DSM265 is one of the new generation of novel antimalarials and has the potential to both treat patients and protect healthy people with a reduced dosing schedule. It also has the potential to address resistance to current treatments. The compound was discovered in partnership with the University of Texas Southwestern (USA), Washington University (USA) and Monash University (Australia), and has since demonstrated safety and efficacy against Plasmodium falciparum in a phase IIa trial in Peru.
DSM265 is being developed with the support of Takeda Pharmaceutical Company Ltd (Japan). DSM265 was the first compound to be studied in sporozoite volunteer infection studies (VIS), (previously known as the controlled human malaria infection model).
Dr Jörg Möhrle, Vice President, Head of Translational Medicine, MMV, talks about the potential of DSM265 and its role in validating the sporozoite volunteer infection study (VIS) platform.
1. What is exciting about DSM265?
A single dose of DSM265 typically clears blood stages of P. falciparum parasites within 48 hours, which is very impressive. It works by targeting an essential enzyme in the malaria parasite (dihydroorotate dehydrogenase, DHODH), which is required to make parasite DNA and RNA. Data from cellular models showed that the compound could block replication of the parasite in human liver cells as well as red blood cells; it should therefore be able to both stop and treat blood-stage infection. On this basis, we decided to test DSM265 in a sporozoite VIS.
2. What is special about the sporozoite VIS platform? How will it be used in the future?
Our approach to these studies comes from the lessons learned in volunteer studies with blood-stage malaria. VIS is a good platform with which to compare new molecules since the studies can be done using a small number of volunteers, and early in clinical development. The key difference between sporozoite VIS and blood-stage VIS is that the former assesses a drug’s ability to protect against infection getting into the bloodstream, whereas the latter is used to assess a drug’s ability to treat infection once it is already established in the bloodstream.
DSM265 was the first compound to be investigated in the sporozoite VIS platform. This study confirmed the chemoprotective activity of one dose of DSM265 given a week before infection. This result was published in The Lancet Infectious Diseases in March 2017.1 All of MMV’s pipeline drugs with similar properties can now be put through this platform to test their chemoprotective potential.
3. What are the next steps?
This DSM265 study helped validate the sporozoite VIS platform, which can now be used for other compounds with liver-stage activity, such as P218. The next steps for DSM265 include confirmatory work on a new therapeutic formulation, and completion of planned combination studies to find a suitable partner. It is still early days, so the final partner drug for DSM265 has not yet been selected. The other question is whether to prioritize its treatment indication, or whether to push forward with its development as a medicine to protect people at risk of infection.
1. Sulyok M et al. “DSM265 for Plasmodium falciparum chemoprophylaxis: a randomised, double blinded, phase 1 trial with controlled human malaria infection.” Lancet Infect Dis. 17(6):636-644 (2017).