Testing DSM265, a novel antimalarial acting through DHODH, in combination with OZ439
Project Completed

Introduction and Background of the Project

New approaches for dose finding need to be developed for antimalarial combination therapy. MMV has collaborated with Prof. James McCarthy from the Queensland Institute of Medical Research to establish a novel way of investigating new antimalarial drug candidates in a human induced malaria infection model (HIMIM). Indicators of the antimalarial effects, such as parasite reduction rate, time to parasite clearance and Minimal Parasiticidal Concentrations (MPCs) of a malaria drug can be estimated in a well-controlled environment and human volunteers with no concomitant medical condition. Recrudescent infection and gametocyte induction can also be observed. We propose to study for the first time a combination of two novel drugs in this setting. Both drugs have already been individually investigated in the HIMIM. The combination of both compounds will provide information on the effects of the combination on pharmacokinetic parameters in healthy subjects and subjects with an induced malaria infection and antiparasitic effects in combination. Importantly the study can confirm whether antiparasitic effects are additive, synergistic or antagonistic when given in combination to the human host. This information will have a direct impact on the decision whether a combination will be further pursued (in case of synergy and additivity) or discontinued (antagonism). Furthermore, the PK/PD analysis can provide a better estimation of the range of both drugs to be investigated in phase IIb trial.


The two drugs DSM265 and OZ439 are two candidate drugs in development by MMV that show great promise to become a single dose combination treatment, therefore the combination of these in the HIMIM can establish the scientific concept and also provide tangible information accelerating the progress of a novel treatment.

How can your partnership (project) address global health challenges?

This project supports current WHO guidelines (WHO 2010) which recommend that combination therapies are used to treat uncomplicated P. falciparum malaria to counter the threat of resistance to monotherapies and improve treatment outcome.


To reduce the development of resistance, the WHO recommends that P. falciparum malaria be treated using a combination of two drugs that act at different biochemical pathways in the parasite. In the past, the selection of the combination of antimalarial drugs and especially the dose finding has been empirical and, in general, formal dose finding was not conducted. As a consequence, therapies were not necessarily optimized.



What sort of innovation are you bringing in your project?

The specific aims of this project are to:

- Study the co-administration DSM265 and OZ439 in healthy volunteer to evaluate any potential drug-drug interaction;

- Study the anti-malarial activity of the combination of DSM265 and OZ439, with endpoints of time to parasite clearance, PRR and time to relapse;

- Study the transmission blocking activity of the combination by standard membrane feeding assay (SMFA) to anopheles with oocyte development as the endpoint;

- Provide information to estimate the optimal doses for future development of a DSM265 and OZ439 combination antimalarial.


OZ439 is currently being developed by MMV in phase II, and fulfils the criteria of MMV’s Target Candidate Profile 1 - TCP1 (fast parasite clearance). DSM265 is in phase Ib, with available information from studies that we have run to date indicating that it fits Target Candidate Profile 2 - TCP2 (long acting). Antimalarial activity and exposure in the patients suggest that a combination of both drugs could provide a single dose antimalarial therapy, thus allowing a single, directly observed administration to patients thereby improving compliance and convenience.


In this project we propose to study this combination in a single trial, conducted at QIMR Berghofer Medical Research Institute, Queensland Australia.


Part I: Eight healthy human volunteers will receive a single dose of DSM265 and OZ439 to confirm that no significant drug-drug interactions are occurring. 

Part II: P. falciparum blood stage challenge. Each of eight participants in the cohort will be inoculated on Day 0 with ~1,800 viable Plasmodium falciparum-infected human erythrocytes (BSPC) administered intravenously.


Following treatment with DSM265/OZ439, subjects will be followed up as in-patients for at least 48 hours, to ensure tolerance of the treatment and clinical response, then if clinically well on an outpatient basis for safety and continued presence of malaria parasites via PCR. The effects of DSM265/OZ439 on parasitemia are expected to be observed for up to sixteen days.

Others (including references if necessary)


Designing the next generation of medicines for malaria control and eradication

Jeremy N Burrows, Rob Hooft van Huijsduijnen, Jörg J Möhrle, Claude Oeuvray and Timothy NC Wells

Malaria Journal 2013, 12:187  doi:10.1186/1475-2875-12-187