Assessing drug efficacy against Plasmodium falciparum liver stages in vivo

Flannery, Erika L.; Foquet, Lander; Chuenchob, Vorada; Fishbaugher, Matthew; Billman, Zachary P.; Navarro, Mary Jane; Betz, William J.; Olsen, Tayla M.; Lee, Joshua; Camargo, Nelly; Nguyen, Trang; Schäfer, Carola; Sack, Brandon K.; Wilson, Elizabeth M.; Saunders, Jessica; Bial, John; Campo, Brice; Charman, Susan A.; Murphy, Sean C.; Phillips, Margaret A.; Kappe, Stefan H. I.; Mikolajczak, Sebastian A.

doi:10.1172/jci.insight.92587

Cited by 23 publications

(24 citation statements)

References 35 publications

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“… 9 , 8 Furthermore, preclinical studies showed equal activity on blood-stage and liver-stage parasites, a property seen with very few molecules in the antimalarial pipeline. 6 , 10 , 11 In studies of healthy human participants, 12 , 13 DSM265 (single doses of ≤1200 mg) was generally well tolerated, with a good pharmacokinetic profile of effectiveness for more than 8 days after a single oral dose in the range of 200–400 mg. In the induced blood stage malaria challenge component of the study by McCarthy and colleagues, 13 a single dose of 150 mg DSM265 showed antimalarial activity against P falciparum , and predicted an efficacious single curative dose of 340 mg for a 60 kg patient.…”

Section: Introductionmentioning

confidence: 99%

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 study

Llanos-Cuentas

Casapía

Chuquiyauri

et al. 2018

The Lancet Infectious Diseases

114

115

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SummaryBackgroundDSM265 is a novel, long-duration inhibitor of plasmodium dihydroorotate dehydrogenase (DHODH) with excellent selectivity over human DHODH and activity against blood and liver stages of Plasmodium falciparum. This study aimed to assess the efficacy of DSM265 in patients with P falciparum or Plasmodium vivax malaria infection.MethodsThis proof-of-concept, open-label, phase 2a study was conducted at the Asociación Civil Selva Amazónica in Iquitos, Peru. Patients aged 18–70 years, weighing 45–90 kg, who had clinical malaria (P falciparum or P vivax monoinfection) and fever within the previous 24 h were eligible. Exclusion criteria were clinical or laboratory signs of severe malaria, inability to take oral medicine, and use of other antimalarial treatment in the preceding 14 days. Patients were divided into cohorts of those with P falciparum (cohort a) or P vivax (cohort b) infection. Two initial cohorts received single oral doses of 400 mg DSM265. Patients were followed up for efficacy for 28 days and safety for 35 days. Further cohorts received escalated or de-escalated doses of DSM265, after safety and efficacy assessment of the initial dose. The 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, the criteria for dose escalation, was defined as ACPR (P falciparum) or crude cure (P vivax) in at least 80% of patients in the cohort. The primary analysis was done in the intention-to-treat population (ITT) and the per-protocol population, and safety analyses were done in all patients who received the study drug. This study is registered at ClinicalTrials.gov (NCT02123290).FindingsBetween Jan 12, 2015, and Dec 2, 2015, 45 Peruvian patients (24 with P falciparum [cohort a] and 21 with P vivax [cohort b] infection) were sequentially enrolled. For patients with P falciparum malaria in the per-protocol population, all 11 (100%) in the 400 mg group and eight (80%) of ten in the 250 mg group achieved ACPR on day 14. In the ITT analysis, 11 (85%) of 13 in the 400 mg group and eight (73%) of 11 in the 250 mg group achieved ACPR at day 14. For the patients with P vivax malaria, the primary endpoint was not met. In the per-protocol analysis, none of four patients who had 400 mg, three (50%) of six who had 600 mg, and one (25%) of four who had 800 mg DSM265 achieved crude cure at day 14. In the ITT analysis, none of five in the 400 mg group, three (33%) of nine in the 600 mg group, and one (14%) of seven in the 800 mg group achieved crude cure at day 14. During the 28-day extended observation of P falciparum patients, a resistance-associated mutation in the gene encoding the DSM265 target DHODH was observed in two of four recurring patients. DSM265 was well tolerated. The most common adverse events were pyrexia (20 [44%] of 45) and headache (18 [40%] of 45), which are both common ...

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Section: Introductionmentioning

confidence: 99%

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 study

Llanos-Cuentas

Casapía

Chuquiyauri

et al. 2018

The Lancet Infectious Diseases

114

115

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“…As such, the most interesting place to intervene with an mAb is at the initial infection of the liver. Currently there are 3 mAbs published with potent activity against the circumsporozoite protein, CSP, and these can reduce the parasitaemia in sporozoite-infected FRG (triple mutant Fah/Raγ2/IL2Rγ) mice that carry a human liver implant [132]. These mAbs include mAb317, cloned from B cells obtained from a patient in the recent RTS,S vaccine trial [133], CIS43 (circumsporozoite protein 43 [56]), and a set that included MGU12 [134], cloned from patients vaccinated with irradiated sporozoites.…”

Section: Malariamentioning

confidence: 99%

Reassessing therapeutic antibodies for neglected and tropical diseases

et al. 2020

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In the past two decades there has been a significant expansion in the number of new therapeutic monoclonal antibodies (mAbs) that are approved by regulators. The discovery of these new medicines has been driven primarily by new approaches in inflammatory diseases and oncology, especially in immuno-oncology. Other recent successes have included new antibodies for use in viral diseases, including HIV. The perception of very high costs associated with mAbs has led to the assumption that they play no role in prophylaxis for diseases of poverty. However, improvements in antibody-expression yields and manufacturing processes indicate this is a cost-effective option for providing protection from many types of infection that should be revisited. Recent technology developments also indicate that several months of protection could be achieved with a single dose. Moreover, new methods in B cell sorting now enable the systematic identification of high-quality antibodies from humanized mice, or patients. This Review discusses the potential for passive immunization against schistosomiasis, fungal infections, dengue, and other neglected diseases.PLOS Neglected Tropical Diseases | https://doi.interactions have proved difficult to block. In addition, there has been great progress in the development of technology. Early generations of antibodies for human use were developed from mAbs developed in mice, antibodies that were then humanized. Recently, the technology used peptide and antibody display on phages, for which part of the 2018 Nobel Prize in Chemistry was awarded to Sir Gregory P. Winter [6]. More recently, new technologies have been developed to clone antibodies from memory B cells [7] or plasma B cells [8, 9], allowing the isolation of individual antibodies from patients with viral infections-approaches that can be applied to any infectious disease.A second reason for the popularity of antibodies in recent years is their success rate in clinical development. Once an antibody reaches testing in humans, it has a success rate of 17% to 25% for approval as a new medicine [10], compared with 5% to 10% for small molecules. This success rate is partly due to the exquisite selectivity of mAbs, enabling them to distinguish between closely related molecular targets. In the case of infectious disease, this selectivity can be absolute, since antibodies can be generated that are specific for the invading pathogen and do not cross-react with host tissues. This lack of cross-reactivity with human tissue can be confirmed by immunohistochemistry on both adult and embryonic tissues prior to the start of clinical trials. This is in stark contrast to small molecules, in which sometimes unexpected onand off-target safety signals are frequently seen in the later stages of clinical development, resulting in expensive late-stage attrition. In addition, antibodies show a relatively narrow range of variation in pharmacokinetic exposure, facilitating early estimation of the human effective dose. This is unlike true xenobiotics, whose metabolism an...

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“…This model allows an endpoint based on asexual blood stage infection from the liver [ 57 ]. Here, the benchmarking with atovaquone shows that a highly efficacious compound should be able to lower the parasite 18S RNA signal in the liver by 10 7 -fold, or a 200-fold reduction in the bioluminescence signal [ 58 ]. DSM265, a novel PfDHODH inhibitor, with demonstrated activity in humans, shows a 10 4 -fold reduction in this model, arguably defining the lower threshold of efficacy.…”

Section: Approaches To Finding and Developing New Small Molecule Tcp-mentioning

confidence: 99%

Injectable anti-malarials revisited: discovery and development of new agents to protect against malaria

Macintyre

Ramachandruni

Burrows

et al. 2018

Malar J

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Over the last 15 years, the majority of malaria drug discovery and development efforts have focused on new molecules and regimens to treat patients with uncomplicated or severe disease. In addition, a number of new molecular scaffolds have been discovered which block the replication of the parasite in the liver, offering the possibility of new tools for oral prophylaxis or chemoprotection, potentially with once-weekly dosing. However, an intervention which requires less frequent administration than this would be a key tool for the control and elimination of malaria. Recent progress in HIV drug discovery has shown that small molecules can be formulated for injections as native molecules or pro-drugs which provide protection for at least 2 months. Advances in antibody engineering offer an alternative approach whereby a single injection could potentially provide protection for several months. Building on earlier profiles for uncomplicated and severe malaria, a target product profile is proposed here for an injectable medicine providing long-term protection from this disease. As with all of such profiles, factors such as efficacy, cost, safety and tolerability are key, but with the changing disease landscape in Africa, new clinical and regulatory approaches are required to develop prophylactic/chemoprotective medicines. An overall framework for these approaches is suggested here.

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Assessing drug efficacy against Plasmodium falciparum liver stages in vivo

Cited by 23 publications

References 35 publications

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 study

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 study

Reassessing therapeutic antibodies for neglected and tropical diseases

Injectable anti-malarials revisited: discovery and development of new agents to protect against malaria

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