SEPRACOR OPTIPURE SINGLE ISOMER FLURBIPROFEN PHASE II

SEPRACOR OPTIPURE SINGLE ISOMER FLURBIPROFEN PHASE II trials as a treatment for periodontal disease are set to begin soon. Sepracor has filed a use patent for a proprietary single isomer form of the drug (currently sold in its racemic form by Upjohn as Ansaid) and is seeking a licensing partner for the project. The privately-held Marlborough, Mass.-based firm envisions a prescription toothpaste form of the nonsteroidal anti-inflammatory as a treatment to prevent bone loss associated with the dental disease. Sepracor specializes in bioactive membrane separation. Optipure, as a single isomer, or "optically pure," drug compound, comprises one side of a chiral molecule, an asymetric molecule which often may have one biologically active side. Creating optically pure compounds -- that is eliminating the non-active portion of the molecule -- may have an effect on such factors as potency, selectivity and adverse effects. FDA expects to publish a draft guidance this spring on what kinds of data on safety and effectiveness the agency will require from sponsor firms submitting INDs or NDAs for single isomers of racemic compounds or stereoisomeric mixtures. The guidance is being developed by the Center for Drug Evaluation and Research's Stereoisomer Committee, chaired by the Office of Drug Evaluation II's Assistant Directors for Pharmacology/Toxicology and Chemistry Judi Weissinger, PhD, and Charles Kumkumian, PhD. Next furthest along in Sepracor's pipeline is an optically pure atenolol that is several times more potent than the racemic molecule of the beta blocker -- now sold by ICI as Tenormin -- and with more cardioselective biological activity, according to the firm. Sepracor also has filed a use patent application for optically pure form of atenolol. Sepracor's chiral separations program is divided into three areas: proprietary chemical processes for large-scale manufacturing at low cost of pharmaceuticals already sold in optically active forms; R&D contracts for developing new drugs based on the single isomer forms of racemic compounds. Additionally, Sepracor is looking to establish use patent positions for pure isomers (its Optipure molecules) of off-patent or nearly off-patent drugs now sold as racemic mixtures. Sepracor would then work either with the innovator company or provide the bulk pure isomers to a generic firm. A number of major drugs are sold today in single-isomer forms, including Marion Merrel Dow's Cardizem (diltiazem), Syntex' Naprosyn (naproxen), Merck's Blocadren (timolol) and Vasotec (enalapril) and Bristol-Myers Squibb's Capoten (captopril). Producing commercial quantities of single-isomer drugs is currently an expensive process. Sepracor is claiming that its technology makes the process more cost-efficient. Drugs currently sold as racemic mixtures include: albuterol (Schering's Proventil and Glaxo's Ventolin), atenolol, ibuprofen, flurbiprofen, ketoprofen (Wyeth-Ayerst's Orudis), Marion Merrell Dow's Seldane (terfenadine), Miles' Baypress (nitrendipine) and Syntex' Cardene (nicardipine). Like flurbiprofen and atenolol, the single isomer form of these other drugs also may offer therapeutic and/or competitive advantages over the racemic mixtures. For example, all the biological activity in ibuprofen resides in the S-isomer; none is linked to the R-isomer, and the optically pure form appears to have a faster onset of action with fewer side effects. At present, it is very expensive to separate the two; however, Sepracor is currently scaling up for pure ibuprofen. Sepracor is also using this approach for diltiazem. Among Sepracor's current partners is Tanabe Seiyaku, diltiazem's licensor. Sepracor was established in 1985. Major investors in the privately-held firm include Smith-Kline Beecham, American Cyanamid, Raytheon, Mitsubishi and Nomura Securities. Three financing rounds have raised approximately $30 mil. in equity. Estimated revenues in 1989 were $5 mil., with about half the business coming from protein purification. Company President Tim Barberich was previously a senior marketer at Millipore. Exec Robert Dishman, PhD, was with Genex, Millipore and Ionics. VP and general manager of chiral separations, James Young, PhD, came from Sandoz and Zoecon, while Senior VP, Research and Commercial Development Robert Bratzler, PhD, was previously with Polaroid and Princeton University. OptiPure consultants include former FDA Cardio-Renal Drugs Division reviewer Thomas Garvey, MD.