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 the last five years � Real growth of $166 million between 1993 and 2004 * � The 2007 estimated total funding for R&D is US$ 422 million � NIH and Gates Foundation make up over 40% of 2007 funding.
Ev Evolution of spending on malaria R&D olution of spending on malaria R&D Source: Roll Back Malaria Partnership: http://www.rollbackmalaria.org/gmap/1-4.html �
New Malaria Ne w Malaria relat related Organizations and d Organizations and Initiatives Initiativ Medicines for Malaria Venture (MMV) PPP engaged in discovery, development and 1999 delivery of new affordable drugs The PATH Malaria Vaccine Initiative PPP accelerating the development of malaria 1999 vaccines (MVI) Malaria Research Reference Reagent Biological resource center providing research 1998 reagents for free to malaria scientists Resource Center (MR4) Multilateral Initiative on Malaria (MIM) Strengthen research and containment capacity 1997 of Malaria endemic countries Partnership facilitating coordination and 1998 Roll Back Malaria (RBM) interaction between many players involved in Malaria BioMalPar A network that coordinates malaria research, 2002 funded by the European Commission Malaria R&D Alliance Drew up a report about how to coordinate 2006 efforts between 15 organizations conducting malaria R&D
Pathogenesis Pathogenesis � Protozoan parasite Plasmodium transmitted by mosquitoes � Two stages � Infection of the hepatic system � Infection of the red blood cells
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
Current treatment f Current treatment for malaria -2 r malaria -2 Ar Artemisinin misinin Quinine Quinine Artemisinin is a sequiterpene lactone Quinine is a natural white crystalline alkaloid derived from the plant Artimisia annua. derived from the bark of the Cinchona tree. It was first used as a therapeutic in the 17 th It is only produced under conditions of abiotic stress century
Challenges with clinical trials in Challenges with clinical trials in the the de developing w loping world orld Major Pr Major Problems oblems Recent solutions cent solutions • State of healthcare systems in • Recent inflow of funding has developing world countries lead to formation of groups (particularly African nations) such as the European and • Lack of basic resources storage Developing Countries Clinical for drugs, sterile equipment etc Trials Partnership (EDCCTP) • Lack of qualified personnel with • Further attempts to standardize relevant understanding of clinical trial protocols and clinical trials provide international oversight • Politics & Corruption • Use of placebo that provide • Ethical considerations 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
WHO St WHO Steps fr eps from malaria contr om malaria control t ol to elimination o elimination Source: WHO, 2008
Stage of Malaria Contr Stage of Malaria Control Source: WHO, 2008
ACTs s are WHO recommended are WHO recommended fr front-line ont-line treatment treatment WHO, 2008
Eurar Eurartesim- esim- an A an ACT CT containing containing dih dihydr ydroar oartemisinin and emisinin and piperaq piperaquine ine Goals: NEt 2 •Minimize drug resistance and prevent HN development of resistant strains •Affordable (cost less than $1 per dose) Cl N chloroquine •Accessible •At least as effective as current O O standard of care O O •Minimal side-effects OH dihydroartemisinin •Simple dosing (once per day)
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
Onse Onset of action and recrudescence af t of action and recrudescence after a er a single single oral dose of 1 oral dose of 100 0 mg/ k mg/ kg. . AS: Artesunate, CQ: Chloroquine, Mef: Mefloquine, OZ A, B, C: The second generation Ozonides
Anti-Malarial and Anti-Malarial and Pr Proph ophylactic A lactic Ability of bility of OZ439 OZ439 Prophylaxis Anti ‐ Malarial Activity Single 30 mg/kg oral dose 24 h prior to P. berghei infection Single 30 mg/kg oral dose to mice ( P. berghei ) (mice)
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).
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 of sporozoites � Subunit is packaged with the antigen of the hepatitis B virus � Focus of RTS,S vaccine is on infants and young children
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).
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
Treatment Com reatment Comparison Char arison Chart Eurartesim OZ439 RTS,S Produced by MMV MMV/ GlaxoSmithKline Penn Pharma Drug Type ACT Ozonide Vaccine Uncomplicated Uncomplicated Infants and Young Target Patient malaria, all malaria, all Children Current Phase Phase III Preclinical Prep. For Phase III Target p. vivax p. falciparum p. falciparum Estimated Time 2009 200? 2011 to Market
Conclusions Conclusions � Still one million deaths annually � Growing philanthropic support leading to more PPPs and drugs in the pipeline � Wide adoption of WHO guidelines for Malaria prevention and treatment � Ongoing drug development compliments preventive measures such as mosquito nets � Rapidly expanding ACT availability
Recommend
More recommend
