Estimating an effective dose for a new drug to treat Ebola with incomplete information: the case of Zmapp
Matthias Machacek (1), Larry Zeitlin (2), Steven Kern (3), Peter Lloyd (4)
(1) LYO-X GmbH, (2) Mapp Biopharmaceutical, (3) Bill & Melinda Gates Foundation, (4) KinDyn Consulting
ZMapp is an experimental drug for the treatment of Ebola virus disease (EVD) and is currently being tested in patients in a phase II study. ZMapp is a cocktail of three IgG1 monoclonal antibodies (mAbs) that are specific to different sites of the viral surface glycoprotein (GP). The currently tested clinical dose regimen is 50 mg/kg given three times at an interval of three days. The acute clinical need and the limited stocks of drug material necessitated an effort to better understand the dose response to see if lower doses with an equivalent clinical outcome would be feasible.
The available data were from studies investigating 50 or 25 mg/kg ZMapp in an EVD model in rhesus monkeys (NHP). ZMapp was administered intravenously twice or three times at a three-day interval. There was no clear difference in the survival rate between the 50 or 25 mg/kg dose levels or between the two or three administrations. Thus the data were not sufficient to identify the minimal effective dose.
In the absence of any PD data that could inform the dose selection, PK considerations were used to rationalize a dose selection. From a rat GLP toxicology study in non-infected animals a population PK model was built and scaled to humans using established allometric scaling parameters for mAbs. PK simulations of different scenarios showed that the 3x50 mg/kg dosing led to a consecutive increase in cmax at each of the administration. In a successful therapy the viral load will have an inverse trend with the highest load at the first dose. Thus accumulation of drug would be unnecessary. An alternative dose regimen was proposed with 50 mg/kg at day one and 25 mg/kg at days four and seven. The alternative dose regimen had the advantage of maintaining a comparable exposure over the 14 days period, critical for the survival of the animals, while saving 1/3 of the drug material meaning that 30% more patients could be treated.
The ongoing study in patients with EBV will provide the PK of ZMapp in infected humans validating the scaling and provide the data if ZMapp PK is altered through binding to the virus. In addition, a new NHP study was proposed to investigate doses of 1 or 10 mg/kg given once or thee times at days one or days one, four and seven to identify a minimal effective dosing that can help to support a lowering of the second and third dose in patients from 50 to 25 mg/kg.