Monday, November 19, 2012
Less than Meets the Eye
While 53 antibiotic new
chemical entities in the clinic look robust, there is less there than meets the
eye, particularly regarding new classes of broad-spectrum drugs that could
treat emerging drug-resistant Gram-negative infections.
BioCentury's review of the
clinical pipeline defines "novel" as compounds or peptides not based
on chemical classes of any approved systemically delivered human antibiotics.
Excluding compounds being
developed exclusively to treat a single pathogen, no compounds derived from
unique chemical classes are in Phase III, and only three broad-spectrum
antibiotics from novel classes are in Phase II.
These include Polymedix
Inc.'s defensin-mimetic membrane-disrupting peptide brilacidin (PMX-30063),
GlaxoSmithKline plc's peptide deformylase (PDF) inhibitor GSK1322322;
and the protein-synthesis inhibiting pleuromutilin BC-3781 from Nabriva
Therapeutics AG and Forest Laboratories Inc.
drug, Altabax retapamulin from GSK, is approved in a topical formulation to
treat impetigo, but there is no marketed systemically administered drug in this
The lack of novel drugs is
beginning to be addressed in early clinical development, with Phase I studies
ongoing for compounds with new mechanisms of action that can act on
Gram-negative bacteria. These include Achaogen Inc.'s
UDP-3-O-[3-hydroxymyristoyl] N-acetylglucosamine deacetylase (LpxC) inhibitor
ACHN-975 and GSK's novel topoisomerase IIA inhibitor GSK2140944 (see SciBX:
Science-Business eXchange, Sept. 2, 2010).
Developing novel classes of
antibiotics is difficult. In February, Phase I and II trials of the leucyl-tRNA
synthetase (LARS; LeuRS) inhibitor GSK2251052 were suspended due to the
emergence of resistance. Last month, GSK returned rights to Anacor
Pharmaceuticals Inc., which has not disclosed future development plans.
In addition to a lack of new
MOAs, half of the broad-spectrum Phase III programs in the pipeline have been
turned down by FDA at least once. Of the 10 broad-spectrum antibiotics
in Phase III development, five previously have had NDAs withdrawn or have
received complete response or approvable letters.
These include the
cephalosporin Ceftobiprole from Basilea AG; the ketolide Restanza
cethromycin from Advanced Life Sciences Holdings Inc.; the glycopeptide
antibiotic dalbavancin from Durata Therapeutics Inc.; the
lipoglycopeptide Oritavancin from The Medicines Co.; and the quinolone
garenoxacin (T-3811) from Toyama Chemical Co. Ltd.
The complete roster of 53
clinical-stage antibiotic new chemical entities is available online. Please see
"Antibiotics NCE Pipeline."
- Chris Cain, Senior