Investment in antimalarial drug development is bearing fruit
Authors: Elizabeth Ashley
Journal: The Lancet Infectious Diseases (2017)

Front-line antimalarial drugs (the artemisinin-based combination therapies) are failing in southeast Asia, making the need for novel antimalarials more pressing than ever.1Amaratunga C Lim P Suon S et al.Dihydroartemisinin-piperaquine resistance in Plasmodium falciparum malaria in Cambodia: a multisite prospective cohort study.Lancet Infect Dis. 2016; 16: 357-365Summary Full Text Full Text PDF PubMed Scopus (324) Google Scholar, 2Phyo AP Ashley EA Anderson TJ et al.Declining efficacy of artemisinin combination therapy against P falciparum malaria on the Thai–Myanmar Border (2003–2013): the role of parasite genetic factors.Clin Infect Dis. 2016; 63: 784-791Crossref PubMed Scopus (141) Google Scholar, 3Thanh NV Thuy-Nhien N Tuyen NT et al.Rapid decline in the susceptibility of Plasmodium falciparum to dihydroartemisinin-piperaquine in the south of Vietnam.Malaria J. 2017; 16: 27Crossref PubMed Scopus (112) Google Scholar In The Lancet Infectious Diseases, two studies of DSM265,4McCarthy 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; (published online March 28.)http://dx.doi.org/10.1016/S1473-3099(17)30171-8PubMed Google Scholar, 5Sulyok 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; (published online March 28.)http://dx.doi.org/10.1016/S1473-3099(17)30139-1PubMed Google Scholar a plasmodium dihydroorotate dehydrogenase inhibitor, are reported. This novel antimalarial, discovered by a team at the University of Texas Southwestern, is in phase 2 clinical development for the prophylaxis and treatment of malaria. 6Phillips MA White KL Kokkonda S et al.A triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with improved drug-like properties for treatment and prevention of malaria.ACS Infect Dis. 2016; 2: 945-957Crossref PubMed Scopus (67) Google Scholar James S McCarthy and colleagues4McCarthy 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; (published online March 28.)http://dx.doi.org/10.1016/S1473-3099(17)30171-8PubMed Google Scholar report antimalarial activity, pharmacokinetics, tolerability, and safety of DSM265 in the first human challenge studies, using a new approach to predict the optimal dose for treatment. Study participants received an intravenous infusion of erythrocytes infected with Plasmodium falciparum. Sub-microscopic parasite densities were tracked using ultra-sensitive PCR methods and DSM265 was given when a pre-defined parasitaemia threshold was reached. This approach enabled in vivo estimation of the minimum inhibitory concentration7White NJ Pharmacokinetic and pharmacodynamic considerations in antimalarial dose optimization.Antimicrob Agents Chemother. 2013; 57: 5792-5807Crossref PubMed Scopus (75) Google Scholar (albeit in participants whose host defences had not been activated by malaria illness), providing a more rational basis for dose selection than the standard approach taken in the past, which relied on a combination of educated guesswork from preclinical studies and in vitro assessment and trial and error using clinical endpoints. Parasiticidal efficacy of DSM265, expressed as the log10 parasite reduction ratio at 48 h, measured 1·55 (95% CI 1·42–1·67), which was lower than that of a 10 mg/kg dose of mefloquine given to controls at 2·34 (95% CI 2·17–2·52). In their study, peak DSM265 concentrations were reached between 1·5 h and 4 h after administration and the elimination half-life was estimated at 86–118 h, making it a possible contender for a single curative dose antimalarial treatment if it is combined with a more potent partner drug with comparable elimination kinetics. In the second report, Mihály Sulyok and colleagues5Sulyok 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; (published online March 28.)http://dx.doi.org/10.1016/S1473-3099(17)30139-1PubMed Google Scholar show that DSM265 was well-tolerated and gave at least 7 days complete protection from malaria infection in five healthy volunteers when given less than 24 h before venous inoculation with P falciparum sporozoites, but this protection dropped to around 50% when the dosing interval before inoculation was prolonged to 7 days. Pharmacokinetic parameters were similar to those estimated in the treatment study (median tmax 3 h, elimination half-life 57–183 h) but there was notable inter-participant variability in drug exposure that correlated with parasitological efficacy. What do these studies tell us about the future of DSM265? In healthy volunteers this is a medium potency, slowly eliminated, well-tolerated antimalarial. If these results are confirmed in acute malaria then it would be a suitable partner drug used in combination with a more rapidly effective agent for malaria treatment. The path through pre-clinical and clinical development appears to have been relatively untroubled but there is still some way to go before registration. Tolerability, safety, and efficacy in larger numbers of symptomatic patients with naturally acquired infections will need to be confirmed, as well as efficacy against non-falciparum species. Even after registration, knowledge gaps are likely to remain, such as whether the chosen dose is as effective in pregnant women and young children, two groups typically neglected in pivotal clinical trials of new drugs. The relatively short period of protection against infection it affords when used as prophylaxis makes it unlikely to be used as a preventive strategy in pregnant women and children in endemic areas in the future. However, if the dose can be optimised to permit weekly administration it would be a possible candidate for the travellers' market, where it could replace mefloquine which continues to fall out of favour. The Achilles heel of all anti-infective drugs is the eventual selection of resistance in the target pathogen, and here DSM265 looks vulnerable. The propensity for development of resistance to DSM265 has already been assessed in vitro by exposing laboratory Dd2 strains of P falciparum to DSM265 continuously. The lowest number of parasites needed to select a resistant parasite was around 2 × 106, which is lower than for atovaquone, a drug known for its low threshold for resistance emergence following antimalarial treatment. A point mutation in the dihydroorotate dehydrogenase gene (G181C) was associated with a 13 times higher IC50 compared with parasites with wild-type enzyme.6Phillips MA White KL Kokkonda S et al.A triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with improved drug-like properties for treatment and prevention of malaria.ACS Infect Dis. 2016; 2: 945-957Crossref PubMed Scopus (67) Google Scholar This vulnerability raises concerns about the longevity of this compound and reinforces the importance of combining it with one or more suitably matched partners for clinical use. Investment in the antimalarial pipeline is finally bearing fruit. Substantial achievements have been made in antimalarial drug development as a result of collaborative endeavours between the public and private sectors and variations on this model are being adopted in the search for new antibiotics.8CARB-XCARB-X homepage.http://www.carb-x.org/Date: 2017Google Scholar, 9Drugs for Neglected Diseases InitativeGlobal Antibiotic Research and Development Partnership (GARDP).http://www.dndi.org/diseases-projects/gardp/Date: 2017Google Scholar DSM265 looks to be a promising antimalarial of the future. But the looming crisis of untreatable malaria being faced in southeast Asia and reports of untreatable bacterial infections from elsewhere show us that current models of anti-infective drug development are not keeping pace with the loss of drugs to resistance. Drastic action is needed. I declare no competing interests. Safety, tolerability, pharmacokinetics, and activity of the novel long-acting antimalarial DSM265: a two-part first-in-human phase 1a/1b randomised studyThe good safety profile, long elimination half-life, and antimalarial effect of DSM265 supports its development as a partner drug in a single-dose antimalarial combination treatment. Full-Text PDF Open AccessDSM265 for Plasmodium falciparum chemoprophylaxis: a randomised, double blinded, phase 1 trial with controlled human malaria infectionA single dose of 400 mg DSM265 was well tolerated and had causal prophylactic activity when given 1 day before CHMI. Future trials are needed to investigate further the use of DSM265 for the prophylaxis of malaria. Full-Text PDF Open Access