Putting chirality to work: the strategy of chiral switches

Key Points Chiral switches are chiral drugs that have already been claimed, approved and marketed as racemates or as mixtures of stereoisomers, but have since been redeveloped as single enantiomers. The essential criterion of a chiral switch is a change in the status of chirality. There are still a significant proportion of racemic drugs among the recently approved new molecular entities. The patentability of single enantiomers in a chiral switch is an extreme case of a selection patent. The novelty of a single enantiomer is not negated by the prior-art disclosure of its racemate. The strategy of enantiomeric pairs of patents of single enantiomers — E 1 and E 2 — in a chiral switch consists of two patents claiming simultaneously that E 1 and E 2 are pharmacologically superior to the racemic drug E 1,2 . This strategy has been questioned. According to the US FDA, single enantiomers in chiral switches are not new molecular entities, and are therefore barred from five-years exclusivity. Such new products are treated as new derivatives of existing drugs or new formulations, on a case-by-case basis. Despite the regulatory acceptance of 'bridging strategies' from racemate to single enantiomer, only a few successful switches have emerged from this route. Successful chiral switches emerge from racemic drugs that have efficacy and/or safety that can be enhanced, leading to significantly superior single enantiomers that are patentable and compete effectively with cheaper generic versions of the racemates. Chiral switches are also eligible in cases in which the mechanisms of action of the single-enantiomer drugs involve achiral intermediates — for example, esomeprazole magnesium — and/or racemization. Paradoxically, a chiral switch can result in the increased use of the racemate, this being a feature of the failure of the chiral switch of fenfluramine to dexfenfluramine and the 'fen–phen' fiasco. The timing of chiral switches of blockbuster drugs is crucial. The new single enantiomer should be launched ideally before the expiration of the patents that cover the racemate, with extended exclusivity and before the incursions of the respective generic drugs. Most of the new drugs reaching the market today are single enantiomers, rather than the racemic mixtures that dominated up to ten years ago. Many of the new single-enantiomer drugs were developed as such, but there are also important examples of new single-enantiomer drugs derived from 'chiral switches' of establishe