Experimental Drug Cures Seven Volunteers Infected With Malaria Parasite

Seven volunteers have been cleared of Plasmodium falciparum (P. falciparum) infection using the experimental drug “DSM265”. The research was published on March 11, in Antimicrobial Agents and Chemotherapy.

What is Plasmodium falciparum?

P. falciparum is one of the species of protozoan parasite capable of causing malaria in humans, and is in fact responsible for the most severe form of the disease. Malaria is transmitted to humans through the bites of female Anopheles mosquitoes infected with the parasite.

According to the World Health Organization, 216 million clinical cases of malaria occurred in 2016, and 445,000 people died of malaria in the same year – most of them children in Africa.

DSM265 – A single-dose cure for malaria?

DSM265 is a novel antimalarial drug that inhibits the P. falciparum enzyme dihydroorotate dehydrogenase DHODH (PfDHODH), which was originally identified via high-throughput screening. This enzyme is vital to P. falciparum’s survival.

Previous studies demonstrated that DSM265 could clear the disease-causing, asexual stage parasites (merozoites) from infected humans.

The most recent study confirmed the findings of the earlier studies. It also showed that a 400 mg single dose of DSM265, given seven days after blood-stage infection was induced in healthy trial subjects (who had not previously been exposed to P. falciparum), was capable of clearing low-level parasitemia.

Coauthor of the study, Jörg Möhrle, PhD, from the Medicines for Malaria Venture (MMV) commented on the significance of a “single dose” treatment in a recent press release: “A single dose cure would provide a treatment that could improve compliance, reduce development of resistance, and eventually contribute to the eradication of this disease."

"DSM265 has the potential to become part of such a single dose cure," He added.

Whilst DSM265 doesn’t clear the sexual stage parasites (known as gametocytes) it still cures malaria in the individual, as the gametocytes are unable to complete their life cycle.

However, to enable the eradication of malaria a companion drug that targets gametocytes would need to be used alongside DSM265, to kill the sexual stages of the malaria parasite, otherwise they can perpetuate the life cycle if taken up by a mosquito during a blood meal.

Study design and drug safety

Study investigators inoculated eight healthy participants* (N = 8) with 2,800 blood-stage malaria parasites. The participants were administered orally 400 mg of DSM265 on day seven post-infection. The seven participants that developed parasitemia completely cleared all asexual parasites following DSM265 treatment.

*Unexpectedly one participant did not develop parasitemia during the study

The investigators used qPCR to track the number of gametocytes in each participant.

On day 23, seven of the participants were administered a second 400 mg dose of DSM265 to investigate the gametocytocidal and transmission-blocking activity of a second dose. This did not clear the gametocytes. On day 28 participants (N = 8) were given systemic rescue treatment with registered antimalarials (artemether-lumefantrine and primaquine).

"The overall favorable safety profile for DSM265 observed in this study agrees with the safety findings from the previous (three) clinical studies," commented Möhrle. The team noted three adverse effects observed in two participants in the most recent study:

• mild abdominal tenderness
• moderate skin rash
• moderate to severe itching

"Currently, MMV is working to improve the formulation of DSM265 and to identify the optimal partner drug to achieve a single dose treatment of P. falciparum malaria," explained Möhrle.

Reference: Collins, K.A. et al. DSM265 at 400 Milligrams Clears Asexual Stage Parasites but Not Mature Gametocytes from the Blood of Healthy Subjects Experimentally Infected with Plasmodium falciparum. Antimicrob Agents Chemother. (2019) DOI: https://doi.org/10.1128/AAC.01837-18 

The study is registered at ClinicalTrials.gov under identifier NCT02573857.

Previous related studies:

• Phillips, M.A., et al. A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria. Science Translational Medicine (2015) DOI: 10.1126/scitranslmed.aaa6645 
  
• Sulyok, M., et al. DSM265 for Plasmodium falciparum chemoprophylaxis: a randomised, double blinded, phase 1 trial with controlled human malaria infection. Lancet Infect Dis (2017) DOI: https://doi.org/10.1016/S1473-3099(17)30139-1
• Ashley, E. Investment in antimalarial drug development is bearing fruit. Lancet Infect Dis. (2017) DOI: https://doi.org/10.1016/S1473-3099(17)30172-X