High dose sertraline monotherapy fails to protect rhesus macaques from lethal challenge with Ebola virus Makona

Abstract

The recent epidemic of Ebola virus disease in West Africa resulted in an unprecedented number of cases and deaths. Due to the scope of the outbreak combined with the lack of available approved treatment options, there was strong motivation to investigate any potential drug which had existing data reporting anti-Ebola activity. Drugs with demonstrated antiviral activity in the nonhuman primate models already approved for another indication or for which there was existing safety data were considered to be priorities for evaluation by the World Health Organization. Sertraline hydrochloride was reported to have anti-Ebola activity in vitro alone and in combination with other approved drugs. Although the efficacy was less than 100% in the murine model, the established safety profile of this product, the potential benefit alone and in combination, as well as the lack of other available options prioritized this compound for testing in the Ebola virus intramuscular rhesus macaque challenge model. Using a blinded dosing strategy, we demonstrated that high dose sertraline monotherapy provided no benefit for the prevention of Ebola virus disease in rhesus macaques with regards to reduction of viral load, morbidity, or survival highlighting the challenges of translating results between in vitro and in vivo models.

Figure 1

Survival analysis of sertraline and placebo treated animals exposed to a lethal dose of Ebola virus. Groups of 6 male rhesus macaques were treated with 200 mg sertraline hydrochloride (red) or placebo (blue) by orogastric tube daily beginning six days prior to intramuscular challenge with EBOV/Mak-C05. The survival analysis (a) shows a median time-to-disposition of 8 and 8.5 days for sertraline- and placebo-treated groups, respectively. Rectal temperatures (b) for sertraline hydrochloride and placebo treated animals were evaluated at each anesthetized physical.

Figure 2

Neutrophil and platelet counts for sertraline hydrochloride and placebo treated animals. Pronounced neutrophilia and thrombocytopenia was observed in all animals by day 6 post exposure. Animals were treated with 200 mg sertraline hydrochloride (red) or placebo (blue) by orogastric tube. Group means are presented as lines, with individual values depicted as shapes.

Figure 3

Serum chemistry profiles for sertraline hydrochloride- and placebo-treated macaques. All animals presented with substantial elevation in serum transaminases (a,b), alkaline phosphatase (not shown) and gamma-glutamyl transpeptidase (e) by day 6 post-exposure. Enzyme levels remained elevated until death. All animals exhibited renal dysfunction with elevated blood urea nitrogen (c) and creatinine (f) with concomittant decrease in serum total calcium (d). Animals were treated with 200 mg sertraline hydrochloride (red) or placebo (blue) by orogastric tube. Group means are presented as lines, with individual values depicted as shapes. Upper or lower dynamic ranges of analytes are shown by dotted lines as applicable.

Figure 4

Circulating viremia of sertraline and placebo treated animals exposed to a lethal dose of Ebola virus. Animals were treated with 200 mg sertraline hydrochloride (red) or placebo (blue) by orogastric tube. Log₁₀ plasma viremia levels as measured by plaque assay (a) and qRT-PCR (b) are shown as group means with SEM. Individual values are depicted as shapes. By day 6 post-exposure, animals exhibited substantial viremia that persisted until death. Statistical analysis showed no significant difference between placebo and sertraline treatment at D6.