Evaluation of Trials Comparing Single-Enantiomer Drugs to Their Racemic Precursors

Abstract

Key Points Question How often do randomized clinical trials directly compare new single-enantiomer drugs to their existing racemic precursors, and how often are efficacy or safety differences observed? Findings In this systematic review of 15 single-enantiomer racemic drug pairs, 185 direct-comparison randomized clinical trials (median, 2 trials; interquartile range, 1-8 trials) were identified, 124 (67.0%) of which studied 1 drug pair. For 9 single-enantiomer drugs, no randomized clinical trials were identified providing evidence of improved efficacy, based on primary end point results, or safety as compared with their racemic precursors. Meaning Results of this systematic review suggest that most newly marketed single-enantiomer drugs are infrequently directly compared with their existing racemic precursors, and when compared, they are uncommonly found to provide improved efficacy or safety, despite their greater costs.

Three Mutations Convert the Selectivity of a Protein Sensor from Nicotinic Agonists to S-methadone for Use in Cells, Organelles, and Biofluids

“…Along with other sensors of opioid signaling 11,27 , this study establishes the first genetically encoded fluorescent protein biosensor for an opioid drug, enabling real-time quantification. Furthermore, the enantioselectivity encourages biosensor development to investigate "chiral switching" of other drugs where a single enantiomer substitutes a clinically used racemate 28 . One enantiomer may serve previously unstudied indications.…”

Three Mutations Convert the Selectivity of a Protein Sensor from Nicotinic Agonists to S-Methadone for Use in Cells, Organelles, and Biofluids

“…Furthermore, the enantioselectivity encourages biosensor development to investigate "chiral switching" of other drugs where a single enantiomer substitutes a clinically used racemate. 33 One enantiomer may serve previously unstudied indications. For example, S-methadone is now under clinical investigation as a rapidly acting antidepressant via nonopioid mechanism(s).…”

“…Along with other sensors of opioid signaling, , this study establishes the first genetically encoded fluorescent protein biosensor for an opioid drug, enabling real-time quantification. Furthermore, the enantioselectivity encourages biosensor development to investigate “chiral switching” of other drugs where a single enantiomer substitutes a clinically used racemate . One enantiomer may serve previously unstudied indications.…”

Chiral Switch: Between Therapeutical Benefit and Marketing Strategy

“…An interesting investigation was published in 2021 by Long et al in which randomized clinical trials directly comparing single-enantiomer drugs to a previously used racemic precursors for efficacy or safety differences were evaluated. Fifteen drugs subject to a chiral switch were evaluated, and for nine of them, no randomized clinical trials that showed enhanced effectiveness or safety when compared to their racemic predecessors were found [52]. It is interesting that more than half of these randomized clinical trials involved bupivacaine versus levobupivacaine.…”

“…It is interesting that more than half of these randomized clinical trials involved bupivacaine versus levobupivacaine. According to the findings of this systematic analysis, newly approved single-enantiomer medications are seldom directly compared to racemic precursors, and when they are, rarely have they been shown to deliver enhanced effectiveness or safety [52]. It should be acknowledged that the regulatory authorities do not have the legal authority to demand comparative effectiveness testing of single enantiomers to the previously registered racemates, prior to approval [9,49,52].…”