Delving into the Latest Updates on Artefenomel Mesylate with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target-

Mechanism-

Therapeutic Areas

Infectious Diseases

Active Indication

Malaria

Inactive Indication

Malaria, Falciparum

Originator Organization

Sanofi

Active Organization

Sanofi

Inactive Organization

Clinical Network Services Pty Ltd.Q-Pharm Pty Ltd.

Drug Highest PhasePhase 3

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC28H39NO5

InChIKeyXLCNVWUKICLURR-VFXIDCLRSA-N

CAS Registry1029939-86-3

A Randomized, Open Label, Parallel-group, Single Dose Regimen, Phase 2a Study, to Investigate the Clinical and Parasiticidal Activity and the Pharmacokinetics of 3 Dose Levels of Artefenomel (OZ439) Given in Combination With Ferroquine (FQ) and FQ Alone, in African Patients With Uncomplicated Plasmodium Falciparum Malaria

Primary Objective:
To show the contribution of artefenomel (OZ439) to the clinical and parasiticidal effect of OZ439/Ferroquine (FQ) combination by analyzing exposure-response of OZ439 measured by Day 28 polymerase chain reaction (PCR)-corrected adequate clinical and parasitological response (ACPR) for the effect and the area under the curve (AUC) of OZ439 as pharmacokinetic (PK) predictor.
Secondary Objectives:
To evaluate the exposure-response of OZ439 combined with FQ on crude Day 28 ACPR.
To evaluate the dose response of OZ439 combined with FQ on PCR-corrected and crude Day 28 ACPR.
To evaluate the dose-response of OZ439 combined with FQ on selected secondary endpoints.
To evaluate the safety and tolerability of different dosages of OZ439 in combination with FQ and FQ alone.
To characterize the PK of OZ439 in plasma, and of FQ and its active metabolite SSR97213 in blood.

Start Date11 Sep 2018

Sponsor / Collaborator

Sanofi

[+1]

NCT03542149

/ CompletedPhase 1IIT

Phase 1b to Assess Safety, Tolerability, Pharmacokinetic Profile, and Antimalarial Activity of Single Doses of Co-administered OZ439and PQP Against Early Plasmodium Falciparum Blood Stage Infection in Healthy Adult Volunteers

A single-centre Phase 1b study to assess the safety, tolerability, pharmacokinetic profile, and antimalarial activity of single doses of coadministered artefenomel (OZ439) and piperaquine phosphate (PQP) against early Plasmodium falciparum blood stage infection in healthy adult volunteers.

Start Date23 Apr 2018

Sponsor / Collaborator

MMV Medicines for Malaria Venture

[+3]

NCT04069221

/ CompletedPhase 1IIT

An Open-label, Two-part Study to Determine the Absolute Bioavailability (BA) of OZ439 Using Simultaneous Intravenous [14C]-OZ439 Microdose/800mg Oral Dosing and to Investigate the Pharmacokinetics (PK) of OZ439 Granules Administered as Single Doses Suspended in Different Volumes and When Co-administered With a Single Dose of Cobicistat, a Strong CYP3A4 Inhibitor, to Healthy Subjects in Fasted State

This study is an open-label, two-part study to determine the absolute bioavailability (BA) of OZ439 using simultaneous intravenous [14C]-OZ439 microdose/800mg oral dosing and to investigate the pharmacokinetics (PK) of OZ439 granules administered as single doses suspended in different volumes and when co-administered with a single dose of Cobicistat, a strong CYP3A4 inhibitor, to healthy subjects in fasted state.

Start Date28 Feb 2017

Sponsor / Collaborator

MMV Medicines for Malaria Venture

100 Clinical Results associated with Artefenomel Mesylate

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100 Translational Medicine associated with Artefenomel Mesylate

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100 Patents (Medical) associated with Artefenomel Mesylate

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70

Literatures (Medical) associated with Artefenomel Mesylate

10 Jan 2025·ACS Infectious Diseases

Reductive Activation of Artefenomel (OZ439) by Fe(II)-Heme, Related to Its Antimalarial Activity

Article

Author: Claparols, Catherine ; Chabbert, Mickaël ; Manaranche, Jeanne ; Nguyen, Michel ; Hamouy, Alexandre ; Augereau, Jean-Michel ; Robert, Anne ; Benoit-Vical, Françoise ; Laurent, Marion ; Paloque, Lucie

The 1,2,4-trioxolane antimalarial drug, OZ439 (artefenomel), exhibits cross-resistance to artemisinins in vitro with similar survival rates of artemisinin-resistant parasites after dihydroartemisinin or OZ439 exposure, suggesting that this drug shares some mechanisms of action with artemisinins. In this way, we investigated the in vitro reductive activation of OZ439 by heme in the presence of dithionite, demonstrating the formation of covalent heme-drug adducts. However, in the presence of the biologically abundant reductant glutathione instead of dithionite, heme-drug adducts were not detected, contrary to artemisinin that efficiently alkylates heme regardless of the reductant used. Conversely, the C-centered radical of OZ439 resulting from heme-mediated activation of the drug reacts with the thiol function of glutathione, thus confirming the ability of this drug to alkylate proteins or other biological targets. So, the difference in the mechanism of action between artemisinin and OZ439 in vivo may rely on the different proportions between heme alkylation and protein alkylation.

21 Nov 2024·mSphere

Enhanced cell stress response and protein degradation capacity underlie artemisinin resistance in Plasmodium falciparum

Article

Author: Rosenthal, Melissa R. ; Vijayrajratnam, Sukhithasri ; Firestone, Tessa M. ; Ng, Caroline L.

ABSTRACTMalaria remains a global health burden, killing over half a million people each year. Decreased therapeutic efficacy to artemisinin, the most efficacious antimalarial, has been detected in sub-Saharan Africa, a worrying fact given that over 90% of deaths occur on this continent. Mutations in Kelch13 are the most well-established molecular marker for artemisinin resistance, but these do not explain all artemisinin-resistant isolates. Understanding the biological underpinnings of drug resistance is key to curbing the emergence and spread of artemisinin resistance. Artemisinin-mediated non-specific alkylation leads to the accumulation of misfolded and damaged proteins and activation of the parasite unfolded protein response (UPR). In addition, the parasite proteasome is vital to artemisinin resistance, as we have previously shown that chemical inhibition of the proteasome or mutations in the β2 proteasome subunit increase parasite susceptibility to dihydroartemisinin (DHA), the active metabolite of artemisinins. Here, we investigate parasites with mutations at the Kelch13 and/or 19S and 20S proteasome subunits with regard to UPR regulation and proteasome activity in the context of artemisinin resistance. Our data show that perturbing parasite proteostasis kills parasites, early parasite UPR signaling dictates DHA survival outcomes, and DHA susceptibility correlates with impairment of proteasome-mediated protein degradation. Importantly, we show that functional proteasomes are required for artemisinin resistance in a Kelch13-independent manner, and compound-selective proteasome inhibition demonstrates why artemisinin-resistant Kelch13 mutants remain susceptible to the related antimalarial peroxide OZ439. These data provide further evidence for targeting the parasite proteasome and UPR to overcome existing artemisinin resistance.IMPORTANCEDecreased therapeutic efficacy represents a major barrier to malaria treatment control strategies. The malaria proteasome and accompanying unfolded protein response are crucial to artemisinin resistance, revealing novel antimalarial therapeutic strategies.

10 Oct 2024·ACS Medicinal Chemistry Letters

Synthesis and In Vivo Profiling of Desymmetrized Antimalarial Trioxolanes with Diverse Carbamate Side Chains

Article

Author: Rosenthal, Philip J. ; Legac, Jenny ; Renslo, Adam R. ; Jaishankar, Priyadarshini ; Kim, Julie ; Gonciarz, Ryan L. ; Cheng, Ke ; Klope, Matthew T. ; Tapia Cardona, Juan A. ; Chen, Jun

The recent withdrawal of artefenomel from clinical development leaves no endoperoxide-class agents in the antimalarial pipeline. Synthetic endoperoxides with a desymmetrized structure have demonstrated promising physiochemical and in vivo properties. Here we expand on our initial investigation of trans-3″ carbamate substitution with a diverse array of amine-, alcohol-, and sulfinyl-terminated analogues prepared in (S,S) and (R,R) configurations. In general, this chemotype combines low-nM antiplasmodial activity with excellent aqueous solubility but widely varying human liver microsome (HLM) stability. We evaluated 20 novel analogues in the P. berghei mouse malaria model, identifying new analogues such as RLA-4767 (9a) and RLA-5489 (9d), with HLM stability and pharmacokinetic profiles superior to analogues from our initial report (e.g., RLA-4776, 8a). These new leads approach or equal the efficacy of artefenomel after two daily oral doses of 10 mg/kg, thus revealing a promising chemotype with the potential to deliver development candidates.

100 Deals associated with Artefenomel Mesylate

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB11809

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Malaria	Phase 3	-	Sanofi	-
Malaria, Falciparum	Preclinical	BJ	Sanofi	25 Jul 2015
Malaria, Falciparum	Preclinical	BF	Sanofi	25 Jul 2015
Malaria, Falciparum	Preclinical	MZ	Sanofi	25 Jul 2015
Malaria, Falciparum	Preclinical	VN	Sanofi	25 Jul 2015
Malaria, Falciparum	Preclinical	GA	Sanofi	25 Jul 2015
Malaria, Falciparum	Preclinical	UG	Sanofi	25 Jul 2015
Malaria, Falciparum	Preclinical	KE	Sanofi	25 Jul 2015

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03542149 (CTgov)	Phase 1	Malaria	24	200 mg OZ 439+640 mg Piperaquine phosphate (Cohort 1:Treatment Group B: 200mg of OZ439 and 640 mg PQP)	llipejvryr(zqefendmsq) = rtnpbcknuk naupsnohjk (qntpagvqvo, zicniquroo - ghmvpzirkd) View more	-	10 May 2024
				200 mg OZ 439+480 mg Piperaquine phosphate (Cohort 1: Treatment Group A: 200mg of OZ439 and 480 mg PQP)	llipejvryr(zqefendmsq) = hcqoptvuap naupsnohjk (qntpagvqvo, hlquorcwpm - wcqmfwlyak) View more
NCT03660839 (Pubmed)	Phase 2	Malaria, Falciparum	140	400 mg ferroquine	ponwijzpih(dtdvhdhxpi) = Adverse events (AEs) of any cause occurred in 51.4% (18/35) of patients with ferroquine 400 mg alone, and 58.3% (21/36), 66.7% (24/36), and 72.7% (24/33) with 300, 600, and 1000 mg artefenomel, respectively xidnewqcjy (ihfxdmurdw ) View more	-	03 Jan 2023
				400 mg ferroquine plus artefenomel 300 mg
NCT02573857 \| NCT02389348 (Pubmed \| J Antimicrob Chemother)	Phase 1/2	Malaria, Falciparum	-	OZ439 800mg + DSM265 450mg	vfuywjquie(dklbenpsxp) = cyhrsfyytu ckbbuexwdm (hlhamjdlmw )	-	28 Jun 2021
NCT02497612 (Pubmed \| Malar J) Manual	Phase 2	Malaria, Falciparum	373	artefenomel+ferroquine	(daskfdmsfm) = 78.4% [64.7; 88.7%] to 91.7% [81.6; 97.2%] for the 400 mg to 1200 mg fyeyhwzjjy (evqwgchmaj ) View more	Negative	19 May 2021
NCT03660839 (CTgov)	Phase 2	Malaria, Falciparum	140	Artefenomel (OZ439)+Ferroquine (SSR97193) (Ferroquine 400 mg + Artefenomel 300 mg)	oosiklzuau(envairzpym) = jnwkctkrgg xzpqxmdimw (avmwiehdll, luakdbbpjm - mgguqeboly) View more	-	02 Dec 2020
				Artefenomel (OZ439)+Ferroquine (SSR97193) (Ferroquine 400 mg + Artefenomel 600 mg)	oosiklzuau(envairzpym) = euljzjmkli xzpqxmdimw (avmwiehdll, ahngdltmzb - jhdjcxaopm) View more
NCT02497612 (FALCI, CTgov)	Phase 2	Malaria, Falciparum	377	Placebo+Artefenomel+Ferroquine SSR97193 (Ferroquine (up to 400 mg) + Artefenomel (up to 800 mg))	kmucxrtrwx(kosqkolzva) = prcpekkopy qzpfadwjyg (nflkmuqton, rbalibxyru - lirlmcgbiv) View more	-	19 Oct 2020
				Placebo+Artefenomel+Ferroquine SSR97193 (Ferroquine (up to 600 mg) + Artefenomel (up to 800 mg))	kmucxrtrwx(kosqkolzva) = akuccgclao qzpfadwjyg (nflkmuqton, fzpqtgugje - zalkvstfhh) View more
NCT02573857 (DSMOZ-2, CTgov)	Phase 1/2	Malaria	16	DSM265 (DSM265 P. Falciparum)	(ghnwgjdtwm) = cvryvzzcax okehijdrfb (fhgvrwpjrm, oewmrqyipi - cmqpxidmmm) View more	-	05 Jun 2020
				OZ439 (OZ439 P. Vivax)	(ghnwgjdtwm) = ixlykqtebb okehijdrfb (fhgvrwpjrm, spaxlxsvek - oakdgtwxdq) View more
NCT02573857 (Pubmed \| J Infect Dis)	Phase 1/2	Malaria, Vivax	8	Artefenomel 200 mg	wxxowkqynj(bdvfzjvigj) = afjwmpwimj tfolrsqnxs (xpfdsoumvt ) View more	Positive	01 Jun 2020
NCT02431650 (OZGAM, CTgov)	Phase 1/2	Malaria	11	Primaquine (Primaquine 15mg)	rmksglkvgz(uahxqchvml) = wgsrknughn jwlvyqujrv (ijjgmpqpkj, qkmueyewdq - hsftxkohzh) View more	-	26 May 2020
				OZ439 (OZ439 500mg)	rmksglkvgz(uahxqchvml) = ynhyxtvpie jwlvyqujrv (ijjgmpqpkj, yjeukycdfj - azjztyltvi) View more
NCT02389348 (Pubmed \| Antimicrob Agents Chemother) Manual	Phase 1/2	Malaria, Falciparum	13	Artefenomel+DSM265 (Cohort 1)	(lztescyfmj) = kazugsmpnm zmpxxlgncn (qftsnisloe ) View more	Positive	20 Dec 2019
				Artefenomel+DSM265 (Cohort 2)	(lztescyfmj) = qlabfvrqmg zmpxxlgncn (qftsnisloe ) View more