Centre for Drug Candidate Optimisation - Case Study

Medicines for Malaria Venture - Drug Discovery Projects

Malaria is a devastating tropical disease caused by the mosquito borne parasite, Plasmodium falciparum, killing between 1 to 2 million people annually. There are approximately 300 to 500 million new clinical cases each year with the majority of victims being children under 5 years of age and pregnant women. Approximately 90% of malaria cases are found in sub Saharan Africa, but malaria also remains a significant problem in other parts of Africa, Asia and South America.

There is an urgent need to discover new and effective drugs at affordable prices to combat the existing drug resistance and provide effective therapies for poor, disease endemic countries. The Medicines for Malaria Venture (MMV, www.mmv.org) was founded in 1999 as a non-profit organisation focused on the discovery and development of new, affordable antimalarial drugs. MMV was among the first public-private partnerships established to tackle a major world disease, arising from discussions between the World Health Organisation (WHO), the International Federation of Pharmaceutical Manufacturers and Associations, and other key organisations. MMV receives funding from the Bill and Melinda Gates Foundation, Rockefeller Foundation, World Bank, ExxonMobil, WHO, BHP Billiton, Wellcome Trust, various governments and others. The Centre is a collaborative partner in two MMV funded projects.

Synthetic peroxide drug discovery project

The synthetic peroxide discovery project was initially funded by MMV in 2000 to identify a new class of fully synthetic, orally active peroxides, which are more potent than the available semi-synthetic artemisinins for the treatment of uncomplicated P. falciparum malaria, and which would provide a much lower cost of treatment when used in combination with an easy-to-use 3-day treatment regimen. The project team consists of medicinal chemists based at the University of Nebraska, USA, biologists and parasitologists from the Swiss Tropical Institute, Basel, Switzerland, and CDCO pharmaceutical scientists who conduct the ADME lead optimisation studies.

 The chemical scaffold of the series contains a 1,2,4 trioxolane moiety (referred to as “OZ” for ozonide) and as a class, these agents are potent inhibitors of the malaria parasite, both in vitro and in vivo, are active against all blood stages of the parasite, and exhibit a rapid onset of action. Similar to the artemisinin derivatives, the peroxide bond is required for biological activity.  A “first generation” development candidate (OZ277 - RBx11160) was identified and results were published in 2004 in the highly regarded international scientific journal Nature, attracting significant coverage in print and electronic media worldwide. The lead candidate from the first generation program has completed Phase 1 clinical trials and is currently being evaluated in Phase 2 trials in malaria patients.

With the insights gained from the first generation lead candidate, and having established the unique nature of the compound class, the “next generation” OZ project began in 2005. The original project goals were extended to identify novel synthetic peroxides with greater pharmacodynamic efficacy, giving the potential for a single-dose oral cure when used in combination with a partner drug. In addition, the aim was to identify synthetic peroxides which have the potential for prophylaxis and intermittent preventative treatment in pregnant women and infants (IPTp and IPTi).

Using a  rational design approach which integrated data from in vitro and in vivo assays, the project team was able identify a new series of compounds with greatly improved properties over the first generation candidate. The next generation compounds provide a single dose oral cure in mouse models of malaria, and greatly exceed the efficacy of comparator compounds in this model. These new compounds also show prophylactic activity, and have a much simpler synthetic route than the first generation compounds which should provide a low cost of treatment.  A clinical development candidate has recently been selected, and preclinical testing is being undertaken to support Phase 1 testing in 2009.

Dihydrofolate Reductase (DHFR) inhibitors drug discovery project

Inhibition of the DHFR enzyme within the parasite disrupts the synthesis of essential folate cofactors, which are ultimately required by the parasite for DNA synthesis. Historically, the DHFR enzyme has been a major molecular target for the treatment of malaria, although point mutations in the enzyme have resulted in the emergence of drug resistance and have limited the clinical success of many older agents such as proguanil, which was originally discovered in the 1960s.

Recent exploration of the structural biology of the DHFR enzyme mutations has revealed that the capability of the DHFR enzyme to mutate is self-limited by the necessity to bind native folate substrates. A maximum of four possible point mutations have been identified and this limited number of mutations provides the opportunity to rationally design, synthesise and assess antimalarial agents, which are active against this validated 'quadruple mutant' target.

An integrated screening approach has been adopted for the iterative assessment and optimisation of orally active DHFR inhibitors and draws upon international expertise. The project partners for this discovery project are BIOTEC at the Thailand National Science and Technology Development Agency (synthetic chemistry, structural biology and in vitro testing), the London School of Hygiene and Tropical Medicine (in vitro / in vivo biological evaluation) and CDCO / Monash University (ADME and lead optimisation).

The initial steps for the project were to identify the ADME limitations for early lead compounds and to overcome these issues through structural modification of the chemical scaffold.