The challenges encountered in overcoming the twin obstacles -- namely, the inability to get compounds across the BBB and, once having done so, to reliably measure the free concentration of the drug candidate in the brain extracellualar fluid (ECF) -- contribute to a significantly lower probability of development success for CNS drug candidates compared with compounds targeting other therapeutic areas.
CNS drug candidates often fail to demonstrate efficacy in the clinic due to poor transport from the blood into ECF. Traditional approaches to delivering compounds into the brain are crude and include the direct injection of therapeutic agents into the brain via neurosurgery. This is both costly as well as invasive.
Equally, in assessing efficacy, it is not sufficient to rely just on a PK profile in blood, when the true need is to assess the PK profile in the ECF of the brain region relevant to the disorder under investigation. Actual measurement of the free concentration of drug candidates in brain ECF has often been overlooked.
