Next Generation OZ
(a synthetic peroxide)
The introduction of ACTs has had a profound impact on the treatment of malaria. The World Health Organization has endorsed this therapy as first-line treatment for uncomplicated Plasmodium falciparum malaria, and as many as 150 million people were treated in 2007. However, the world cannot rely solely on ACTs as the only class of drugs to treat malaria. The potential for the emergence of resistance to artemisinin is real, and clinical experts are of the opinion that this might soon affect clinical outcomes. To stay one step ahead of resistance and have better treatment options ready to supplement or replace ACTs, MMV is supporting the development of affordable and effective synthetic alternatives to artemisinin.
The clinical utility of ACTs relies heavily on the rapid onset of action and potent antiparasitic activity of the artemisinin component. Building on this strength, the project team has designed a new generation of synthetic peroxides with improved properties, which could provide a more convenient dosing regimen leading to better patient compliance compared with some of the therapies currently available.
In addition, the new synthetic peroxides could show a different profile of efficacy, which would be an important feature should artemisinin-resistant strains ever become a significant issue in the years ahead.
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 chemical scaffold of the compound series contains a 1,2,4 trioxolane moiety, referred to as “OZ” for ozonide.
As a class, these agents are potent inhibitors of the 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. In the early stages, a first generation development candidate (OZ277/RBx11160) was identified.
However, development of this compound was discontinued because it did not meet MMV’s target product profile for new antimalarial drugs.
With the insights gained from the first lead candidate, and having established the unique nature of this class of compounds, 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 for intermittent preventative treatment in pregnant women and infants (IPTp and IPTi).
To achieve the goals of a single-dose oral cure and prophylaxis, the project team predicted that a substantial increase in the plasma drug exposure profile following oral administration would be required.
Initially, a series of mechanistic studies showed that the in vivo clearance of prototype compounds was partially due to a reaction with iron-containing components present in red blood cells. The team quickly focussed on this bloodmediated chemical instability pathway
as a means of reducing clearance and increasing the plasma exposure of the drugs. This was a challenge, since the same iron-mediated cleavage of the peroxide bond causing compound breakdown is also thought to be part of the mechanism of biological activity against the parasite. By a rational design approach, which integrated data from in vitro and in vivo assays, the project team was able to tease apart these two activities. The resultant compounds show much less blood-mediated degradation, reduced in vivo clearance, and therefore increased plasma exposure to the drugs, but still maintain potent antimalarial activity.
The next generation compounds provide a single-dose cure in mouse models of malaria, and greatly exceed the efficacy of artemisinin comparators 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. The project team is now conducting the final series of experiments to enable selection of a clinical development candidate.
The project team
The work of the OZ team – which has remained together since the beginning of the project – is an excellent example of focused and results-driven scientific drug discovery, supported by the product development partnership (PDP) model that has proved to be successful in creating synergies and leveraging the best from the private and public sectors. The team’s success was built on the integration of the specialized ozonide chemistry in the laboratory of Professor Jonathan Vennerstrom ( University of Nebraska ), the in-depth understanding of the metabolism and pharmacokinetic properties provided by the research group of Professors Susan and Bill Charman (Monash University), and the in vitro and in vivo biological characterization conducted by Drs Sergio Wittlin and Jacques Chollet and their team at the Swiss Tropical Institute and by Dr. Hugues Matile from Hoffman-La Roche. Dr. Heinrich Urwyler from Basilea Pharmaceutica has provided toxicological expertise, and Dr. Sarah Arbe-Barnes, of Fulcrum Pharma Developments Ltd., has led the project management activities.