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

Abstract

BackgroundTKM-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.Methods and FindingsIn 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.ConclusionsAdministration 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.Trial registrationPan African Clinical Trials Registry PACTR201501000997429

Novel Stable Ebola Virus Minigenome Replicon Reveals Remarkable Stability of the Viral Genome

“…A clinical trial of small interfering RNA (siRNA)-based therapy (TKM-Ebola) was suspended because the results of interim analysis were not encouraging (31). Our results showed that shRNA (shL2 and shL3) targeting the 3= UTR of EBOV L gene displayed a decent ability to decrease the minigenome mRNA level (Fig.…”

Monoclonal antibodies for the treatment of Ebola virus disease

“…TKM-100802 is a small RNA-interfering (siRNA) molecule directed against the gene products encoding for two viral proteins: L polymerase, involved in transcription and replication of EBOV, and Viral Protein-35, involved in suppression of the host immune response [25]. Survival rate was 100% in a limited number of NHPs treated [26].…”

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siRNA rescues nonhuman primates from advanced Marburg and Ravn virus disease

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