Experimental Treatment of Ebola Virus Disease with TKM-130803: A Single-Arm Phase 2 Clinical Trial

TKM-130803, a small interfering RNA lipid nanoparticle product, has been developed for the treatment of Ebola virus disease (EVD), but its efficacy and safety in humans has not been evaluated. In this single-arm phase 2 trial, adults with laboratory-confirmed EVD received 0.3 mg/kg of TKM-130803 by...

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Published in:	PLoS medicine Vol. 13; no. 4; p. e1001997
Main Authors:	Dunning, Jake, Sahr, Foday, Rojek, Amanda, Gannon, Fiona, Carson, Gail, Idriss, Baimba, Massaquoi, Thomas, Gandi, Regina, Joseph, Sebatu, Osman, Hassan K, Brooks, Timothy J G, Simpson, Andrew J H, Goodfellow, Ian, Thorne, Lucy, Arias, Armando, Merson, Laura, Castle, Lyndsey, Howell-Jones, Rebecca, Pardinaz-Solis, Raul, Hope-Gill, Benjamin, Ferri, Mauricio, Grove, Jennifer, Kowalski, Mark, Stepniewska, Kasia, Lang, Trudie, Whitehead, John, Olliaro, Piero, Samai, Mohammed, Horby, Peter W
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 19-04-2016 Public Library of Science (PLoS)
Subjects:	Adult Aged Aged, 80 and over Antiviral agents Antiviral Agents - therapeutic use Biology and Life Sciences Body fluids Clinical trials Drug dosages Drug therapy Ebola hemorrhagic fever Ebola virus Ebolavirus - genetics Ebolavirus - pathogenicity Enrollments Female Health aspects Hemorrhagic Fever, Ebola - diagnosis Hemorrhagic Fever, Ebola - drug therapy Hemorrhagic Fever, Ebola - genetics Hemorrhagic Fever, Ebola - mortality Hemorrhagic Fever, Ebola - virology Host-Pathogen Interactions Humans Infusions, Intravenous Laboratories Male Medicine and Health Sciences Middle Aged Nanoparticles Patients Research and analysis methods Researchers RNA, Small Interfering - administration & dosage RNA, Small Interfering - therapeutic use RNA, Viral - blood RNA, Viral - genetics RNAi Therapeutics - adverse effects RNAi Therapeutics - methods Sierra Leone Studies Survival Analysis Time Factors Treatment Outcome Viral Load - drug effects Viral Load - genetics Young Adult Sierra Leone United Kingdom Ireland West Africa
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Summary:	TKM-130803, a small interfering RNA lipid nanoparticle product, has been developed for the treatment of Ebola virus disease (EVD), but its efficacy and safety in humans has not been evaluated. In this single-arm phase 2 trial, adults with laboratory-confirmed EVD received 0.3 mg/kg of TKM-130803 by intravenous infusion once daily for up to 7 d. On days when trial enrolment capacity was reached, patients were enrolled into a concurrent observational cohort. The primary outcome was survival to day 14 after admission, excluding patients who died within 48 h of admission. After 14 adults with EVD had received TKM-130803, the pre-specified futility boundary was reached, indicating a probability of survival to day 14 of ≤0.55, and enrolment was stopped. Pre-treatment geometric mean Ebola virus load in the 14 TKM-130803 recipients was 2.24 × 109 RNA copies/ml plasma (95% CI 7.52 × 108, 6.66 × 109). Two of the TKM-130803 recipients died within 48 h of admission and were therefore excluded from the primary outcome analysis. Of the remaining 12 TKM-130803 recipients, nine died and three survived. The probability that a TKM-130803 recipient who survived for 48 h will subsequently survive to day 14 was estimated to be 0.27 (95% CI 0.06, 0.58). TKM-130803 infusions were well tolerated, with 56 doses administered and only one possible infusion-related reaction observed. Three patients were enrolled in the observational cohort, of whom two died. Administration of TKM-130803 at a dose of 0.3 mg/kg/d by intravenous infusion to adult patients with severe EVD was not shown to improve survival when compared to historic controls. Pan African Clinical Trials Registry PACTR201501000997429.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Conceived and designed the experiments: PWH TL PO JW. Performed the experiments: JD FS AR FG GC BI TM RG SJ HKO TJGB AJHS IG LT AA LM LC RH-J RP-S BH-G MF JG MK KS TL JW PO MS PWH. Analyzed the data: KS JW PWH JD. Contributed reagents/materials/analysis tools: TJGB AJHS LT AA IG. Wrote the first draft of the manuscript: PWH JD FS PO. Contributed to the writing of the manuscript: TL FS GC AR FG IG JW KS. Enrolled patients: JD AR BI TM RG SJ. Agree with the manuscript’s results and conclusions: JD FS AR FG GC BI TM RG SJ HKO TJGB AJHS IG LT AA LM LC RH-J RP-S BH-G MF JG MK KS TL JW PO MS PWH. All authors have read, and confirm that they meet, ICMJE criteria for authorship. We have read the journal's policy and the authors of this manuscript have the following competing interests: MK is an employee of Arbutus Biopharma (previously known as Tekmira Pharmaceuticals). Membership of the RAPIDE-TKM trial team is provided in the Acknowledgments.
ISSN:	1549-1676 1549-1277 1549-1676
DOI:	10.1371/journal.pmed.1001997