This targeted molecule inhibits a vital enzyme (dihydroorotate dehydrogenase; DHODH) in the malaria parasite essential for its survival, while the human enzyme remains unaffected at therapeutic concentrations with a wide safety margin. In 2015, the molecule successfully demonstrated safety and efficacy against Plasmodium falciparum in a phase IIa trial in malaria patients in Peru. Phase III trials will be the next step to confirm this activity specifically against P. falciparum.
Development of DSM265 by MMV is being supported by Takeda Pharmaceutical Company, Japan, with funding from the Global Health Innovative Technology Fund (GHIT) and pro bono support from AbbVie. Senior Director Robert Arch explains the molecule’s exciting potential and next steps.
1. What is special about DSM265 as a potential antimalarial drug?
I find the excellent research that was published on DSM265 in the journal Science Translational Medecine particularly exciting.1 A strong partnership with industry players was built early on, and was an important factor in developing this successful molecule. Even more exciting are DSM265’s characteristics, for example, its safety and tolerability profile to date and its proven activity against P. falciparum as a single-dose monotherapy used up to 28 days. These characteristics could make a huge difference to the lives of populations suffering from malaria.
2. In 2015, DSM265 successfully completed a phase IIa study in Peru. What did the study teach us about the molecule? What challenges did the team face?
The most important element of the study was to show the efficacy of the molecule in real-life settings. While the molecule was shown to be a highly efficacious selective inhibitor of P.falciparum-DHODH (leading to striking single/monotherapy efficacy against P. falciparum), we did encounter some challenges; for instance the compound is not as potent against P.vivax. While this is disappointing, it will not stop us from studying the molecule’s effects against P. falciparum.
3. How is the controlled human malaria infection (CHMI) model supporting the development of DSM265?
While the real-life experience of patients has been very important, the CHMI model (Figure 1, page 18) has helped us to learn more about the parasite’s response to a single dose of DSM265. With this model, we can also carefully monitor the start of infection
and time our intervention accordingly. This provides greater understanding of DSM265’s effect on different stages of the parasite’s lifecycle, which will help us determine whether it should be used for treatment or prevention.
4. What is the strategy moving forward?
The next stage will be the phase IIb studies to explore single doses of DSM265 in combination with a partner drug. These studies will define an appropriate combination and dose for a phase III study.
The phase III study will then determine if DSM265 has the potential to be a simpler treatment than the present-day standard of care, which requires multiple doses over several days. This will involve testing DSM265 and its partner drug in a larger number of patients in a single dose to see if it will provide efficacious treatment as well as the data required for approval.
We are all very excited about the development programme. The collaboration between MMV, Takeda and GHIT, as well as other partners, will be very important to its success.
1 Phillips MA et al. “A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria.” Sci Transl Med. 7(296):296ra111 (2015).