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.

One pleuromutilin-based drug, Altabax retapamulin from GSK, is approved in a topical formulation to treat impetigo, but there is no marketed systemically administered drug in this class.

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 Of the 10 broad-spectrum antibiotics in Phase III development, five previously have had NDAs withdrawn or have received complete response or approvable letters.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 Writer