- Awarded Year2016
- Awarded Amount$7,499,822
- Development StageClinical Phase1
- Collaboration PartnersTakeda Pharmaceutical Company Limited, Medicines for Malaria Venture (MMV)
Introduction and Background of the Project
Malaria remains a major health threat as more than three billions of the world’s population are currently at risk and half a million deaths, mostly young children, are reported each year. Over the last decade, a combined effort has generated a broad portfolio of new generation antimalarial drug candidates, amongst them are the Plasmodia specific dihydroorotate dehydrogenase (DHODH) inhibitors (lead DSM265 and back-up DSM421).
DSM265 has entered clinical Phase I in 2014 and its potency as a single dose treatment for P. falciparum malaria has recently been demonstrated in patients. Comparable clearance of P. vivax could not be achieved with a similar or even higher dose of DSM265. The strategy for the back-up molecule of DSM265 includes the objective to improve two features:
- Comparable potency against P. falciparum and P. vivax;
- Reduced cost of goods by increasing solubility and simplifying drug product formulation.
The candidate DSM421 is a potent plasmodial DHODH inhibitor and shows excellent anti-parasitic activity in vitro and in vivo. In contrast to DSM265, DSM421 showed equal potency against P. falciparum and P. vivax isolates in ex-vivo assays. The solubility of DSM421 is much improved compared to DSM265 which should allow a simple and inexpensive formulation.
DSM421 has the potential of being a back-up to DSM265, which is currently in Phase IIa clinical trials. DSM421 is a pre-clinical candidate in the MMV portfolio with the potential to be part of a Single Encounter Radical Cure (SERC) against P. falciparum and P. vivax or for chemoprevention. DSM421 is predicted to be a slowly eliminated, long acting drug in humans.
The overall objective presented in this proposal is to develop DSM421 up to Phase Ib challenge studies with a GO / GO NO decision for development as SERC or chemopretective agent.
The overall goal of this proposal is the assessment of safety of DSM421 in phase I clinical studies and efficacy in phase Ib challenge studies, as well as supporting pre-clinical toxicology studies to advance into phase IIa clinical trials. The project design is divided into 6 parts:
1. Document the safety, tolerability and pharmacokinetics of DSM421 when administered to healthy volunteers (First in Human study (FIH).
2. Assess the blood stage activity of DSM421 against P. falciparum and P. vivax in an
Induced Blood Stage Malaria challenge study (IBSM).
3. Assess the activity of DSM421 against P. falciparum liver stages in a Controlled Human Malaria Infection study (CHMI). This model allows confirming the activity of DSM421 as a chemoprotective agent.
4. Based on the outcome of points 2 and 3, decide whether to pursue treatment of blood stage infection or a chemoprotection indication in a Phase IIa study
5. Manufacture the clinical supplies to support the above phase I studies.
6. Complete the required non-clinical safety studies to support Phase IIa clinical trials (treatment or chemoprevention) and assess the embryofetal safety of DSM421 in light of potential use in pregnant women.
How can your partnership (project) address global health challenges?
More than 200 million cases and 438,000 deaths caused by malaria were reported in 2015*; these remain unacceptably high numbers for a preventable and treatable disease. 88% of all malaria deaths occur in sub-Saharan Africa mediated majority by P. falciparum, killing globally over 300,000 children under five years of age1.
P. vivax infection represents a major health issue as well. More than 13.8 million cases of P. vivax malariawere reported in 2015 causing more than 50% of all deaths attributed to malaria outside Africa1.
Furthermore, the emergence of resistance against existing antimalarials and insecticides threatens the rapid progress in malaria control and elimination. Parasite resistance to artemisinin – the core compound of ACTs – has been detected in five countries in South-East Asia: in Cambodia, the Lao People’s Democratic Republic, Myanmar, Thailand and Vietnam.
The top priorities for the development of novel malaria treatments are to provide the next generation of medicines as a single exposure radical cure (abbreviated to SERC) in order to overcome growing resistance issues and improve treatment compliance.
What sort of innovation are you bringing in your project?
DSM421 is a potent and highly specific inhibitor of the Plasmodium DHODH, which is a new mode of action for the treatment or chemoprotection against malaria. DSM421 has the potential of being a back-up to DSM265. DSM421 has several features that differentiate it from DSM265 and from other antimalarials:
1) DSM421 showed equal activity on P. vivax and P. falciparum ex-vivo field isolates providing strong indication to overcome the liabilities of DSM265 in curing P. vivax infections.
2) DSM421 is simple to synthesize and its improved drug like properties (e.g. increased solubility) compared to DSM265 allows simpler and more cost effective formulation.
3) DSM421 has a long predicted half-life (predicted to be ~83 h in humans). This long half-life will allow the compound to persist until parasites have been eliminated (post treatment prophylaxis).
4) DSM421 inhibits a novel target. DHODH has previously not been exploited for antimalarial chemotherapy. It represents a differentiated therapeutic mode of action, and thus is active against current drug resistant strains and is expected to have activity on resistant strains that may emerge following to use of current therapies.
Role and Responsibility of Each Partner
MMV as designated grantee for this proposal is responsible for delivering the work plan to the agreed timeline and budget, in addition to required GHIT reporting.
The project will be conducted by a team comprising the project director, scientists from MMV and Takeda, and further supported in kind by AbbVie colleagues and consultants on specific subject matters. It will be this project team that is responsible for all activities. The studies will be conducted in collaboration between MMV/Takeda, the principal investigators and the clinical monitor.
Takeda’s responsibility is consulting within the project team on non-clinical and clinical science, clinical operations, regulatory, ethical approval processes, CMC and other scientific aspects.
Others (including references if necessary)
1. WHO. World Malaria Report 2015. WHO (2015)