Be Careful What You Ask for: Challenges of Predicting Human Clearance for a Low Metabolic Turnover Compound, ELND006
The discovery of a new chemical entity (NCE) suitable for CNS drug development is a
challenging endeavor as many different properties require simultaneous optimization. One of
these properties, metabolic stability, is a surrogate for in vivo clearance (CL). A common
practice of discovery project teams is to select NCEs with the greatest metabolic stability for
further evaluation. With NCEs that exhibit low or no turnover in in vitro systems, it becomes
very challenging to project human CL and thereby the plasma profile of the compound (i.e.,
half-life; T1/2). Compounds with excessively long T1/2 can pose development challenges (e.g.,
long washout times for cross-over study designs, necessitating loading doses for rapid onset of
activity, ensuring an adequate duration of exposure coverage from safety studies, etc.). While
these are not “show stoppers”, a priori projections of pharmacokinetic (PK) properties of these
NCEs does provide a basis for the rationale design of early clinical development programs prior
to the availability of human data. In addition, very low turnover of an NCE complicates the
characterization of metabolites. One criterion for the selection of non-rodent species for safety
assessment is the similarity of its metabolite profile to humans.
ELND006, a potent and APP selective gamma secretase inhibitor that lowers A in the
CNS of rodents and nonhuman primates was selected from a series of NCEs based, in part, on
its metabolic stability in both NADPH and UDPGA supplemented liver microsomes. This high metabolic stability proved challenging for ELND006 since human CL could not be
predicted based on in vitro data and the low turnover generated only trace levels of metabolites
making identification of them difficult. Ultimately, ELND006 was evaluated in clinical studies.
These studies showed that ELND006 exhibited very low CL (0.054 L/h/kg) following oral
administration, resulting in a very long half-life (220 to 306 hours).
challenging endeavor as many different properties require simultaneous optimization. One of
these properties, metabolic stability, is a surrogate for in vivo clearance (CL). A common
practice of discovery project teams is to select NCEs with the greatest metabolic stability for
further evaluation. With NCEs that exhibit low or no turnover in in vitro systems, it becomes
very challenging to project human CL and thereby the plasma profile of the compound (i.e.,
half-life; T1/2). Compounds with excessively long T1/2 can pose development challenges (e.g.,
long washout times for cross-over study designs, necessitating loading doses for rapid onset of
activity, ensuring an adequate duration of exposure coverage from safety studies, etc.). While
these are not “show stoppers”, a priori projections of pharmacokinetic (PK) properties of these
NCEs does provide a basis for the rationale design of early clinical development programs prior
to the availability of human data. In addition, very low turnover of an NCE complicates the
characterization of metabolites. One criterion for the selection of non-rodent species for safety
assessment is the similarity of its metabolite profile to humans.
ELND006, a potent and APP selective gamma secretase inhibitor that lowers A in the
CNS of rodents and nonhuman primates was selected from a series of NCEs based, in part, on
its metabolic stability in both NADPH and UDPGA supplemented liver microsomes. This high metabolic stability proved challenging for ELND006 since human CL could not be
predicted based on in vitro data and the low turnover generated only trace levels of metabolites
making identification of them difficult. Ultimately, ELND006 was evaluated in clinical studies.
These studies showed that ELND006 exhibited very low CL (0.054 L/h/kg) following oral
administration, resulting in a very long half-life (220 to 306 hours).
