Development of DSM265 as a long acting antimalarial compound
Project Completed

Introduction and Background of the Project

DSM265 is a clinical candidate in the portfolio of Medicines for Malaria Venture. DSM265 is a novel, selective inhibitor of Plasmodium DHODH and has just entered Phase I studies in healthy volunteers. The compound has the potential as an antimalarial for both acute treatment and prophylaxis.

DSM265 is a specific inhibitor of plasmodium DHODH. The overall project goal is to develop this compound to become an alternative to the 4 aminoquinolines or aminoalcohols that are currently part of artemisinin combination therapies. These historical partner drugs are at risk due to resistance or have a suboptimal safety profile, and DSM265 is one of the few existing molecules in humans that has a realistic chance of being a credible replacement.
Medicines for Malaria Venture and Takeda Pharmaceuticals propose to collaborate to progress the molecule through to a Proof of Concept study (Phase IIa) in patients, in addition to a prophylaxis Proof of Concept study (Phase Ib) in healthy volunteers bitten by malaria infected mosquitoes. Potentially, PoC in both sub-indications be reached in 2014.

Whilst this partnership is principally focused on clinical studies to be led by MMV it could potentially form the basis for a longer-term partnership for the development and ultimately commercialization of DSM265 within a Japanese regulatory context.

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

The top priorities for the development of novel malaria treatments are to provide the next generation of medicines – a single exposure radical cure and prophylaxis (abbreviated to SERCaP). ‘Radical’ in this context refers to the elimination of all species of Plasmodium in a patient, including the dormant liver stages or hypnozoites and asymptomatic sexual stages or gametocytes. The new medicines need to be able to prevent transmission from one infected patient to the next, to safely protect a patient from the relapses with P. vivax and P. ovale, and to provide significant post-treatment prophylaxis (treatment of a malaria case providing protection against future infection). These medicines must be safe enough for use in sensitive patient groups, including pregnant women, the youngest of children and patients with other comorbidities, such as HIV and Tuberculosis (TB) infection, or malnutrition.

DSM265 is believed to target the same pathway as atovaquone and a similar if not slightly longer half-life (104 vs 48-72 hr). It is believed to be a slow acting drug with a lag time of 24-48 hours and thus would need to be combined with a fast acting antimalarial for blood stage malaria treatment. Currently approved antimalarial drugs use a combination of a fast acting drug like artesunate and a slower acting, long lasting partner like piperaquine, mefloquine or lumefantrine. These drugs have safety liabilities which restrict their use (e.g. mefloquine) or PK profile requiring twice a day dosing (e.g. lumefantrine). If the safety profile of DSM265 is shown to be superior to that of mefloquine and piperaquine and its PK profile supports its use as a single dose cure it could become the replacement drug for such combination treatments required a long-lasting partner. If in addition, it shows to have prophylactic potential against liver stages of the parasite, it would dramatically change the landscape of malaria treatment in disease endemic countries.

What sort of innovation are you bringing in your project?

A SERCaP will most likely require three to four molecules: one that provides fast clearance of parasites (Target Candidate Profiles - TCP-1), one with a long duration of action (preferably longer than 1 week to provide post-treatment prophylaxis especially in high transmission zones (Target Candidate Profiles - TCP-2), one with relapse prevention (Target Candidate TCP-3a) and transmission-blocking activity (Target Candidate Profiles - TCP-3b).

TCP-2 refers to molecules with long half-lives that provide prolonged antiparasite activity to ensure complete sterilization. The DSM265 project fits into TCP2, whilst its parasite reduction rate is not predicted to be sufficiently fast to be a TCP-1 compound, its plasma pharmacokinetics could support a long pharmacologically effective half-life. DSM265 is an antimalarial candidate which recently entered first in human studies. DSM265 is a novel triazolopyrimidineinhibitor designed to target the parasite dihydroorotate dehydrogenase (DHODH) enzyme thus blocking de novo pyrimidine nucleotide biosynthesis & parasite growth.

DSM265 also shows high potency in vivo in a rodent model of malaria, with a low predicted efficacious dose in humans. Its pharmacokinetic profile in animals and more recently in human volunteers shows a low clearance and long half-life.

The predicted human efficacious dose was recently administered to healthy volunteers inoculated with P. falciparum infected red blood cells and its blood stage antiparasitic efficacy is currently being examined.

If the data looks promising, MMV would like to continue with examine repeat dosing in healthy volunteers in order to examine the PK and safety profile of the compound after multiple doses. Such administration schedule may be useful for a prophylaxis indication including intermittent preventive therapy in disease endemic countries. A sporozoite challenge model in healthy human volunteers would be needed to determine whether the compound has causal prophylactic activity by killing the liver stages of the parasite. Lastly, MMV would like to examine the efficacy of single dosing in a Phase IIa/Proof-of-Concept study in P. falciparum and P. vivax infected malaria patients in Peru.

Others (including references if necessary)

•    Coterón, J.M., Marco, M., Esquivias, J., Deng, X., White, K.L., White, J., Koltun, M., El Mazouni, F., Kokkonda, S., Katneni, K., Bhamidipati, R., Shackleford, D., Barturen, I., Ferrer, S., Jimenez-Diaz, M.B., Gamo, F.J., Goldsmith, E.J., Charman, B., Bathurst, I., Floyd, D. Matthews, D., Burrows, J.N., Rathod, P.K., Charman, S.A. and Phillips, M.A. (2011) Structure-guided lead optimization of triazolopyrimidine-ring substituents identifies potent Plasmodium falciparum dihydroorotate dehydrogenase inhibitors with clinical candidate potential, J. Med. Chem., 54(15), 5540-5561.

•    Burrows JN et al. “Designing the next generation of medicines for malaria control and elimination.” Malar J. (submitted for publication), (2013).