Chirality of New Drug Approvals (2013–2022): Trends and Perspectives

Many drugs are chiral with their chirality determining their biological interactions, safety, and efficacy. Since the 1980s, there has been a regulatory preference to bring single enantiomer to market. This perspective discusses trends related to chirality that have developed in the past decade (2013–2022) of new drug approvals. The EMA has not approved a racemate since 2016, while the average for the FDA is one per year from 2013 to 2022. These 10 include drugs which have been previously marketed elsewhere for several decades, analogues of pre-existing drugs, or drugs where the undefined stereocenter does not play a role in therapeutic activity. Two chiral switches were identified which were both combined with drug repurposing. This combination strategy has the potential to produce therapeutically valuable drugs in a faster time frame. Two class III atropisomers displaying axial chirality were approved between 2013 and 2022, one as a racemate and one as a single enantiomer.


Methods
Terminology is used in accordance with IUPAC (International Union of Pure and Applied Chemistry) definitions stated in "Basic Terminology of Stereochemistry".(1)

COMPILING EMA NEW DRUG APPROVALS DATA
The EMA "Human Medicines: highlights of (year)" reports were used to identify medicines which contained a NAS which were approved by the EMA in the years 2015 to 2022.(2) These reports provide the trade names of new medicines which have been approved each year and classify them according to their general therapeutic area.Those which contain a NAS are highlighted.No other information on the drug is provided.Based on these reports a list was compiled of the trade names of all medicines approved by the EMA in the period 2015-2022 which contained a NAS.
This list was then cross-referenced with a spreadsheet listing all medicine European Public Assessment Reports (EPARs) downloaded from the EMA website.(3) This spreadsheet provides significantly more detail than the highlights reports including medicine name, active substance(s), exact marketing authorisation date, use/indication etc.It does not, however, indicate which medicines contain active substances which have not previously been authorised thus necessitating the use of the "Human Medicines: highlights of (year)" reports.
The final stage in compiling the EMA data was classification of the NASs according to their chirality.The list of active substances was firstly filtered to remove the majority of biologics.This was achieved by removing drugs classed as vaccines then leveraging naming conventions used for biopharmaceuticals.NASs whose name contained the suffixes listed in Table S1 were classified as biologics and not considered for further classification.Similarly, all vaccines were classed as biologics and not further classified.
The remaining medicines were then classified according to their chirality; chiral or achiral.Some additional biologics and non-biologic macromolecules were identified which were excluded from the chirality classification.Chiral molecules were further classified according to whether they are marketed as a single enantiomer or as a racemate.For simplicity, mixtures of diastereomers were classified as racemic drugs.Chiral drug molecules were also classified based on their type of chirality and, in the case of molecules containing one or more stereocentres, the number and stereocentre type.This was achieved by accessing the EPARs on the EMA website for each medicine.The Active Substance section of each report provides the structure of the active substance and details of the molecule's chirality.
As the EMA "Human Medicines: highlights of (year)" reports were not published prior to 2015, an alternative approach was employed to the compilation of EMA data for years 2013 and 2014.The list of all medicines approved in those years from the Medicine EPAR spreadsheet was filtered to remove biologics.The EPARs for all remaining medicines were accessed on the EMA website.These reports were used to identify which active substances were NASs and also classify them according to their chirality as described above.

Monoclonal antibodies -mab
Peptides and glycopeptides -tide

COMPILING FDA NEW DRUG APPROVALS DATA
Data on FDA NME drug approvals was collected from the FDA web page "New Drugs at FDA: CDER's New Molecular Entities and New Therapeutic Biological Products".(5) This site lists the trade names of all medicines approved by the FDA since 2015 that contain NMEs or NBEs.In addition, it provides the name of the new active substance, approval date and the medicine's approved use.Biologics were filtered from the extracted list based on their nomenclature as described above (Table S1).The remaining medicines were cross-referenced with the EMA list such that the classifications of medicines also appearing in the EMA list could be transposed.In order to classify the remaining NMEs according to their chirality, their structures were obtained from PubChem, the website of the US National Library of Medicine.(6) The stereochemistry of each compound was confirmed using the Global Substance Registration System website.(7) As data has previously been published by Modroiu and Hancu classifying FDA drug approvals from 2010-2020 based on their chirality, only new FDA drug approvals from 2020-2022 were analysed as part of the study.(8) 2020 was included in this analysis to confirm that the previously published data was replicated using the approach described here.

COMPILING CHIRAL SWITCH DATA
In order to identify new active substances that had been brought to market in the last ten years using the chiral swich approach, the naming conventions for chiral switch drugs was leveraged.
The prefixes es-and ar-may be used where a racemate is chiral switched to the S or R enantiomer, respectively.Alternatively, the prefixes dextro-or dex-may be used for a chiral swich drug that displays dextrorotary optical activity or levo-or lev-where is displays levorotary optical activity.(9) The EPARs spreadsheet from the EMA website was filtered for the relevant time period (2013-2022).(3)Searches for the chiral switch prefixes were carried out within the filtered list.Each search result was examined to determine whether it was the result of chiral switch within the period of interest.Several active substances fulfilled the search criteria but were not the result of a chiral switch strategy e.g.artesunate, aripiprazole, estetrol monohydrate.Others were the result of chiral switching but had previously been marketed prior to 2013 e.g.esomeprazole, levofloxacin.
The same search procedure was applied to the compiled list of FDA drug approvals from 2020-2022.For the years 2013-2019, this search procedure was applied to the relevant lists of new drug approvals on the FDA web page "New Drugs at FDA: CDER's New Molecular Entities and New Therapeutic Biological Products".(5)

SEARCH STRATEGY LIMITATIONS
A limitation of this search strategy is that axial chirality arising from atropisomerism has the potential to be overlooked, specifically in the case of Class II atropisomers.Stable Class III atropisomers are expected to be clearly identified and Class I molecules are not considered chiral.

Table S5 .
Comparison of the number and percentage of achiral, single enantiomer and racemic small molecule NASs approved by the EMA from 2013-2022.......... S8 TableS6.Categorisation of biologic, achiral and chiral NASs approved by the EMA between 2013-2022 according to the general therapeutic area for which they are indicated. .

Table S7 .
Comparison of the number of stereocentres present in chiral small molecule NMEs approved by the FDA between 2020-2022. .

Table S8 .
Comparison of the number of stereocentres present in chiral small molecule NASs approved by the EMA between 2013-2022. .

Table S9 .
(5) medicines containing new therapeutic entities (NTEs) approved for marketing authorisation by the FDA from 2020-2022 classified as either biologic, achiral, single enantiomer or racemate.Data was gathered from the FDA website and excludes "vaccines, allergenic products, blood and blood products, plasma derivatives, cellular and gene therapy products, or other products that the Center for Biologics Evaluation and Research approved".(5)Note:an Excel file containing these tables is also available as Supporting Information.
-LunsumioTo treat adults with relapsed or refractory follicular lymphoma, a type of non-Hodgkin lymphoma -SunlencaTo treat adults with HIV whose HIV infections cannot be successfully treated with other available treatments due to resistance, intolerance, or safety considerationsPress -RolvedonTo decrease the incidence of infection in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with clinically significant incidence -DaxxifyTo treat moderate-to-severe glabellar lines associated with corrugator and/or procerus muscle activityNote: an Excel file containing these tables is also available as Supporting Information.