Seeking an optimal dosing regimen for OZ439/DSM265 combination therapy for treating uncomplicated falciparum malaria

Dini, Saber; Zaloumis, Sophie; Price, David J.; Gobeau, Nathalie; Kümmel, Anne; Cherkaoui, Mohammed; Moehrle, Joerg J.; McCarthy, James S.; Simpson, Julie A.

doi:10.1093/jac/dkab181

Cited by 10 publications

(8 citation statements)

References 34 publications

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“…Initially characterizing the PK-PD relationship from monotherapy studies is important for guiding dose optimization before being deployed as a combination therapy. Information on contribution of individual drugs and their interactions (i.e., on drug concentration, parasite growth and killing, or both) derived from monotherapy and combination studies is a prerequisite for defining rational dosing regimens of antimalarial combinations ( 41 – 44 ).…”

Section: Search Resultsmentioning

confidence: 99%

Scoping Review of Antimalarial Drug Candidates in Phase I and II Drug Development

Abd-Rahman

Zaloumis

McCarthy

et al. 2022

Antimicrob Agents Chemother

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The emergence and spread of parasite resistance to currently available antimalarials has highlighted the importance of developing novel antimalarials. This scoping review provides an overview of antimalarial drug candidates undergoing phase I and II studies between 1 January 2016 and 28 April 2021. PubMed, Web of Science, Embase, clinical trial registries and reference lists were searched for relevant studies. Information regarding antimalarial compound details, clinical trial characteristics, study population, drug pharmacokinetics and pharmacodynamics (PK-PD) were extracted. A total of 50 studies were included of which 24 had published their results and 26 were unpublished. New antimalarial compounds were evaluated as monotherapy (28 studies, 14 drug candidates) and combination therapy (9 studies, 10 candidates). Fourteen active compounds were identified in the current antimalarial drug development pipeline together with 11 compounds that are inactive; six due to insufficient efficacy. PK-PD data were available from 24 studies published as open-access articles. Four unpublished studies have made their results publicly available on clinical trial registries. The terminal elimination half-life of new antimalarial compounds ranged from 14.7 to 483 hours. The log 10 parasite reduction ratio over 48 hours and parasite clearance half-life for P. falciparum following a single dose monotherapy were 1.55–4.1 and 3.4–9.4 hours, respectively. The antimalarial drug development landscape has seen a number of novel compounds, with promising PK-PD properties, evaluated in phase I and II studies over the past 5 years. Timely public disclosure of PK-PD data is crucial for informative decision-making and drug development strategy.

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Section: Search Resultsmentioning

confidence: 99%

Scoping Review of Antimalarial Drug Candidates in Phase I and II Drug Development

Abd-Rahman

Zaloumis

McCarthy

et al. 2022

Antimicrob Agents Chemother

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“…The findings showed that severe degrading at higher parasitemia concentrations inhibited the mechanism of effect of synthetic ozonides (90% concentration). OZ439 4b has been tested in conjunction with AM piperaquine 243,244 . Also, OZ439 4b is presently being studied in arrangement with ferroquine to treat the untreated P. falciparum malaria in Phase II‐b clinical studies.…”

Section: Some Antimalarial Endoperoxide Moieties Other Than 124‐triox...mentioning

confidence: 99%

“…OZ439 4b has been tested in conjunction with AM piperaquine. 243,244 Also, OZ439 4b is presently being studied in arrangement with ferroquine to treat the untreated P. falciparum malaria in Phase II-b clinical studies. In 2020, Renslo et al recent time reported that trans-3′ carbamate trioxolane analogue 176 has excellent AM efficacy in vivo (100% treatment of P.…”

Section: Trioxolane-polyamine Conjugatesmentioning

confidence: 99%

An overview on the antimalarial activity of 1,2,4‐trioxanes, 1,2,4‐trioxolanes and 1,2,4,5‐tetraoxanes

Shukla

Rathi

Hassam³

et al. 2023

Medicinal Research Reviews

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The demand for novel, fast‐acting, and effective antimalarial medications is increasing exponentially. Multidrug resistant forms of malarial parasites, which are rapidly spreading, pose a serious threat to global health. Drug resistance has been addressed using a variety of strategies, such as targeted therapies, the hybrid drug idea, the development of advanced analogues of pre‐existing drugs, and the hybrid model of resistant strains control mechanisms. Additionally, the demand for discovering new potent drugs grows due to the prolonged life cycle of conventional therapy brought on by the emergence of resistant strains and ongoing changes in existing therapies. The 1,2,4‐trioxane ring system in artemisinin (ART) is the most significant endoperoxide structural scaffold and is thought to be the key pharmacophoric moiety required for the pharmacodynamic potential of endoperoxide‐based antimalarials. Several derivatives of artemisinin have also been found as potential treatments for multidrug‐resistant strain in this area. Many 1,2,4‐trioxanes, 1,2,4‐trioxolanes, and 1,2,4,5‐tetraoxanes derivatives have been synthesised as a result, and many of these have shown promise antimalarial activity both in vivo and in vitro against Plasmodium parasites. As a consequence, efforts to develop a functionally straight‐forward, less expensive, and vastly more effective synthetic pathway to trioxanes continue. This study aims to give a thorough examination of the biological properties and mode of action of endoperoxide compounds derived from 1,2,4‐trioxane‐based functional scaffolds. The present system of 1,2,4‐trioxane, 1,2,4‐trioxolane, and 1,2,4,5‐tetraoxane compounds and dimers with potentially antimalarial activity will be highlighted in this systematic review (January 1963–December 2022).

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“…With a very different starting point but also on the malaria front, the remarkable ozonides OZ277/ arterolane (41) [210,211] and OZ439/artefenomel (42) [212- 214] stemmed from academic collaborations across the world which started in 2000. While arterolane ( 41) is a drug used in combination with piperaquine (Synriam), the analog artefenomel ( 42) is undergoing clinical trials, including in combination with DSM-265 (39) [215][216][217][218]. Of note is that prior to 1971, thinking of developing a peroxide-containing compound for a clinical use against malaria would have not been considered relevant.…”

Section: Suggestions To Improve the Output Of Academic Drug Discovery...mentioning

confidence: 99%

On drug discovery against infectious diseases and academic medicinal chemistry contributions

Janin¹

2022

Beilstein J. Org. Chem.

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This perspective is an attempt to document the problems that medicinal chemists are facing in drug discovery. It is also trying to identify relevant/possible, research areas in which academics can have an impact and should thus be the subject of grant calls. Accordingly, it describes how hit discovery happens, how compounds to be screened are selected from available chemicals and the possible reasons for the recurrent paucity of useful/exploitable results reported. This is followed by the successful hit to lead stories leading to recent and original antibacterials which are, or about to be, used in human medicine. Then, illustrated considerations and suggestions are made on the possible inputs of academic medicinal chemists. This starts with the observation that discovering a “good” hit in the course of a screening campaign still rely on a lot of luck – which is within the reach of academics –, that the hit to lead process requires a lot of chemistry and that if public–private partnerships can be important throughout these stages, they are absolute requirements for clinical trials. Concerning suggestions to improve the current hit success rate, one academic input in organic chemistry would be to identify new and pertinent chemical space, design synthetic accesses to reach these and prepare the corresponding chemical libraries. Concerning hit to lead programs on a given target, if no new hits are available, previously reported leads along with new structural data can be pertinent starting points to design, prepare and assay original analogues. In conclusion, this text is an actual plea illustrating that, in many countries, academic research in medicinal chemistry should be more funded, especially in the therapeutic area neglected by the industry. At the least, such funds would provide the intensive to secure series of hopefully relevant chemical entities which appears to often lack when considering the results of academic as well as industrial screening campaigns.

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Seeking an optimal dosing regimen for OZ439/DSM265 combination therapy for treating uncomplicated falciparum malaria

Cited by 10 publications

References 34 publications

Scoping Review of Antimalarial Drug Candidates in Phase I and II Drug Development

Scoping Review of Antimalarial Drug Candidates in Phase I and II Drug Development

An overview on the antimalarial activity of 1,2,4‐trioxanes, 1,2,4‐trioxolanes and 1,2,4,5‐tetraoxanes

On drug discovery against infectious diseases and academic medicinal chemistry contributions

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