INTRODUCTION TO BIOMARKERS - Flow Cytometry in Drug Discovery and Development - page 56

40

30

20

10

Mean ± SD

0

0 25 50 75 100 125

Omapatrilat (mg)

FIGURE 3.1 Mean ( SD) 24 h urinary excretion of ANP after single oral dose of omapatrilat
(n ¼ 6 per dose group) or placebo (n ¼ 21) in healthy volunteers (from Ref. 39, with
permission).

the NEP inhibition in a clinical study using a dose of 25mg of omapatrilat or higher
(Figure 3.1).
Discovery of new biomarkers often takes place at academic institutions, but the use
of newly discovered biomarkers in the discovery and development of drugs usually
takes place at pharmaceutical companies. The concept has been to provide measure-
ments of new and novel biomarkers that could potentially give the drug developer
an advantage over other developers. The challenge with using novel biomarkers is the
fact that they are “novel” and we therefore have limited understanding of their utility.
In addition, many of the assays used to measure novel biomarkers have undergone
very limited analytical validation or characterization (see Section 3.5). There is
therefore a need for more critical analytical validation of the biomarker assays used
in the discovery phase.
Measurements of biomarkers in the late stage of discovery using validated assays
would significantly improve the biomarker information available to the clinical
teams. In addition, the use of larger animal species, such as nonhuman primates,
could provide very valuable information about the PK and PD relationship. Knowl-
edge of the PK/PD relationship from an in vivo animal experiment, prior to the first
clinical development studies, will considerably improve the planning and designing
of the clinical studies when it comes to measurement of biomarkers.
We have numerous times experienced programs where lack of information about
the preclinical PD effects in an in vivo animal model led to a less than optimal study
design in the first clinical study. Often the PD effect was missed because too few
samples were collected or the timing of the sample collection was outside the time
window of the PD effect.