DSM265: a novel drug for single-dose cure of Plasmodium falciparum malaria
Authors: Sabine Bélard, Michael Ramharter
Journal: The Lancet Infectious Diseases (2018)

In The Lancet Infectious Diseases, Alejandro Llanos-Cuentas and colleagues1Llanos-Cuentas A Casapia M Chuquiyauri R et al.Antimalarial activity of single-dose DSM265, a novel plasmodium dihydroorotate dehydrogenase inhibitor, in patients with Plasmodium falciparum or Plasmodium vivax malaria infection: a proof-of-concept, open-label, phase 2a study.Lancet Infect Dis. 2018; (published online June 13.)http://dx.doi.org/10.1016/S1473-3099(18)30309-8Summary Full Text Full Text PDF PubMed Scopus (72) Google Scholar report a pivotal phase 2a proof-of-concept study analysing different doses of the novel antimalarial compound DSM265 against uncomplicated Plasmodium falciparum and Plasmodium vivax malaria in Iquitos, Peru. An impressive decline of malaria-related morbidity and mortality has occurred over the past decade, facilitated by improved coverage of mosquito control, improved diagnostics, and the availability of insecticide-treated bed nets and highly efficacious treatments with artemisinin-based combination therapies.2WHOWorld malaria report 2017. World Health Organization, Geneva2017http://www.who.int/malaria/publications/world-malaria-report-2017/en/Date accessed: May 5, 2018Google Scholar However, this trend has halted recently and even reversed in some areas, indicating the continuous challenges to malaria elimination. The emergence of multidrug resistance and poor treatment adherence with current 3-day drug regimens are the most formidable challenges for effective treatment of malaria. The quest for highly efficacious single-dose antimalarial regimens, which are also available in child-friendly formulations, to preclude development of drug resistance, is therefore of highest priority.3Mischlinger J Agnandji ST Ramharter M Single dose treatment of malaria—current status and perspectives.Expert Rev Anti Infect Ther. 2016; 14: 669-678Crossref PubMed Scopus (12) Google Scholar DSM265 belongs to a promising class of antimalarials that inhibit the plasmodium dihydroorotate dehydro-​genase enzyme required for pyrimidine biosynthesis. Its good in-vitro efficacy, activity on blood and liver stages, pharmacokinetic profile suitable for single dosing, and good tolerability and safety profiles in phase 1 clinical assessments make it one of the most promising drug candidates in the global antimalarial portfolio.4McCarthy JS Lotharius J Rückle T et al.Safety, tolerability, pharmacokinetics, and activity of the novel long-acting antimalarial DSM265: a two-part first-in-human phase 1a/1b randomised study.Lancet Infect Dis. 2017; 17: 626-635Summary Full Text Full Text PDF PubMed Scopus (79) Google Scholar The study by Llanos-Cuentas and colleagues1Llanos-Cuentas A Casapia M Chuquiyauri R et al.Antimalarial activity of single-dose DSM265, a novel plasmodium dihydroorotate dehydrogenase inhibitor, in patients with Plasmodium falciparum or Plasmodium vivax malaria infection: a proof-of-concept, open-label, phase 2a study.Lancet Infect Dis. 2018; (published online June 13.)http://dx.doi.org/10.1016/S1473-3099(18)30309-8Summary Full Text Full Text PDF PubMed Scopus (72) Google Scholar assessed single doses of oral DSM265 in sequential dosing cohorts in 24 patients with P falciparum and 21 patients with P vivax malaria. Primary endpoints were the proportion of patients achieving PCR-adjusted adequate clinical and parasitological response (ACPR) by day 14 for patients infected with P falciparum and the proportion of patients achieving a crude cure by day 14 for those infected with P vivax. Cohort success was defined as a proportion of at least 80% of patients achieving the criteria. The primary efficacy endpoint was reached in the P falciparum groups by all of 11 patients receiving the 400 mg dose and eight (80%) of ten patients who received the 250 mg dose, indicating high efficacy against P falciparum malaria despite a slower onset of action than other available treatments. Notably, a single point mutation in the dhodh gene, not present at baseline, was identified in patients with P falciparum recurrence, indicating the propensity of DSM265 to rapidly induce specific drug resistance. By contrast, treatment efficacy of ascending doses on day 14 was disappointingly low for patients with P vivax malaria and none of these patients achieved cure at day 28. No patients had any treatment-related serious adverse events. These remarkable findings require careful considerations to guide the further development programme of DSM256. The pharmacodynamic and pharmacokinetic profile of DSM265 are strikingly reminiscent of the only previous single-dose antimalarial, sulfadoxine-pyrimethamine. Good bioavailability and high efficacy of a single dose against P falciparum but not P vivax malaria, combined with favourable safety and tolerability made sulfadoxine-pyrimethamine first-line treatment for malaria in Africa and particularly attractive for public health programmes, including intermittent preventive treatment in pregnancy. However, the therapeutic lifespan of sulfadoxine-pyrimethamine was short because of the rapid development of drug resistance. To safeguard the therapeutic potential of DSM265 over a longer time, its development in a carefully chosen antimalarial combination is therefore warranted. The ideal combination partner drug for DSM265 will need to be defined in the context of a comprehensive target-product profile. To develop DSM265 primarily for the treatment of P falciparum malaria will require further assessment of DMS265 in combination with a pharmacokinetically matched single-dose partner. To further minimise the risk of drug resistance, triple combinations need to be considered early on in the drug development process, despite the regulatory challenges of such multidrug combinations. In the short term, these hurdles could be circumvented by combining DSM265 with an existing 3-day antimalarial combination therapy. Combinations with other novel single-dose antimalarials, including artefenomel, ferroquine, cipargamin, or KAF156 might, however, be particularly appealing and have the advantage of no pre-existing drug pressure.5Supan C Mombo-Ngoma G Dal-Bianco MP et al.Pharmacokinetics of ferroquine, a novel 4-aminoquinoline, in asymptomatic carriers of Plasmodium falciparum infections.Antimicrob Agents Chemother. 2012; 56: 3165-3173Crossref PubMed Scopus (65) Google Scholar, 6Macintyre F Adoke Y Tiono AB et al.A randomised, double-blind clinical phase II trial of the efficacy, safety, tolerability and pharmacokinetics of a single dose combination treatment with artefenomel and piperaquine in adults and children with uncomplicated Plasmodium falciparum malaria.BMC Med. 2017; 15: 181Crossref PubMed Scopus (38) Google Scholar These drug combinations will most likely also be effective in P vivax malaria, for which DSM265 monotherapy seems unsuitable. Such a single-dose antimalarial combination therapy could be a game changer for mass drug administration programmes in the setting of malaria elimination campaigns, for seasonal malaria chemoprevention, or intermittent preventive treatment in pregnancy. Liver stage activity of DSM265 is attractive for its development as a prophylactic drug in travel medicine. Its long half-life of up to 5 days might allow for single-dose prophylactic intake before short-term travel. Human malaria challenge models will be crucial to establish optimal dosing regimens for this indication.7Sulyok M Rückle T Roth A et al.DSM265 for Plasmodium falciparum chemoprophylaxis: a randomised, double blinded, phase 1 trial with controlled human malaria infection.Lancet Infect Dis. 2017; 17: 636-644Summary Full Text Full Text PDF PubMed Scopus (62) Google Scholar In summary, DSM265 is an exciting new candidate antimalarial bearing the promise that a single-dose antimalarial regimen will again become available. Further clinical development of DSM265 requires thoughtful decisions to ensure the greatest possible benefit from the unique antimalarial properties of this drug. SB is a participant in the Charité Clinical Scientist Program funded by the Charité–Universitätsmedizin Berlin and the Berlin Institute of Health, and was an investigator in Medicines for Malaria Venture (MMV)-funded clinical trials in 2007–08. MR served as principal investigator in several MMV-funded clinical trials and acted as consultant for MMV. Antimalarial activity of single-dose DSM265, a novel plasmodium dihydroorotate dehydrogenase inhibitor, in patients with uncomplicated Plasmodium falciparum or Plasmodium vivax malaria infection: a proof-of-concept, open-label, phase 2a studyAfter a single dose of DSM265, P falciparum parasitaemia was rapidly cleared, whereas against P vivax, DSM265 showed less effective clearance kinetics. Its long duration of action provides the potential to prevent recurrence of P falciparum after treatment with a single dose, which should be further assessed in future combination studies. Full-Text PDF Open Access