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When drug companies suffer, the
FDA often suffers with them, especially when the
problem is safety-related. Hence, it is not surprising
that one of the first projects to spring from the
agency’s Critical Path initiative is the Liver
Toxicity Biomarker Study (LTBS) being conducted by the
FDA’s National Center for Toxicology Research (NCTR;
Arkansas) and the private company BG Medicine
(Waltham, Mass.). Hepatotoxicity is a vital area both
economically and clinically: According to BG’s chief
scientific officer Robert McBurney, it accounts for 27
percent of drugs withdrawn from the market in the past
40 years. It still causes a “substantial”
proportion of the 40-plus percent of clinical-phase
drug candidate terminations due to toxicity.
Announced in October 2005, LTBS
aims to discover a new preclinical biomarker for
hepatotoxicity that will improve on the existing
ALT/AST enzyme markers. The project will study five
pairs of compounds spanning a wide range of chemical
classes. Each pair will comprise two very similar
molecules with the same pharmacological action: for
example, one pair is famotidine/ranitidine. Both
compounds in each pair were chosen because they were
toxicologically clean in preclinical development, but
one in each pair showed hepatotoxicity problems
further down the line (in the named case, ranitidine).
BG and NCTR will conduct 28-day
studies of all five pairs of compounds in rats. The
resulting 1,368 terminal liver and plasma samples,
5,448 TVB (total volatile bases) plasma samples, and
7,248 urine samples will then be put through a huge
battery of tests. These, says McBurney, include MALDI/ESI
mass spectrometry and gel electrophoresis for
proteomics; NMR, polar and lipid LC-MS, and GC-MS for
metabonomics; and cDNA microarray hybridization for
gene expression profiling.
The tests will first identify
differences between the effects of each compound in a
pair—for example, the difference between the effects
of famotidine and ranitidine. Once all these
differentials have been tabulated for all five
compound pairs, the researchers will search for a
differential that is common to all five pairs. Any
such differential could be a root cause of
drug-induced liver necrosis and thus—hopefully—a
candidate for a general-purpose hepatotoxicity
biomarker.
That’s the theory. The study
is expected to take some 13 months and cost $12
million, says BG’s business development VP, Scott
Wallace. Sponsors get early sight of the results, full
access to project data, and perpetual royalty-free
licenses on the biomarkers. Eventually, the FDA will
publish the results, says Wallace: “But sponsors get
a serious time advantage, as well as the licenses,”
he says.
It’s a “very smart”
experimental design, says Paul Rolan, a pharmacology
professor at Australia’s Adelaide University. “A
consortium like this has the muscle to do the top-down
screening approach needed to discover new biomarkers,
though we’ll still need to use traditional bottom-up
research methods to identify how they work,” he
says. “The marriage of the two methods means we are
now poised for a big leap forward in safety
biomarkers.”
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