krestin Principles and Practice of Drug Development December 4 th 2008 Fu Funding f for M Malaria R R&D Steady increase in
SLIDE 2
SLIDE 3
Ev Evolution of spending on malaria R&D
- lution of spending on malaria R&D
- Source: Roll Back Malaria Partnership: http://www.rollbackmalaria.org/gmap/1-4.html
SLIDE 4
Medicines for Malaria Venture (MMV)
PPP engaged in discovery, development and delivery of new affordable drugs 1999
The PATH Malaria Vaccine Initiative (MVI)
PPP accelerating the development of malaria vaccines 1999
Malaria Research Reference Reagent Resource Center (MR4)
Biological resource center providing research reagents for free to malaria scientists 1998
Multilateral Initiative on Malaria (MIM)
Strengthen research and containment capacity
- f Malaria endemic countries
1997
Roll Back Malaria (RBM)
Partnership facilitating coordination and interaction between many players involved in Malaria 1998
BioMalPar
A network that coordinates malaria research, funded by the European Commission 2002
Malaria R&D Alliance
Drew up a report about how to coordinate efforts between 15 organizations conducting malaria R&D 2006
Ne New Malaria w Malaria relat related Organizations and d Organizations and Initiativ Initiatives
SLIDE 5
Pathogenesis Pathogenesis
Protozoan parasite
Plasmodium transmitted by mosquitoes
Two stages
Infection of the hepatic
system
Infection of the red blood
cells
SLIDE 6
Current T Current Treatments f eatments for Malaria-1 r Malaria-1
- The first line of defense is prevention
– Mosquito Nets, DDT
- Combination therapy for uncomplicated malaria as mandated by WHO
is the gold standard
– ACT – Artemisinin Combination Therapy consists of an artemisinin derivative,
and a quinine derivative or antibiotic (eg. Artensunate + Mefloquine)
- Current treatments can be effective but has side-effects
– Type 1 Hypersensitivity – Long courses of medication – Use of single agents intended to be a part of combination therapy causes
resistance to drugs
- Artemisinin is not approved for use in the US
– Treatment is stratified according to region of exposure – Quinine derivatives in combination with antibiotics are the gold standard for
malaria
SLIDE 7
Current treatment f Current treatment for malaria -2 r malaria -2
Ar Artemisinin misinin Quinine Quinine
Artemisinin is a sequiterpene lactone derived from the plant Artimisia annua. It is only produced under conditions of abiotic stress Quinine is a natural white crystalline alkaloid derived from the bark of the Cinchona tree. It was first used as a therapeutic in the 17th century
SLIDE 8
Challenges with clinical trials in Challenges with clinical trials in the the de developing w loping world
- rld
Major Pr Major Problems
- blems
Recent solutions cent solutions
- State of healthcare systems in
developing world countries (particularly African nations)
- Lack of basic resources storage
for drugs, sterile equipment etc
- Lack of qualified personnel with
relevant understanding of clinical trials
- Politics & Corruption
- Ethical considerations
- Recent inflow of funding has
lead to formation of groups such as the European and Developing Countries Clinical Trials Partnership (EDCCTP)
- Further attempts to standardize
clinical trial protocols and provide international oversight
- Use of placebo that provide
benefit to patients, such as rabies and hepatitis vaccines
Key to the success in combating endemic disease is a substantial increase in cooperation between African countries with regards to clinical trials, healthcare and biomdical research
SLIDE 9
WHO St WHO Steps fr eps from malaria contr
- m malaria control t
- l to elimination
- elimination
Source: WHO, 2008
SLIDE 10
Stage of Malaria Contr Stage of Malaria Control
Source: WHO, 2008
SLIDE 11
ACTs s are WHO recommended are WHO recommended fr front-line
- nt-line
treatment treatment
WHO, 2008
SLIDE 12
Eurar Eurartesim- esim- an A an ACT CT containing containing dih dihydr ydroar
- artemisinin and
emisinin and piperaq piperaquine ine
N HN Cl NEt2 O O O O OH
Goals:
- Minimize drug resistance and prevent
development of resistant strains
- Affordable (cost less than $1 per dose)
- Accessible
- At least as effective as current
standard of care
- Minimal side-effects
- Simple dosing (once per day)
chloroquine dihydroartemisinin
SLIDE 13
SLIDE 14
OZ439 OZ439
second generation ozonide that
provides a single-dose oral cure (in combination) for patients with uncomplicated P. falciparum malaria
- potential for prophylactic treatment and intermittent preventative
treatment in pregnant women and infants (IPTpand IPTi)
- Development of OZ439 in its preclinical phase.
– Funded by MMV .
- Penn Pharma in UK will start developing and manufacturing OZ439 in
December of 2008.
- Clinical trials to start in Africa, Asia and the U.S. in 2009
SLIDE 15
Onse Onset of action and recrudescence af t of action and recrudescence after a er a single single oral dose of 1
- ral dose of 100
0 mg/ k mg/ kg. .
AS: Artesunate, CQ: Chloroquine, Mef: Mefloquine, OZ A, B, C: The second generation Ozonides
SLIDE 16
Anti-Malarial and Anti-Malarial and Pr Proph
- phylactic A
lactic Ability of bility of OZ439 OZ439
Prophylaxis
Single 30 mg/kg oral dose 24 h prior to P. berghei infection (mice)
Anti‐Malarial Activity
Single 30 mg/kg oral dose to mice (P. berghei)
SLIDE 17
Targets f rgets for V r Vaccine De accine Development elopment
Pre-erythrocytic stage
Prime against sporozoites to limit infection of liver cells.
Considered a promising approach because parasite numbers are still limited during initial infection. Blood stage
Defend against red blood cell invasion or endothelial
- cytoadhesion. Merozoites can only be targeted during the
brief windows between cell rupture and new cell invasion. Mosquito stage
Build immunity to gametocytes to reduce transmission
through mosquito vector. Does not alleviate symptoms of malaria but can slow outbreaks during high season.
De Perre. Lancet 364 (2004).
SLIDE 18
RTS,S V RTS,S Vaccine ccine
Created in 1987 GSK & Walter Reed Army Institute of Research Supported by the PATH Malaria Vaccine Initiative and the Gates
Foundation
Contains subunit of the circumsporozoite protein found on the surface
- f sporozoites
Subunit is packaged with the antigen of the hepatitis B virus
Focus of RTS,S vaccine is on infants and young children
SLIDE 19
RTS,S Clinical T TS,S Clinical Trial R ial Results esults
2004 Phase IIb study of children aged 1-4 in Mozambique
and 2005 single-blind extended follow-up:
Trial conducted during height of transmission season, when infective mosquito
bites averaged 38 per person per year
Antibodies against circumsporozoites and hepatitis B spike drastically Vaccine was found to:
- reduce the risk of malaria by 29%
delay the time to first infection
by 45%
reduce the incidence of severe malaria
by 49%
Vaccine effectiveness extends past 21
months.
Alonso et al. Lancet 366 (2005).
SLIDE 20
What t What to Expect in Expect in the Near F the Near Future uture
Vaccine is expected to enter Phase
III trials (the first malaria vaccine to do so) by the end of this year
Aiming to submit to regulatory
authorities by 2011.
RTS,S applying for inclusion in the
Expanded Program of Immunization
SLIDE 21
Eurartesim OZ439 RTS,S Produced by MMV MMV/ Penn Pharma GlaxoSmithKline Drug Type ACT Ozonide Vaccine Target Patient Uncomplicated malaria, all Uncomplicated malaria, all Infants and Young Children Current Phase Phase III Preclinical
- Prep. For Phase III
Target
- p. vivax
- p. falciparum
- p. falciparum
Estimated Time to Market 2009 200? 2011
Treatment Com reatment Comparison Char arison Chart
SLIDE 22