DRUG APPROVALS DECLINED IN 2010 REGULATION: Industry faced tough
FDA scrutiny of new products
F
DA APPROVALS of new small-molecule and bio-
logic drugs decreased last year after a two-year plateau. In 2010, the first full year under a new commissioner, U.S. regulators approved 21 new drug substances, down from 25 in 2009 and 24 in 2008. Full FDA performance statistics are not yet available for 2010, but the total number of new applications filed has been rising since 2005, mostly for new indications and formulations. Applications for new molecular entities have remained nearly constant. Most of the notable 2010 approvals came in the second half of the year. They include Amgen’s osteoporosis drug Prolia, Novartis’ multiple sclerosis therapy Gilenya, and Boehringer Ingelheim’s anticoagulant Pradaxa. As telling as those drugs that made it through, however, are drugs that failed to get approved, were recalled, or have been delayed. In 2010, the agency rejected a longacting form of the diabetes drug Byetta from Amylin Pharmaceuticals and Eli Lilly & Co., as well as weightloss drugs from Arena Pharmaceuticals and Vivus. Regulators also took a firm stand on safety. Heart
PROBING THE ANOMERIC EFFECT CARBOHYDRATE CHEMISTRY:
Peptide sensor provides clues to phenomenon that stabilizes sugars
A
NEW SENSOR probes a well-known, but poorly
understood, effect in carbohydrate chemistry that controls the conformations of many biologically relevant sugars. The work provides experimental evidence for the electronic interactions that underlie the so-called anomeric effect. In the anomeric effect, a sugar ring is stabilized by an electronegative substituent at the C1 carbon, also known as the anomeric center. The stabilization is thought to result from interactions between lone electron pairs on oxygen and a C1 antibonding orbital. The effect is called endo-anomeric when the lone pair comes from the oxygen atom in the sugar ring and exoanomeric when the lone pair comes from oxygen in a substituent on C1. Benjamin G. Davis, John P. Simons, and coworkers at the University of Oxford use a peptide as a sensor to study the gas-phase anomers of methyl d-galactopyranoside (Nature, DOI: 10.1038/nature09693). The two
problems were behind the withdrawal of Abbott Laboratories’ weight-loss drug Meridia and the generic painkiller propoxyphene. On the same grounds, FDA limited the use of GlaxoSmithKline’s diabetes drug Avandia. And in a recent high-profile case, FDA will remove breast cancer from the indicated uses for Roche’s GO-AHEAD Number of new FDAblockbuster drug Avastin. approved drugs hitting the market declines The agency’s safety-based Approvals decision ran counter to 40 the European Medicines Agency’s view. 30 Some FDA decisions were shifted into 2011. 20 The agency will take more time to review MannKind’s 10 inhaled insulin Afrezza, AstraZeneca’s blood thin0 1999 00 01 02 03 04 05 06 07 08 09 10 ner Brilinta, Bristol-Myers Squibb’s ipilimumab canNOTE: Approvals of new molecular entities and biologics. SOURCE: U.S. Food & Drug Administration cer therapy, and Benlysta, a lupus drug from Human Genome Sciences and GSK. Michael Kleinrock, director of market insights at the research firm IMS Health, notes that the lower number of approvals in recent years has been accompanied by lower average sales from those approvals. If this trend were to continue, there could be long-lasting negative implications, he says, “but the industry has experienced this in the past and has rebounded.”—ANN THAYER
ends of the peptide form hydrogen bonds with different regions of the sugar. The infrared spectrum reveals information about the shape and bonding of each peptide-anomer complex, Davis says. In both peptide-anomer complexes, the peptide comes close enough to the sugar’s enSTABILITY Sensor docyclic oxygen to sense the electronic densiforms hydrogen bonds ty there. Davis’ team concluded that, for both with a model sugar anomers, the exo-anomeric effect is stronger (only hydroxyl groups than the endo-anomeric effect. that participate in the Their experimental measurements and interaction are shown). calculations highlight the importance of the substituent at C2, Davis notes. “The substituO ent at position 2 can have an enormous influH3C CH3 N N ence on the orientation of the bonds at the H H O anomeric center and strongly modulate the exo-anomeric effect,” he says. The C2 position is one that often is modified in naturally occurring sugars, he says. Peptide sensor Vernon G. S. Box, an emeritus chemistry N professor at the City College of New York, points out that other sugars such as glycosyl O H esters are known to have stronger anomeric effects than methyl-glycosides. “It would be nice if their work was extended to the glycosyl HO O H esters and glycosyl halides to provide more insight into and evidence for a truly valid raO tionalization of what is observed experimenOCH3 tally,” he says.—CELIA ARNAUD
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