Safety, pharmacokinetics, and immunogenicity of a co-formulated cocktail of three human monoclonal antibodies targeting Ebola virus glycoprotein in healthy adults: a randomised, first-in-human phase 1 study

Sivapalasingam, Sumathi; Kamal, Mohamed; Slim, Rabih; Hosain, Romana; Shao, Weiping; Stoltz, Randall; Yen, Joseph; Pologe, Laura G.; Cao, Yuan; Partridge, M.; Sumner, Giane; Lipsich, Leah

doi:10.1016/s1473-3099(18)30397-9

Cited by 76 publications

(62 citation statements)

References 13 publications

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“…The first outbreak resulted in 54 EVD cases (38 confirmed and 16 probable) and 33 deaths (overall case‐fatality ratio of 61%) as of 24 July, 2018 (declared the end of this outbreak), while the latter is ongoing, which includes 238 cases (203 confirmed and 35 probable) and 155 deaths resulting in a case‐fatality rate of 65.1% (as of 21 October, 2018) . Preclinical efforts toward specific EBOV countermeasures have been enduring for years with first treatment and vaccine clinical trials conducted during the 2013 to 2016 EBOV outbreak in West‐Africa . During the DRC outbreaks, the countermeasures were evaluated in West‐Africa EVD outbreak and demonstrated their clinical efficacy.…”

Section: Introductionmentioning

confidence: 99%

“…Very recently, adeno‐associated virus‐mediated mAb 5D2 or 7C9 delivers 100% protection against mouse‐adapted EBOV infection, whereas neutralizing mAb 2G4 revealed 83% protection . Also, a coformulated cocktails REGN3470‐3471‐3479 (three human 3‐mAb cocktails REGN3470, REGN3471, and REGN3479 in 1:1:1 ratio) is currently being evaluated and proved safe and well tolerated with no observed immunogenicity after a randomized, first‐in‐human Phase I clinical trial (NCT002777151) …”

Section: Introductionmentioning

confidence: 99%

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Perspectives towards antiviral drug discovery against Ebola virus

Mirza

Vanmeert

Ali

et al. 2019

Journal of Medical Virology

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Ebola virus disease (EVD), caused by Ebola viruses, resulted in more than 11 500 deaths according to a recent 2018 WHO report. With mortality rates up to 90%, it is nowadays one of the most deadly infectious diseases. However, no Food and Drug Administration‐approved Ebola drugs or vaccines are available yet with the mainstay of therapy being supportive care. The high fatality rate and absence of effective treatment or vaccination make Ebola virus a category‐A biothreat pathogen. Fortunately, a series of investigational countermeasures have been developed to control and prevent this global threat. This review summarizes the recent therapeutic advances and ongoing research progress from research and development to clinical trials in the development of small‐molecule antiviral drugs, small‐interference RNA molecules, phosphorodiamidate morpholino oligomers, full‐length monoclonal antibodies, and vaccines. Moreover, difficulties are highlighted in the search for effective countermeasures against EVD with additional focus on the interplay between available in silico prediction methods and their evidenced potential in antiviral drug discovery.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Perspectives towards antiviral drug discovery against Ebola virus

Mirza

Vanmeert

Ali

et al. 2019

Journal of Medical Virology

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“…Once daily IV dosed remdesivir has demonstrated 100% survival in non-human primates only (44) and on this basis has been tested in humans during the current EBOV outbreak. Recently, a significant portion of data was described (499 individuals) from a clinical trial involving the investigation of multiple therapeutics against EBOV (NCT03719586) with ZMapp (a monoclonal antibody cocktail) (45)), remdesivir, MAb114 (a monoclonal antibody) (46)) and REGN-EB3 (monoclonal antibody combination) (47)). These results showed that the antibodies REGN-EB3 and mAb114 had overall survival rates of 71% and 66%, respectively, and were much more effective with patients with low viremia levels.…”

Section: Discussionmentioning

confidence: 99%

Pyronaridine Tetraphosphate Efficacy Against Ebola Virus Infection in Guinea Pig

Lane

Massey²,

Comer³

et al. 2020

Preprint

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31The recent outbreaks of the Ebola virus (EBOV) in Africa have brought global visibility to 32 the shortage of available therapeutic options to treat patients infected with this or closely 33 related viruses. We have recently computationally identified three molecules which have 34 all demonstrated statistically significant efficacy in the mouse model of infection with 35 mouse adapted Ebola virus (ma-EBOV). One of these molecules is the antimalarial 36 pyronaridine tetraphosphate (IC 50 range of 0.82-1.30 µM against three strains of EBOV 37 and IC 50 range of 1.01-2.72 µM against two strains of Marburg virus (MARV)) which is 38 an approved drug in the European Union and used in combination with artesunate. To 39 date, no small molecule drugs have shown statistically significant efficacy in the guinea 40 pig model of EBOV infection. Pharmacokinetics and range-finding studies in guinea pigs 41 directed us to a single 300mg/kg or 600mg/kg oral dose of pyronaridine 1hr after 42 infection. Pyronaridine resulted in statistically significant survival of 40% at 300mg/kg 43 and protected from a lethal challenge with EBOV. In comparison, oral favipiravir (300 44 mg/kg dosed once a day) had 43.5 % survival. The in vitro metabolism and metabolite 45 identification of pyronaridine and another of our EBOV active molecules, tilorone, which 46 suggests significant species differences which may account for the efficacy or lack 47 thereof, respectively in guinea pig. In summary, our studies with pyronaridine 48 demonstrates its utility for repurposing as an antiviral against EBOV and MARV, 49 providing justification for future testing in non-human primates. 50 51 52 4 Importance 53There is currently no antiviral small molecule drug approved for treating Ebola Virus 54 infection. We have previously used machine learning models to identify new uses for 55 approved drugs and demonstrated their activity against the Ebola virus in vitro and in 56 vivo. We now describe the pharmacokinetic properties of the antimalarial pyronaridine in 57 the guinea pig. In addition, we show that this drug is effective against multiple strains of 58 EBOV and MARV in vitro and in the guinea pig model of Ebola virus infection. These 59 combined efforts indicate the need to further test this molecule in larger animal efficacy 60 studies prior to clinical use in humans. These findings also may be useful for 61 repurposing this drug for use against other viruses in future. 62 63

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“…Vaccination has been deployed across at-risk populations as a means to prevent infection. Large-scale randomised clinical trials are assessing anti-Ebola antibody-based medications mAb114, 13 REGN3470-3471-3479, 14 ZMapp, 15 and an antiviral medication remdesivir (NCT03719586). To have the greatest opportunity to detect potential clinical benefits, given the fairly moderate number (hundreds) of patients, the level of supportive care must be consistently good to reduce the risk of not identifying treatment effects against a background of variable overall care and mortality.…”

mentioning

confidence: 99%