Extrapolation of Oligonucleotide Dose Levels Used in Nonclinical Toxicity Studies to Selection of Safe Starting Dose Levels in Human Clinical Trials.

One of the key questions for nearly all oligonucleotide therapeutic programs is how to properly extrapolate no-observed adverse effect levels (NOAELs) identified in nonclinical (animal) toxicity studies to the human equivalent dose to enable selection of an appropriate safe starting dose level in normal subjects or patients. There is a strong historical precedent, mainly driven by a guidance document issued from the U.S. Food and Drug Administration, for converting NOAELs expressed as milligram per kilogram body weight (mg/kg) to an NOAEL based on body surface area (BSA), often referred to as allometric scaling. This conversion imparts an additional safety factor of variable magnitude, depending on the species from which the NOAEL has been characterized. The primary impetus for the application of BSA-based dose extrapolation across species derives from cross-species comparisons of the sensitivity to small-molecule anticancer agents and other small-molecule drugs, for which poor predictivity of human sensitivity was obtained with direct extrapolation of mg/kg dose levels and for which much better predictivity was obtained when doses were converted to BSA (mg/m2). The primary question that is raised in the discussion presented herein is whether that widely used allometric scaling paradigm is broadly applicable to all oligonucleotide therapeutics and whether the adherence to this paradigm might result in the unnecessary administration of subpharmacologic doses to initial patient cohorts with life-threatening or severe disease conditions.