Promising New Drug Can Stop Malaria After Mosquito Bite

MedicalResearch.com Interview with:

Dr Mihály Sulyok MD Eberhard Karls University Institute of Tropical Medicine, Tübingen, Germany

Dr Mihály Sulyok

Dr Mihály Sulyok MD
Eberhard Karls University
Institute of Tropical Medicine,
Tübingen, Germany

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: New antimalarials are desperately needed, not just for treatment, but also for prophylaxis. DSM265, a novel antimalarial compound that selectively inhibits the plasmodial dihydroorotate dehydrogenase has a promising pharmacokinetic profile characterized by a long elimination half-life.

We performed a study at the Institute of Tropical Medicine, Eberhard Karls University (Tübingen, Germany) to investigate safety, tolerability and efficacy of DSM265 using controlled human malaria infection. In the first cohort, 400mg of DSM265 was administered orally to five healthy, malaria naive individuals one day before direct venous inoculation of an established infective dose of P. falciparum sporozoites (PfSPZ Challenge). Placebo was administered to two volunteers. The study was randomized and double blinded. In this cohort all placebo participants developed malaria, whereas all DSM265 participants were protected.

In a second cohort, 400mg DSM265 was administered 7 days before the sporozoite inoculation for six participants, two participants recieved placebo. In this cohort, the two placebo and three of six DSM265 volunteers developed thick blood smear positive malaria. The remaining three DSM265 volunteers developed transient submicroscopic parasitemia without symptoms or thick blood smear positivity. The only possible DSM265-related adverse event was a slight transient elevation in serum bilirubin in one volunteer.

The study was funded by the Global Health Innovative Technology Fund, Wellcome Trust, Bill & Melinda Gates Foundation through Medicines for Malaria Venture, and the German Center for Infection Research.

MedicalResearch.com: What should readers take away from your report?

Response: I think the most important message is, that DSM265 has a prophylactic activity that correlates with the plasma exposure. It was able to prevent malaria in all participants if administered one day before the inoculation of sporozoites.

On the other hand, using direct venous inoculation of P. falciparum sporozoites of PfSPZ Challange offers a highly standarized model for testing antimalarial compounds in the early phases of clinical development.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Response: I think to target a once weekly dosing would be a practical and reasonable aim. Probably this could be achieved by further dose increase, since dose limiting toxicity has not  been observed yet. In the study of James S McCarthy et al. DSM265 dose was increased up to 1200mg, and it was very good tolerated- just as in our study. Nevertheless, in our study three out of six volunteers were protected even if only 400mg was administered 7 days before the inoculation of the sporozoites. Of note, in three volunteers we have seen a submicroscopic parasitaemia without breakthrough infection. This indicates in my interpretation, that even this relatively ’low ’dose’ of 400mg could controlled blood stage infection in half of the participants, even if the pre-erythrocytic development was not completely blocked. So increasing the dose seems to be a promising approach. The Achilles heel of DSM265 is probably the low resistance barrier. Thus, using DSM265 in combination with other antimalarials would be justified- not just as a potential single-dose malaria treatment but also for a prophylactic indication. And of course, efficacy against naturally acquired infections and other plasmodium species should be also tested. I think future studies need to focus on these question mainly.

MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.

Citation:

DSM265 for Plasmodium falciparum chemoprophylaxis: a randomised, double blinded, phase 1 trial with controlled human malaria infection
Sulyok, Mihály et al.
The Lancet Infectious Diseases , Volume 0 , Issue 0 ,

DOI: http://dx.doi.org/10.1016/S1473-3099(17)30139-1
Published: 28 March 2017
http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(17)30139-1/abstract

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