Safety, tolerability, pharmacokinetics, and antimalarial efficacy of a novel Plasmodium falciparum ATP4 inhibitor SJ733: a first-in-human and induced blood-stage malaria phase 1a/b trial

Gaur, Aditya H.; McCarthy, James S.; Panetta, John C.; Dallas, Ronald H.; Woodford, John; Li, Tang; Smith, Amber M.; Stewart, Tracy B.; Branum, Kristen; Freeman, Burgess B.; Patel, Nehali; John, Elizabeth; Chalon, Stephan; Ost, Shelley; Heine, Ryan N.; Richardson, Julie; Christensen, Robbin; Flynn, Patricia M.; Gessel, Yvonne Van; Mitasev, Branko; Möhrle, Jörg J.; Gusovsky, Fabián; Bebrevska, Lidiya; Guy, R. Kiplin

doi:10.1016/s1473-3099(19)30611-5

Cited by 62 publications

(74 citation statements)

References 18 publications

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“…The raised asymptomatic raised liver enzymes, with no associated signi cant rise in bilirubin, have been reported in previous IBSM studies [28,29], sporozoite VIS [30] and in naturally occurring malaria [28,31]. Similarly, the reduction in white cell counts, especially lymphopenia and neutropenia have previously been reported in IBSM VIS, sporozoite VIS and clinical malaria [12,16,[32][33][34].…”

Section: Discussionsupporting

confidence: 60%

“…In these studies, healthy, malaria-naïve participants are inoculated with Plasmodium-infected erythrocytes, enabling the assessment of the blood stage schizont activity of antimalarial drug candidates [5,6,[9][10][11]. As of March 2020, 401 volunteers have been inoculated with the Plasmodium falciparum 3D7 clone, most at QIMR Berghofer in Brisbane, Australia (n=335), but some at sites in the Netherlands and United Kingdom (n=66) [6,[12][13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

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Development and Evaluation of a New P. Falciparum 3D7 Blood Stage Malaria Cell Bank for Use in Malaria Volunteer Infection Studies

Woolley

Fernandez

Rebelo

et al. 2020

Preprint

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BackgroundNew antimalarial therapeutics are required to counter the threat of increasing drug resistance. Malaria volunteer infection studies (VIS), particularly the induced blood stage malaria (IBSM) model, play a key role in accelerating antimalarial drug development. Supply of the reference 3D7-V2 Plasmodium falciparum malaria cell bank (MCB) is limited. We aimed to develop a new MCB, and compare the safety and infectivity of this MCB with the existing 3D7-V2 MCB, in a VIS. A second bank (3D7-V1) developed in 1995 was also evaluated.MethodsWe expanded the 3D7-V2 MCB in vitro using a bioreactor to produce a new MCB designated 3D7-MBE-008. This bank and 3D7-V1 were then evaluated using the IBSM model, where healthy participants were intravenously inoculated with blood-stage parasites. Participants were treated with artemether-lumefantrine when parasitaemia or clinical thresholds were reached. Safety, infectivity and parasite growth and clearance were evaluated. ResultsThe in vitro expansion of 3D7-V2 produced 200 vials of the 3D7-MBE-008 MCB, with a parasitaemia of 4.3%. This compares to 0.1% in the existing 3D7-V2 MCB, and <0.01% in the 3D7-V1 MCB. All four participants, (two per MCB) developed detectable Plasmodium falciparum infection after inoculation with approximately 2800 parasites. The parasite multiplication rates of 48 hours (PMR48) for the two participants inoculated with 3D7-MBE-008 MCB were 26 and 61, similar to the parental (3D7-V-2) line, with both parasitaemia in both participants exceeding 10,000/mL by day 8. Growth of the 3D7-V1 was slower (PMR48 of 8 and 18), with parasitaemia exceeded 10,000 parasites/mL on days 10 and 8.5 respectively. Rapid parasite clearance followed artemether-lumefantrine treatment in all four participants (clearance half-lives of 4.01 and 4.06 hours for 3D7-MBE-008 and 4.11 and 4.52 hours for 3D7-V1). A total of 59 adverse events occurred, most were of mild severity with three being severe in the 3D7-MBE-008 study. ConclusionThe safety, growth and clearance profiles of the expanded 3D7-MBE-008 MCB closely resemble that of its parent, indicating its suitability for future studies.Trial RegistrationAustralian New Zealand Clinical Trials registry numbers:P3487 (3D7-V1): ACTRN12619001085167P3491 (3D7-MBE-008): ACTRN12619001079134

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Section: Discussionsupporting

confidence: 60%

Section: Introductionmentioning

confidence: 99%

Development and Evaluation of a New P. Falciparum 3D7 Blood Stage Malaria Cell Bank for Use in Malaria Volunteer Infection Studies

Woolley

Fernandez

Rebelo

et al. 2020

Preprint

Self Cite

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“…This selection strategy using a range of pharmacokinetic and toxicokinetic studies enables using PKPD modeling to support dose simulation in human. The preclinical results were predictive of the human results, where SJ733 showed no significant adverse effects up to doses of 1200 mg as reported in Phase I findings (10). SJ733 has progressed into Phase 2a trials.…”

Section: Resultsmentioning

confidence: 53%

“…We have previously disclosed studies leading to the discovery of (+)-SJ733 (9), which has recently completed Phase 1 trials (10). (+)-SJ733 is the second inhibitor of PfATP4, a parasite proton-sodium antiporter, that has entered clinical trialsthe other being cipargamin (11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

Selecting an anti-malarial clinical candidate from two potent dihydroisoquinolones

Chen

Zhu²,

Hammill

et al. 2020

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Background The ongoing global malaria eradication campaign requires development of potent, safe, and cost-effective drugs lacking cross-resistance with existing chemotherapies. One critical step in drug development is selecting a suitable clinical candidate from late leads. Herein we present the process used to select the clinical candidate SJ733 from two potent dihydroisoquinolone (DHIQ) late leads, SJ733 and SJ311, based on their physicochemical, pharmacokinetic (PK), and toxicity profiles. Methods The compounds were tested to define their physicochemical properties including kinetic and thermodynamic solubility, partition coefficient, permeability, ionization constant, and binding to plasma and microsomal proteins. Metabolic stability was assessed in both microsomes and hepatocytes derived from mice, rats, dogs, and humans. Cytochrome p450 inhibition were assessed using recombinant human cytochrome enzymes. The pharmacokinetic profiles of single intravenous or oral doses were investigated in mice, rats, and dogs. Results Both compounds displayed similar physicochemical properties, but SJ733 was more permeable and metabolically less stable than SJ311 in vitro. Single dose PK studies of SJ733 in mice, rats, and dogs demonstrated appreciable oral bioavailability (60–100%), whereas SJ311 had lower oral bioavailability (mice 23%, rats 40%) and higher renal clearance (10–30 fold in rats and dogs), suggesting less favorable exposure in humans. SJ311 also displayed a narrower range of dose-proportional exposure, with plasma exposure flattening at doses above 200 mg/kg. Conclusion SJ733 was chosen as the candidate based on a more favorable dose proportionality of exposure and stronger expectation of the ability to justify a strong therapeutic index to regulators.

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“…A number of within-host models describing the dynamics of malaria infection (Fig. 3 ) have been developed to predict outcomes with and without preventative measures and antimalarial drug treatment [ 4 , 39 , 40 – 41 , 42 ••, 43 ]. By combining mechanistic model simulations with statistical learning, Georgiadou et al [ 39 ] predicted that slower parasite growth and a longer duration of illness could distinguish severe anemia from cerebral malaria in infected individuals.…”

Section: Parasitesmentioning

confidence: 99%

Leveraging Computational Modeling to Understand Infectious Diseases

et al. 2020

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Purpose of Review Computational and mathematical modeling have become a critical part of understanding in-host infectious disease dynamics and predicting effective treatments. In this review, we discuss recent findings pertaining to the biological mechanisms underlying infectious diseases, including etiology, pathogenesis, and the cellular interactions with infectious agents. We present advances in modeling techniques that have led to fundamental disease discoveries and impacted clinical translation. Recent Findings Combining mechanistic models and machine learning algorithms has led to improvements in the treatment of Shigella and tuberculosis through the development of novel compounds. Modeling of the epidemic dynamics of malaria at the within-host and between-host level has afforded the development of more effective vaccination and antimalarial therapies. Similarly, in-host and host-host models have supported the development of new HIV treatment modalities and an improved understanding of the immune involvement in influenza. In addition, large-scale transmission models of SARS-CoV-2 have furthered the understanding of coronavirus disease and allowed for rapid policy implementations on travel restrictions and contract tracing apps. Summary Computational modeling is now more than ever at the forefront of infectious disease research due to the COVID-19 pandemic. This review highlights how infectious diseases can be better understood by connecting scientists from medicine and molecular biology with those in computer science and applied mathematics.

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Safety, tolerability, pharmacokinetics, and antimalarial efficacy of a novel Plasmodium falciparum ATP4 inhibitor SJ733: a first-in-human and induced blood-stage malaria phase 1a/b trial

Cited by 62 publications

References 18 publications

Development and Evaluation of a New P. Falciparum 3D7 Blood Stage Malaria Cell Bank for Use in Malaria Volunteer Infection Studies

Development and Evaluation of a New P. Falciparum 3D7 Blood Stage Malaria Cell Bank for Use in Malaria Volunteer Infection Studies

Selecting an anti-malarial clinical candidate from two potent dihydroisoquinolones

Leveraging Computational Modeling to Understand Infectious Diseases

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