Resurrection Men Dig through the Drug Graveyard: ARYx Revives Problem Blockbuster Drugs

Abstract

Large pharmaceutical companies have tightened up their screening databases and broadened their patents after incidents of drugs slipping through pharmaceutical patents and being restructured by enterprising startups. Notably in 1996, Sepracor transformed Hoechst Marion Roussel Ltd.'s problematic antihistamine Seldane into a single isomer drug and then licensed it back to HMR as Allegra (fexofenadine/pseudoephedrine). Seldane was subsequently banned by the FDA. “It will be a matter of being very clever at identifying the best candidates, both from the chemical standpoint and from an intellectual property point of view,” John Lazo says. “There are a number of compounds out there that could be reengineered for the benefit of mankind.”ARYx is not the only company in the resurrection business. For example, Jazz Pharmaceuticals in Palo Alto, CA raised $250 million in 2004, the largest second-round financing for a drug company to date. Jazz has no proprietary technology and does not plan to do R&D but rather purports to license, improve, develop, and market known compounds for neurological and psychiatric disorders. ARYx is also competing against pharmaceutical companies themselves, which are developing other drugs to meet the same market needs as the ones they abandoned.“We do the same old lab bench-work medicinal chemistry that everybody else does,” says Druzgala, “and have to establish all the same preclinical data for the FDA. We believe our advantages are that we are not attempting to create new validated targets. The big advantage we have is that we can look at an old drug with many years of research and postmarket surveillance.”ARYx's approach bypasses the long screening stages of drug discovery because it deals with known compounds brought through FDA approval—but the revamped drugs would still have to go through the most expensive parts of phase III human clinical testing and resubmission to the FDA as well as pass post-FDA extended clinical use. Even if a drug has well-characterized structure-activity relationships, redirecting its properties in a complex system, for example, fiddling with fat versus water solubility, can cause other unexpected effects, such as changes in the drug localization within the body, local toxicity of a drug, and its rate of uptake and resulting bioavailability.The company hopes to offload the cost of the clinical phase. “We don't expect to be in partnership with the drug company that made the original drug. Our business is based on entering into a commercial partnership which will work with us under phase III trials and commercialization,” says David Nagler.Resurrection is one thing. Redemption in the market for refurbished drugs known to have a toxic history is another. It remains an open question if doctors will be willing to prescribe drugs that have a bad reputation, even if they have been revived, reworked, and renamed.