NEWS OF THE WEEK
TEVA SETTLES PAYFOR-DELAY CASE O
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ANTITRUST: Drugmaker will pay $1.2 billion to refund buyers who paid too much for Provigil
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Provigil
agreed to pay $1.2 billion to settle a Federal Trade Commission allegation that its Cephalon subsidiary illegally blocked the launch of low-cost generic versions of its blockbuster sleepdisorder drug Provigil. This is the first FTC case to be resolved since the Supreme Court ruled in 2013 in FTC v. Actavis that patent settlements in which a brand-name drugmaker pays a generic maker to delay entering the market could be subject to antitrust challenges. “The FTC has been very committed to putting a stop to these kinds of deals,” says FTC Chairwoman Edith Ramirez. “There’s no question that pharmaceutical companies have gotten very creative in the way they try to get around the antitrust laws. We’re going to continue our fight.”
D.A. WEINSTEIN/CUSTOM MEDICAL STOCK PHOTO/NEWSCOM
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EVA PHARMACEUTICAL INDUSTRIES has
NEW INSIGHT ON RNA SPLICING DRUG DISCOVERY: Molecular-level
view could aid discovery of drugs for RNA-splicing diseases
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ISCOVERY OF THE first molecular mechanism
of action for a small molecule that improves RNA splicing in cells could lead to new therapeutics for the genetic disorder spinal muscular atrophy (SMA) and perhaps other conditions involving improper RNA processing. After cells transcribe genomic DNA into RNA, an RNA-protein complex called the spliceosome removes noncoding sequences, or introns, from RNA transcripts, enabling the coding sequences, or exons, to be translated into functional proteins. Currently, no approved drugs are specifically designed to address errors in RNA splicing. SMA is the leading genetic cause of infant mortality, with more than half of patients dying before age two. It is caused by the absence of the gene SMN1, which CEN.ACS.ORG
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ADAPTED FROM NAT. CHEM. BIOL.
NVS-SM1 (line structure) most likely works by stabilizing sequence-specific binding of a spliceosomeassembling complex to the interface between SMN2’s exon 7 and intron 7. A, C, G, and U are RNA bases, and p is phosphate.
The settlement stems from a 2008 FTC lawsuit, which charged that Cephalon unlawfully protected its Provigil monopoly through a series of agreements with four generic drug manufacturers in late 2005 and early 2006. FTC alleged that Cephalon sued the generic drug makers for patent infringement and later paid them more than $300 million in total to drop their patent challenges and forgo marketing their generic products for six years, until April 2012. Were it not for the deals, the drug would have faced competition in 2006, reducing costs for consumers. Under the settlement, Teva will pay $1.2 billion to compensate purchasers, including drug wholesalers, pharmacies, and insurers, who overpaid for Provigil. FTC will allow Teva to count its settlement with direct purchasers in related litigation as a credit toward the total amount paid to the commission. Israel-based Teva also agreed not to enter into any similar patent settlements in its future U.S. operations. Teva notes that the deals that prompted the FTC inquiry occurred years before it purchased Cephalon in 2011. “We are pleased to have reached an agreement with the government. In relation to the consent decree, Teva believes it is the right path for our company, for the industry, and for the patients we serve,” Teva says.—GLENN HESS
encodes SMN, a protein that protects motor neurons. There is a duplicate gene called SMN2, but it cannot fully make up for the resulting SMN deficiency because its RNA transcript is often spliced incorrectly. Susanne E. Swalley and Rajeev Sivasankaran of Novartis Institutes for Biomedical Research, in Cambridge, Mass., and coworkers now report that an orally active small molecule called NVS-SM1 doubled cells’ ability to produce fully functional protein from SMN2 and doubled life-span in a majority of treated mice with SMA (Nat. Chem. Biol. 2015, DOI: 10.1038/nchembio.1837). Their mechanistic study shows that the compound likely works by stabilizing sequence-specific binding of a spliceosome-assembling complex to the exon-intron interface at which incorrect splicing occurs. Novartis is currently recruiting participants for a Phase II trial of NVS-SM1. The agent is competing with two other SMN2 splice-correcting drug candidates— the small molecule RG7800, which Roche, the SMA Foundation, and PTC Therapeutics have in a Phase II trial, and ISIS-SMNRx, an antisense oligonucleotide that Isis Pharmaceuticals and Biogen have in Phase III. Adrian R. Krainer of Cold Spring Harbor Laboratory, in New York, who collaborated on the discovery of ISIS-SMNRx, comments that the ability to develop small molecules that can correct other RNA-splicing defects “could be facilitated by elucidating the mechanism of action of small molecules, such as the ones reported in the new study.”—STU BORMAN
JUNE 8, 2015
