A year in pharmacology: new drugs approved by the US Food and Drug Administration in 2023

Abstract

With 54 new drugs and seven cellular and gene therapy products, the approvals by the US Food and Drug Administration (FDA) recovered 2023 from the 2022 dent back to the levels of 2020–2021. As in previous years of this annual review, we assign these new drugs to one of three levels of innovation: first drug against a condition (“first-in-indication”), first drug using a novel molecular mechanism (“first-in-class”), and “next-in-class,” i.e., a drug using an already exploited molecular mechanism. We identify four (7%) “first-in-indication,” 22 (36%) “first-in-class,” and 35 (57%) “next-in-class” drugs. By treatment area, rare diseases (54%) and cancer drugs (23%) were once again the most prevalent (and partly overlapping) therapeutic areas. Other continuing trends were the use of accelerated regulatory approval pathways and the reliance on biopharmaceuticals (biologics). 2023 marks the approval of a first therapy based on CRISPR/Cas9 gene editing.

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Naunyn-Schmiedeberg's Archives of Pharmacology (2024) 397:2949–2970
https://doi.org/10.1007/s00210-024-03063-1
REVIEW
A year inpharmacology: new drugs approved bytheUS Food
andDrug Administration in2023
GizemKayki‑Mutlu1· ZinnetSevvalAksoyalp2· LeszekWojnowski3· MartinC.Michel3
Received: 27 February 2024 / Accepted: 19 March 2024 / Published online: 26 March 2024
© The Author(s) 2024
Abstract
With 54 new drugs and seven cellular and gene therapy products, the approvals by the US Food and Drug Administration
(FDA) recovered 2023 from the 2022 dent back to the levels of 2020–2021. As in previous years of this annual review, we
assign these new drugs to one of three levels of innovation: first drug against a condition (“first-in-indication”), first drug
using a novel molecular mechanism (“first-in-class”), and “next-in-class,” i.e., a drug using an already exploited molecular
mechanism. We identify four (7%) “first-in-indication,” 22 (36%) “first-in-class,” and 35 (57%) “next-in-class” drugs. By
treatment area, rare diseases (54%) and cancer drugs (23%) were once again the most prevalent (and partly overlapping)
therapeutic areas. Other continuing trends were the use of accelerated regulatory approval pathways and the reliance on
biopharmaceuticals (biologics). 2023 marks the approval of a first therapy based on CRISPR/Cas9 gene editing.
Keywords FDA· New drugs· First-in-class· Next-in-class
Introduction
Analyzing patterns of new drug approval testifies to the
activities and priorities of the pharmaceutical industry
and provides information on trends in novel treatment
approaches. The US Food and Drug Administration (FDA)
approved 37 new molecular entities in 2022 (Kayki-Mutlu
etal. 2023), 50 in 2021 (Kayki-Mutlu etal. 2022), and 53
in 2020 (Kayki-Mutlu and Michel 2021). The dip in new
approvals in 2022 apparently reflected reduced trial comple-
tions and regulatory filings during the COVID-19 pandemic.
With 54 drugs plus seven cellular and gene therapy products
in 2023, the approvals have recovered to the levels in 2020
and 2021. As in our previous annual reviews, we briefly
summarize key efficacy and tolerability data. We classify
the degree of innovation as first-in-indication, i.e., drugs for
the treatment of a condition for which no approved medical
treatments existed; first-in-class, i.e., drugs with a molecu-
lar mechanism of action that had not been used by previ-
ously approved medical treatments; and next-in-class, i.e.,
novel chemical or biological entities that exploit a molecular
mechanism already available for the treatment of the same
condition (Table1). Table2 breaks down the approvals
according to the molecular structure (small molecule, anti-
body, peptide and protein, cellular and gene therapy). The
increasingly common orphan drugstatus is given in Table3.
All approvals are discussed according to therapeutic areas.
It is explicitly not our intention to compare novel treat-
ments with their specific advantages and disadvantages with
existing ones, because this is best done by experts in a thera-
peutic area. Similarly, we do not discuss drug pricing for
novel treatments. Such discussion can only be meaningful
based on input from experts within a specific therapeutic
Gizem Kayki-Mutlu and Zinnet Sevval Aksoyalp contributed
equally to the manuscript.
* Martin C. Michel
marmiche@uni-mainz.de
Gizem Kayki-Mutlu
gkayki@ankara.edu.tr
Zinnet Sevval Aksoyalp
zinnetsevval.aksoyalp@ikcu.edu.tr
Leszek Wojnowski
wojnowsk@uni-mainz.de
1 Department ofPharmacology, Faculty ofPharmacy, Ankara
University, Ankara, Türkiye
2 Department ofPharmacology, Faculty ofPharmacy, Izmir
Katip Celebi University, Izmir, Türkiye
3 Department ofPharmacology, University Medical Center,
Johannes Gutenberg University, Langenbeckstr. 1,
55118Mainz, Germany
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2950 Naunyn-Schmiedeberg's Archives of Pharmacology (2024) 397:2949–2970
Table 1 Newly approved drugs grouped by novelty. For definitions,
see Introduction. Percentages are those of first-in-indication, first-in-
class, and next-in-class drugs with all drugs (included cellular and
gene therapies) approved in 2023 taken as 100%. Where available, the
International Nonproprietary Name stems in drug names have been
highlighted by underlining based on the WHO Stem Book (https://
cdn. who. int/ media/ docs/ defau lt- source/ inter natio nal- nonpr oprie tary-
names- (inn)/ inn- bio- review- 2022. pdf? sfvrsn= f8db1 66f_ 3& downl
oad= true; https:// cdn. who. int/ media/ docs/ defau lt- source/ inter natio
nal- nonpr oprie tary- names- (inn)/ stemb ook- 2018. pdf)
First-in-indica-
tion (n = 4, 7%)
Approved for First-in-class (n = 22,
36%)
Approved for Next-in-class (n = 35,
57%)
Approved for
Leniolisib Phosphoinositide
3-kinase delta syn-
drome
Beremagene geper-
pavec-svdt
Dystrophic epidermoly-
sis bullosa
Avacincaptad pegol Geographic atrophy
Omaveloxolone Friedreich’s ataxia Birch triterpenes Dystrophic and junc-
tional epidermolysis
Bexagliflozin Type 2 diabetes mellitus
Palovarotene Heterotopic ossification Capivasertib Breast cancer Bimekizumab-bkzx Psoriasis
Pozelimab-bbfg CHAPLE Disease Daprodustat Anemia Cipaglucosidase Alfa-
Atga
Late-onset Pompe
disease
Delandistrogene
moxeparvovec-rokl
Duchenne muscular
dystrophy
Efbemalenograstim
alfa-vuxw
Neutropenia
Donislecel-jujn Type 1 diabetes mel-
litus
Elacestrant Breast cancer
Exagamglogene auto-
temcel
Sickle cell disease Elranatamab-bcmm Relapsed or refractory
multiple myeloma
Fezolinetant Menopause Epcoritamab-bysp Diffuse large Bcell
lymphoma
Iptacopan Paroxysmal nocturnal
hemoglobinuria
Eplontersen Polyneuropathy of
hereditary tran-
sthyretin-mediated
amyloidosis
Lotilaner Demodex blepharitis Etrasimod Ulcerative colitis
Lovotibeglogene auto-
temcel
Sickle cell disease Flotufolastat F 18 Prostate-specific
membrane antigen
(PSMA)-positive
lesions
Nedosiran Primary hyperoxaluria Fruquintinib Metastatic colorectal
cancer
Nirmatrelvir, ritonavir COVID-19 Gepirone Major depressive
disorder
Nirogacestat Progressing desmoid
tumors
Glofitamab-gxbm Diffuse large Bcell
lymphoma
Omidubicel-onlv Hematologic malignan-
cies
Lecanemab-irmb Alzheimer’s disease
Perfluorohexyloctane Dry eye disease Mirikizumab-mrkz Ulcerative colitis
Sparsentan Proteinuria in primary
immunoglobulin A
nephropathy
Momelotinib Myelofibrosis
Talquetamab-tgvs Relapsed or refractory
multiple myeloma
Motixafortide Multiple myeloma
Tofersen Amyotrophic lateral
sclerosis
Nirsevimab-alip RSV
Trofinetide Rett syndrome Pegunigalsidase Alfa-
Iwxj
Alpha-galactosidase A
deficiency
Valoctocogene roxapar-
vovec-rvox
Hemophilia A Pirtobrutinib Mantle cell lymphoma
Velmanase alfa-tycv Alpha-mannosidase Quizartinib Acute myeloid leukemia
Repotrectinib ROS1-positive non-
small cell lung cancer
Retifanlimab-dlwr Merkel cell carcinoma
Rezafungin Candidiasis
Ritlecitinib Alopecia areata
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2951Naunyn-Schmiedeberg's Archives of Pharmacology (2024) 397:2949–2970
area who can judge on the added clinical value of a treat-
ment. They fall into the responsibility of Health Technology
Assessment bodies such as the National Institute for Health
and Care Excellence in the UK.
Methods
Our analyses follow the same protocol as those for newly
approved drugs in 2020–2022 (Kayki-Mutlu and Michel
2021; Kayki-Mutlu etal. 2022, 2023) with one exception.
Unlike in previous years, we have included cellular and
gene therapies approved by the FDA (U.S. Food and Drug
Administration 2023a, b) into our analysis. However, we
exclude generics, or generic versions of biopharmaceuticals
(“biosimilars”), and already approved drugs that received
marketing authorizations for one or more additional indica-
tions and/or in a novel formulation in 2023. Newly approved
drug combinations were only considered if at least one of
the combination partners (mostly therapeutic antibodies)
is a novel chemical or biopharmaceutical entity. We would
like to emphasize that other regulatory agencies may have
approved the same compounds earlier than the FDA (among
this year’s approvals, e.g., toripalimab and fruquintinib in
China and daprodustat in Japan), may do so at later points in
time, may choose not to approve some of these compounds,
or may choose to approve compounds not approved by the
FDA. Our focus on drug approvals by the FDA does not
imply any opinion on the scientific quality of approvals by
the FDA as compared to the regulatory authorities in other
jurisdictions, but rather uses the FDA as a point of refer-
ence, due to its status as one of the most influential drug
regulatory authorities. All indications refer to adults unless
specifically noted otherwise.
Oncology
Bruton tyrosine kinase (BTK) is involved in B cell develop-
ment and maturation and plays a role in B cell malignan-
cies such as mantle cell lymphoma (Keam 2023c). BTK
inhibitors are the standard treatment for B cell malignan-
cies (Hatashima etal. 2022). The C481S mutation of BTK
is the most common resistance mechanism restricting the
treatment efficacy of covalent BTK inhibitors (Naeem etal.
2023). The next-in-class small molecule pirtobrutinib is an
oral, potent, highly selective, and noncovalent BTK inhibi-
tor regardless of the BTK C481S mutation status (Mato
etal. 2021). Pirtobrutinib was first approved in January
2023 under accelerated approval for treating of relapsed or
refractory mantle cell lymphoma in adults following two or
more lines of systemic therapy (Keam 2023c). In December
2023, pirtobrutinib was approved for chronic lymphocytic
leukemia and small lymphocytic lymphoma. Pirtobrutinib
received priority review, fast track designation, and orphan
drug designation. Low levels of neutrophils, lymphocytes,
platelets and hemoglobin, tiredness, pain, bruising, and diar-
rhea are the most frequent adverse effects (AE) of pirtobru-
tinib (Keam 2023c).
Diffuse large B cell lymphoma is the most common
type of non-Hodgkin’s lymphoma and often relapses or is
refractory to treatment, which limits the available treatment
options (Riaz etal. 2023). Bispecific T cell recruiting anti-
bodies are a class of immunotherapeutics used in treating
Bcell lymphomas that target both T-cells and antigens on
malignant cells (Minson and Dickinson 2021). Epcoritamab-
bysp is an immunoglobulin G (IgG)1-based bispecific anti-
body and CD20-directed CD3 Tcell engager that binds to
CD3 on T cells and CD20 on B cells (Engelberts etal. 2020).
Epcoritamab has been approved for relapsed or refractory
Table 1 (continued)
First-in-indica-
tion (n = 4, 7%)
Approved for First-in-class (n = 22,
36%)
Approved for Next-in-class (n = 35,
57%)
Approved for
Rozanolixizumab-noli Myasthenia gravis
Somatrogon-ghla Growth hormone defi-
ciency
Sotagliflozin Heart failure
Sulbactam, durlobac-
tam
Pneumonia
Toripalimab-tpzi Metastatic or recur-
rent nasopharyngeal
carcinoma
Vamorolone Duchenne muscular
dystrophy
Zavegepant Migraine
Zilucoplan Myasthenia gravis
Zuranolone Postpartum depression
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2952 Naunyn-Schmiedeberg's Archives of Pharmacology (2024) 397:2949–2970
diffuse large Bcell lymphoma and high-grade B cell lym-
phoma after at least two prior systemic treatments via prior-
ity review and accelerated approval (Frampton 2023). The
most common treatment-related AE include cytokine release
syndrome, injection area reactions, decreased neutrophile
levels, tiredness, and pyrexia (Riaz etal. 2023).
Another CD20 x CD3 T cell-binding bispecific monoclo-
nal antibody approved in 2023 is glofitamab-gxbm (Shirley
2023a). Glofitamab has been approved for relapsed or refrac-
tory diffuse, large B cell lymphoma, not otherwise specified,
or large B cell lymphoma arising from follicular lymphoma
after at least two prior systemic therapies. Glofitamab-gxbm
received priority review and fast track designation. As with
epcoritamab, the mechanism of action of glofitamab is T
cell-mediated lysis of CD20-expressing B cells (Shirley
2023a). Glofitamab has a boxed warning for the risk of
cytokine release syndrome. Other AE include neutropenia,
anemia, and thrombocytopenia (Shirley 2023a).
G protein-coupled receptor family C group 5 mem-
ber D (GPRC5D) shows high and selective expression on
multiple myeloma cells and is a target for immunothera-
peutic treatments (Verkleij etal. 2021). Talquetamab-
tgvs is a humanized, bispecific GPRC5D-targeting Tcell
engager (Verkleij etal. 2021), which acts through binding
to GPRC5D-expressing cells and CD3 on T cells (Kaplon
etal. 2023). Talquetamab is the first IgG4 bispecific anti-
body treatment to be approved for the treatment of relapsed
or refractory multiple myeloma in adults who have received
at least four therapies (Keam 2023d). Talquetamab received
priority review, breakthrough, and orphan drug designation,
and underwent accelerated approval (Kaplon etal. 2023;
Keam 2023d). The most frequent AE of talquetamab are
Table 2 Newly approved drugs grouped by drug type. Percentages are those of small molecule, antibody, peptide-protein drugs, cellular and
gene therapy, with all drugs approved by the FDA in 2023 taken as 100%
Small molecule (n = 30,
49%)
Antibody (n = 12, 20%) Peptide and protein (n = 8,
13%)
Nucleic-acid based (n = 4,
7%)
Cellular and gene products
(n = 7, 11%)
Bexagliflozin Bimekizumab-bkzx Cipaglucosidase alfa-atga Avacincapted pegol Beremagene geperpavec-svdt
Birch triterpenes Elranatamab-bcmm Efbemalenograstim alfa-
vuxw
Eplontersen Delandistrogene moxeparvo-
vec-rokl
Capivasertib Epcoritamab-bysp Motixafortide Nedosiran Donislecel-jujn
Daprodustat Glofitamab-gxbm Pegunigalsidase alfa-iwxj Tofersen Exagamglogene autotemcel
Elacestrant Lecanemab-irmb Somatrogon-ghla Lovotibeglogene autotemcel
Etrasimod Mirikizumab-mrkz Trofinetide Omidubicel-onlv
Fezolinetant Nirsevimab-alip Velmanase alfa-tycv Valoctocogene roxaparvovec
Flotufolastat F 18 Pozelimab-bbfg Zilucoplan
Fruquintinib Retifanlimab-dlwr
Gepirone Rozanolixizumab-noli
Iptacopan Talquetamab-tgvs
Leniolisib Toripalimab-tpzi
Lotilaner
Momelotinib
Nirmatrelvir, ritonavir
Nirogacestat
Omaveloxolone
Palovarotene
Perfluorohexyloctane
Pirtobrutinib
Quizartinib
Repotrectinib
Rezafungin
Ritlecitinib
Sotagliflozin
Sparsentan
Sulbactam, durlobactam
Vamorolone
Zavegepant
Zuranolone
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2953Naunyn-Schmiedeberg's Archives of Pharmacology (2024) 397:2949–2970
fever, cytokine release syndrome, pain, tiredness, weight
loss, xerostomia, dysphagia, upper respiratory tract infec-
tions, diarrhea, hypotension, taste, swallowing, and nail, and
skin problems (Keam 2023d).
Another drug approved in 2023 via accelerated approval
for treating relapsed or refractory multiple myeloma is elra-
natamab-bcmm (Dhillon 2023b). Elranatamab is a bispe-
cific B cell maturation antigen (BCMA) directed-CD3+ T
cell engager antibody (Rais etal. 2023). Elranatamab binds
CD3 on T cell to BCMA on the surface of myeloma cells
and induces a potent cytotoxic response against BCMA-
expressing myeloma cells by activating T cells (Dhillon
2023b; Rais etal. 2023). Elranatamab has been approved for
relapsed or refractory multiple myeloma after four or more
prior therapies following priority review, breakthrough, and
orphan drug designation (Dhillon 2023b). Elranatamab is
well tolerated, and the most common non-hematologic treat-
ment-emergent AE are cytokine release syndrome, diarrhea,
tiredness, loss of appetite, and fever (Lesokhin etal. 2023).
Myelofibrosis is a progressive, Philadelphia chro-
mosome-negative myeloproliferative neoplasm that is
characterized by a dysregulation of the Janus kinase and
signal transducer and activator of transcription (JAK-
STAT) signaling pathway (Passamonti and Mora 2023).
This leads to inflammation and fibrosis and to hyperacti-
vation of the activin A receptor type I (ACVR1), which
results in increased expression of hepcidin and impaired
iron metabolism (Chifotides etal. 2022; Verstovsek etal.
2023). Momelotinib is a small molecule, first-in-class oral
inhibitor of JAK1/JAK2 and ACVR1 (Keam 2023b; Ver-
stovsek etal. 2023), which reduces the hepcidin expression
and increases the availability of iron for erythropoiesis
Table 3 2023 FDA orphan drug
approvals. Percentage is that of
orphan drugs within all drugs
approved by the FDA in 2023
taken as 100% (https:// www.
acces sdata. fda. gov/ scrip ts/ opdli
sting/ oopd/ listR esult. cfm)
Drug (n = 33, 54%) Major indications
Beremagene geperpavec-svdt Dystrophic epidermolysis bullosa
Birch Triterpenes Dystrophic and junctional epidermolysis
Cipaglucosidase alfa-atga Late-onset Pompe disease
Elranatamab-bcmm Relapsed or refractory multiple myeloma
Eplontersen Transthyretin-mediated amyloidosis
Exagamglogene autotemcel Sickle cell disease
Iptacopan Paroxysmal nocturnal hemoglobinuria
Leniosilib Phosphoinositide 3-kinase delta syndrome
Lovotibeglogene autotemcel Sickle cell disease
Momelotinib Myelofibrosis
Motixafortide Stem cell mobilization
Nedosiran Primary hyperoxaluria
Nirogacestat Desmoid tumors
Omaveloxolone Friedreich’s ataxia
Omidubicel-onlv Hematologic malignancies
Palovarotene Heterotopic ossification
Pirtobrutinib Mantle cell lymphoma
Pozelimab-bbfg CHAPLE disease
Quizartinib Acute myeloid leukemia
Repotrectinib ROS1-positive non-small cell lung cancer
Retifanlimab-dlwr Merkel cell carcinoma
Rezafungin Candidiasis
Rozanolixizumab-noli Myasthenia gravis
Somatrogon-ghla Growth hormone deficiency
Sparsentan Proteinuria in primary immunoglobulin A nephropathy
Talquetamab-tgvs Relapsed or refractory multiple myeloma
Tofersen Amyotrophic lateral sclerosis
Toripalimab-tpzi Metastatic or recurrent nasopharyngeal carcinoma
Trofinetide Rett syndrome
Valoctocogene roxaparvovec Hemophilia A
Vamorolone Duchenne muscular dystrophy
Velmanase alfa-tycv Alpha-Mannosidase
Zilucoplan Myasthenia gravis
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2954 Naunyn-Schmiedeberg's Archives of Pharmacology (2024) 397:2949–2970
(Tremblay and Mesa 2022). Momelotinib is approvedfor
intermediate or high-risk primary myelofibrosis and
secondary myelofibrosis with anemia (Keam 2023b).
Momelotinib was granted fast track and orphan drug des-
ignation. The most frequent AE are thrombocytopenia,
diarrhea, bleeding, tiredness, nausea, infections, pain,
itching, increased liver enzymes, and fever (Keam 2023b).
Recurrent or metastatic nasopharyngeal carcinoma is a
rare malignancy. The standard first-line treatment is plati-
num-based chemotherapy, but survival outcomes are poor
(Han etal. 2023). Toripalimab-tpzi is a selective, recom-
binant, programmed death receptor-1 (PD-1) monoclonal
antibody that prevents the binding of programmed death
ligands 1 (PD-L1) and 2 (PD-L2) to PD-1 receptors and
improves the anti-tumor response of T cells (Zhang etal.
2021). Toripalimab was approved in China in 2018 to treat
nasopharyngeal and urothelial carcinoma and in 2021 to
treat unresectable or metastatic melanoma (Keam 2019;
Zhang etal. 2021). In 2023, the FDA approved toripalimab
for adults with metastatic or recurrent, locally advanced
nasopharyngeal carcinoma, both as first-line therapy in
combination with cisplatin and gemcitabine, and as mono-
therapy during or after platinum-containing chemotherapy.
Toripalimab received priority review, breakthrough designa-
tion, and orphan drug designation. The most common AE of
monotherapy are tiredness, hypothyroidism, and pain.
The standard treatment for metastatic colorectal cancer
includes chemotherapy doublets/triplets combined with
monoclonal antibodies against the epidermal growth factor
receptor or the vascular endothelial growth factor receptor
(VEGFR) (Lavacchi etal. 2023). Fruquintinib is a potent
and highly selective tyrosine kinase inhibitor antibody
against VEGFR1, 2, and 3 that inhibits angiogenesis (Shirley
2018). In 2018, fruquintinib was approved in China to treat
metastatic colorectal cancer (Shirley 2018). In 2023, it was
approved by the FDA via priority review for metastatic
colorectal cancer in adults. The most common AE were
increased blood pressure and thyroid-stimulating hormone
levels, palmar-plantar erythrodysesthesia, proteinuria, and
hoarseness (Shirley 2018).
A rearrangement of the ROS proto-oncogene 1 (ROS1)
has been identified as a novel molecular subtype of non-
small cell lung cancer (NSCLC), as ROS1 rearrangements
enhance cell proliferation and decrease apoptosis (Kim etal.
2013). ROS1 fusion is rare (prevalence approximately 1–3%
among NSCLC), but it is considered an interesting target
for treating metastatic NSCLC (Dyrbekk etal. 2023). The
development of resistance to ROS1 tyrosine kinase inhibi-
tors over time requires novel inhibitors (Yun etal. 2020).
The tyrosine kinase inhibitor repotrectinib was approved
for locally advanced or metastatic ROS1-positive NSCLC.
Repotrectinib received priority review, breakthrough, and
fast track designation. The most common AE are dizziness,
taste disorder, peripheral neuropathy, constipation, dysp-
nea, ataxia, tiredness, cognitive disorders, and muscular
weakness.
Endocrine therapy plays a key role in the treatment of
estrogen receptor (ER)-positive breast cancer. Mutations in
the ESR1 gene encoding the ER-α receptor lead to the devel-
opment of resistance and disease progression in ER-positive
metastatic breast cancer patients receiving endocrine therapy
(Lloyd etal. 2022). Elacestrant is a selective estrogen recep-
tor degrader (Beumer and Foldi 2023). It is the first, oral,
selective estrogen receptor degrader and has dose-depend-
ent agonist/antagonist effects on the ER (Beumer and Foldi
2023). Elacestrant has been approved for treating postmeno-
pausal women or adult men with ER-positive, human epider-
mal growth factor receptor 2 (HER2)-negative, ESR1 gene
mutation-positive, advanced or metastatic breast cancer
that has progressed after endocrine therapy (Hoy 2023b).
Elacestrant received priority review and fast track designa-
tion. The safety profile of elacestrant as a monotherapy was
manageable and acceptable in phase 1 and phase 3 trials
(Bardia etal. 2021; Bidard etal. 2022). The most frequent
AE were nausea and vomiting, tiredness, and loss of appetite
(Hoy 2023b). Elacestrant is susceptible to drug interactions
because it is mainly metabolized by CYP3A4 (Beumer and
Foldi 2023).
Another drug approved by the FDA for breast cancer via
priority review in 2023 is capivasertib. Capivasertib is a
first-in-class, selective, highly potent ATP-competitive pan-
AKT kinase (protein kinase B) inhibitor with similar activi-
ties against the three isoforms AKT1, AKT2, and AKT3
(Andrikopoulou etal. 2022; Mullard 2023). Capivasertib has
been approved for treating hormone receptor-positive (estro-
gen or progesterone receptors, or both), HER2-negative,
locally advanced or metastatic breast cancer in combination
with the estrogen receptor antagonist fulvestrant in with the
presence of one or more biomarker alterations (PIK3CA,
AKT1 or PTEN) (Mullard 2023). The most frequent AE of
the combination of capivasertib and fulvestrant are skin rash
and diarrhea (Mullard 2023).
Merkel cell carcinoma is a rare, aggressive form of skin
cancer. Anti-PD-1 and PD-L1 immunotherapy is recom-
mended as a first-line systemic therapy for patients with
advanced disease (Gauci etal. 2022). Retifanlimab-dlwr is
a humanized monoclonal antibody that blocks PD-1, pre-
venting PD-L1 binding and thereby stimulating an immune
response against cancer by increasing T cell activity (Kang
2023). Retifanlimab was approved for metastatic or recurrent
locally advanced Merkel cell carcinoma under accelerated
approval, priority review, fast track, and orphan drug desig-
nation (Kang 2023). In addition, retifanlimab is in phase III
trials for anal squamous cell carcinoma and NSCLC (Kang
2023). The most frequent AE are tiredness, pain, itching,
diarrhea, rash, fever, and nausea (Kang 2023).
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2955Naunyn-Schmiedeberg's Archives of Pharmacology (2024) 397:2949–2970
Activating mutations of the fms-like tyrosine kinase 3
(FLT3) gene are associated with a poor outcome in patients
with acute myeloid leukemia (Ambinder and Levis 2021;
Killock 2023). Quizartinib, a potent and specific oral FLT3
inhibitor, exerts an anti-cancer effect by inhibiting the activ-
ity of the mutation-activated FLT3, which causes tumor cells
to undergo apoptosis (Naqvi and Ravandi 2019). Quizarti-
nib has been approved for newly diagnosed acute myeloid
leukemia that is FLT3 internal tandem duplication-positive.
Quizartinib received priority review, fast track, and orphan
drug designation. The safety profile of quizartinib is man-
ageable (Kayser and Levis 2023).
Desmoid tumors, also known as aggressive fibromatosis,
are rare, benign, invasive, non-metastatic, highly recurrent
soft-tissue tumors (Gounder etal. 2023). Nirogacestat, an
oral, selective, noncompetitive, reversible gamma-secretase
inhibitor, has been approved for progressing desmoid tumors
in adults who require systemic treatment (Zheng etal. 2024).
Nirogacestat works by cleaving the Notch protein, which is
part of the signaling pathway leading to the development of
desmoid tumors (Rohail etal. 2023). Nirogacestat received
priority review, fast track, breakthrough therapy, and orphan
drug designation (Rohail etal. 2023). The most common
adverse events are decreased phosphate levels and appetite,
diarrhea, nausea-vomiting, tiredness, and skin rash (Mess-
ersmith etal. 2015).
Hematology
Anemia is a common condition in people with chronic kid-
ney disease. It is characterized by reduced red blood cell
number due to insufficient erythropoietin production (Koury
and Haase 2015). Hypoxia-inducible factors (HIF) mediate
the cellular response to hypoxia, leading to an increase in the
production of erythropoietin. HIF-specific prolyl hydroxy-
lases induce HIF degradation (Sanghani and Haase 2019).
Prolyl hydroxylase inhibitors to treat anemia associated with
chronic renal failure are under development (Johansen etal.
2023). Daprodustat, a first-in-class reversible inhibitor of
HIF-specific prolyl hydroxylase, was first approved in Japan
for treating of renal anemia in 2020 (Dhillon 2020) by the
FDA in 2023. Daprodustat is the first and only approved
treatment for anemia due to chronic kidney disease in
adults on dialysis for at least 4months in the USA that is
given orally (Haider etal. 2023). Serious AE did not differ
between daprodustat and placebo groups in the phase III trial
(Johansen etal. 2023).
Paroxysmal nocturnal hemoglobinuria is a non-malig-
nant, rare blood disorder manifesting as hemolytic anemia,
bone marrow failure, thrombosis, and complement defi-
ciency (Brodsky 2014). Iptacopan is a first-in-class, oral,
and selective inhibitor of complement factor B, which is an
initiator in the complement alternative pathway (Han etal.
2022; Jang etal. 2022). In the complement alternative path-
way, iptacopan controls both extravascular C3b-dependent
and intravascular terminal complement-dependent hemoly-
sis. It has been approved for paroxysmal nocturnal hemoglo-
binuria with breakthrough therapy and orphan drug designa-
tion. The most common AE are diarrhea, pain, infections,
nausea, and skin rash.
Hemophilia A is an inherited bleeding disorder caused
by a deficiency of the coagulation factor VIII which is an
essential cofactor in the coagulation pathway (Fassel and
McGuinn 2021). Valoctocogene roxaparvovec-rvox is an
adeno-associated virus type-5 (AAV-5)-based gene therapy
vector approved to treat severe hemophilia A in adults who
do not have antibodies to AAV-5. Valoctocogene roxapar-
vovec was granted orphan drug, breakthrough therapy, and
regenerative medicine advanced therapy designation (Blair
2022). The most frequent AE are raised liver enzymes, nau-
sea, and pain (Blair 2022).
Febrile neutropenia is a type of neutropenia associated
with high fever and increased susceptibility to infections in
patients receiving myelosuppressive chemotherapy (Blayney
and Schwartzberg 2022). Recombinant granulocyte-colony
stimulating factor (G-CSF) is used to prevent neutropenia,
but its short half-life of G-CSF limits its use. A long-acting
G-CSF was developed using fusion protein technology (Blair
2023a). The first long-acting G-CSF product, eflapegrastim-
xnst, was approved by the FDA last in 2022 (Kayki-Mutlu
etal. 2023). In 2023, efbemalenograstim alfa-vuxw has been
approved to reduce the incidence of infections with febrile
neutropenia in adult patients with non-myeloid malignan-
cies who are receiving myelosuppressive therapy and are at
risk of developing febrile neutropenia. Efbemalenograstim
alfa is a dimeric recombinant fusion protein, including two
G-CSF molecules and an IgG2-Fc fragment (Blair 2023b).
Efbemalenograstim alpha stimulates survival, prolifera-
tion, and differentiation of hematopoietic cells by specifi-
cally binding to the G-CSF receptor (Crawford and Oswalt
2023). The most common AE are nausea, anemia, and low
platelet count.
Allogeneic hematopoietic cell transplantation is the sole
potential curative therapy option in many hematological
malignancies (Lin etal. 2023). Hematopoietic stem cells
can be collected from umbilical cord blood as well as bone
marrow and peripheral blood (Saiyin etal. 2023). The disad-
vantage of umbilical cord blood is that it provides low num-
bers of hematopoietic stem cells, which may lead to treat-
ment failure. An exvivo culture strategy has been developed
to enhance the number of hematopoietic stem cells (Saiyin
etal. 2023). Omidubicel-onlv is a nicotinamide-modified
stem cell transplant that is derived from the blood of the
umbilical cord (Heo 2023a). Omidubicel is the first-in-class
allogeneic hematopoietic progenitor cell therapy approved
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2956 Naunyn-Schmiedeberg's Archives of Pharmacology (2024) 397:2949–2970
for adults and children (≥ 12years) with hematological
malignancies undergoing cord blood transplantation after
myeloablative conditioning to reduce the risk of infection
and the time to neutrophil recovery (Heo 2023a). Omidubi-
cel received priority review, breakthrough, and orphan drug
designation. Infusion reactions, infections, and graft-versus-
host disease have been reported as AE with omidubicel (Heo
2023a).
Sufficient hematopoietic stem cell mobilization during
treatment is necessary for autologous stem cell transplan-
tation to be successful in patients with multiple myeloma
(Giralt etal. 2014). The interaction of the C-X-C motif
chemokine ligand 12 (CXCL12) with its receptor CXCR4
enables hematopoietic stem cells to be retained in the bone
marrow, and CXCL12/CXCR4 axis inhibition is a notable
therapeutic approach (Ladikou etal. 2020). Motixafortide
is a selective CXCR4 inhibitor that acts as a hematopoietic
stem cell mobilizer (Crees etal. 2023a). Motixafortide was
approved for use in combination with filgrastim to mobilize
hematopoietic stem cells to the peripheral blood in patients
with multiple myeloma (Hoy 2023d). Motixafortide was
found to be well tolerated, with the most frequent AE being
transient injection-site reactions (pain, erythema, and pruri-
tis) and systemic reactions (flushing, pruritis, urticaria, and
erythema) (Crees etal. 2023b).
Neurology
In Alzheimer’s disease, the accumulation of amyloid-β
aggregates is believed to be the trigger for the onset and
progression of the pathological processes (Yadollahikhales
and Rojas 2023). The first anti-amyloid-β antibody, aduca-
numab, received FDA approval in 2021 (Kayki-Mutlu etal.
2022). Anti-amyloid immunotherapy has emerged as the
first effective disease-modifying treatment for Alzheimer’s
disease (Yadollahikhales and Rojas 2023). Lecanemab-irmb
is an IgG1 monoclonal antibody that binds aggregated solu-
ble and insoluble forms of amyloid-β peptide (Hoy 2023c).
Lecanemab-irmb received fast track, priority review, and
breakthrough therapy designations and received accelerated
approval. The presence of amyloid-ß pathology should be
confirmed prior to the initiation of lecanemab, and treat-
ment should be initiated in patients with a mild stage of the
disease (Hoy 2023c). The most frequent AE with lecanemab
are infusion-related reactions, amyloid-related imaging
abnormalities, headache, and falls (Hoy 2023c). The risk of
amyloid-related imaging abnormalities (brain swelling or
bleeding) is a safety concern, particularly in patients taking
anticoagulants (Couzin-Frankel and Piller 2022).
Friedreich’s ataxia is a rare, progressive genetic neurode-
generative disease and involves a defect in the nuclear fac-
tor (erythroid-derived 2)-like 2 (Nrf2) antioxidant signaling
pathway (Abeti etal. 2018). Suppression of the Nrf2 signal-
ing pathway leads to oxidative stress, mitochondrial dys-
function, and cellular damage (Abeti etal. 2018). Omavelox-
olone, an oral Nrf2 inducer, enhances the antioxidant activity
of the Nrf2 pathway (Abeti etal. 2018). Omaveloxolone has
been approved as first-in-indication treatment of Friedreich’s
ataxia in people older than 16years (Lee 2023). Omavelox-
olone has been granted orphan drug, fast track, priority
review, and rare pediatric disease designations (Dayalan
Naidu and Dinkova-Kostova 2023). Frequent AE include
increased liver enzymes, headache, nausea, pain, tiredness,
and diarrhea (Lee 2023).
Two drugs gained approval for the treatment of Duchenne
muscular dystrophy (DMD), a rare X-linked genetic neu-
romuscular disorder resulting from mutations in the DMD
gene, which encodes dystrophin, a protein crucial for proper
muscle function (Keam 2023f). One of these drugs is vam-
orolone, a synthetic glucocorticoid designed to exert anti-
inflammatory and immunosuppressant effects in patients
over 2years old with DMD. Orally administered vamorolone
has demonstrated effectiveness in improving various param-
eters over a 24-week period in patients, including the time
to stand from supine, 6-min walk distance, time to run/walk
10m, and time to climb 4 stairs. Additionally, bone turnover
markers were found to be reduced with prednisone but not
with vamorolone treatment (Guglieri etal. 2022). Long-term
vamorolone treatment has been reported to exhibit reduced
side effects compared to traditional glucocorticoid treatment
(Mah etal. 2022). Reported side effects include Cushingoid
features, psychiatric problems, vomiting, increased weight,
and vitamin D deficiency. Vamorolone has received designa-
tions for fast track, orphan drug, and rare pediatric disease.
The second drug approved for treating DMD marks a
groundbreaking advancement as the first gene therapy indi-
cated for this disease. Delandistrogene moxeparvovec-rokl is
a non-replicating, recombinant adeno-associated virus vector
containing a microdystrophin transgene, which confers dys-
trophin activity. This therapy is specifically intended for use
in children with a confirmed DMD gene mutation, who can
still walk, and is administered as a single-dose intravenous
infusion. Results from clinical studies have confirmed the
achievement of dystrophin expression with delandistrogene
therapy, leading to improved motor functions as assessed
by North Star Ambulatory Assessment scores. Notably, the
medication has demonstrated a high level of tolerability
(Mendell etal. 2023; Zaidman etal. 2023). The most com-
monly reported AE include vomiting and nausea, pyrexia,
and thrombocytopenia. The therapy has been granted accel-
erated approval.
The release of calcitonin gene-related peptide (CGRP) is
involved in the migraine pathophysiology and monoclonal
antibodies and small molecule CGRP receptor antagonists
have been approved against this disease (Nisar etal. 2023).
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2957Naunyn-Schmiedeberg's Archives of Pharmacology (2024) 397:2949–2970
Zavegepant is a third generation, highly potent, selective,
competitive, intranasally administered CGRP receptor
antagonist that is approved for the acute, but not for the
prophylactic treatment, of migraine (Dhillon 2023c; Larik
etal. 2023). Intranasal zavegepant may benefit patients with
migraine for whom oral medications are ineffective, slow-
acting, or intolerable due to vomiting (Lipton etal. 2023).
The most frequent AE are taste disorders, nausea-vomiting,
and nasal discomfort (Dhillon 2023c).
Rett syndrome is a rare genetic neurodevelopmental dis-
order that is characterized by X-linked methyl-CpG-bind-
ing protein 2 (MECP2) mutation that can lead to perma-
nent neurological damage or death in children (Hudu etal.
2023; Parent etal. 2023). Trofinetide is the first treatment
approved for Rett syndrome in adults and pediatric patients
(≥ 2years) (Keam 2023e). Trofinetide was granted priority
review, orphan, and fast track drug designations. Trofinet-
ide is a synthetic peptidase-resistant analogue of the neu-
roprotective tripeptide glycine-proline-glutamate, a product
of the cleavage of insulin-like growth factor 1 in the brain
(Hudu etal. 2023). The exact mechanism of action of tro-
finetide is not fully understood. However, there is evidence
that it modulates the insulin-like growth factor 1 pathway,
improves synaptic function, and reduces levels of inflamma-
tory mediators, apoptosis, and oxidation (Hudu etal. 2023;
Parent etal. 2023). The most frequent AE are diarrhea and
vomiting (Keam 2023e).
Amyotrophic lateral sclerosis (ALS) is a neurodegenera-
tive disease, and a mutation in the superoxide dismutase 1
(SOD1) gene is the cause of about 2% of adult cases of ALS
(Jin and Zhong 2023; Mead etal. 2023). The development
of disease-modifying gene therapies is a priority in ALS.
Tofersen is an intrathecally administered antisense oligo-
nucleotide and is the first approved treatment for ALS in
adults with a confirmed mutation in the SOD1 gene (Blair
2023c). Tofersen was granted priority review and orphan
drug and fast track drug designations. Tofersen received an
accelerated approval because it was shown to reduce plasma
neurofilament light chain, a biomarker of neurodegenera-
tion (Blair 2023c; Jin and Zhong 2023). The mechanism
of action of tofersen involves binding to the SOD1 mRNA,
leading to decreased synthesis of the SOD1 protein (Mead
etal. 2023). The most frequent AE are pain, tiredness, and
increased white blood cells in the cerebrospinal fluid (Blair
2023c).
Myasthenia gravis is a chronic, neuroimmunological
disorder attributed to autoantibodies affecting post-synap-
tic neuromuscular junctions in the skeletal muscle (Menon
and Bril 2022). In most cases of myasthenia gravis, IgG
antibodies block the binding of acetylcholine to the nico-
tinic acetylcholine receptor (AChR) and muscle-specific
kinase (MuSK), and AChR antibodies induce internaliza-
tion of the AChR and destruction of synaptic transmission
at the neuromuscular junction (Menon and Bril 2022).
Rozanolixizumab-noli is an IgG4 monoclonal antibody
that blocks the human neonatal Fc receptor and inhibits the
interaction of the Fc receptor with IgG4, resulting in the
removal of unbound IgG4 via the lysosomal degradation
pathway (Smith etal. 2018; Menon and Bril 2022). Rozano-
lixizumab is the first drug approved to treat both anti-AChR
and anti-MuSK antibody-positive adult generalized myas-
thenia gravis (Hoy 2023e). It received the priority review
and orphan drug designation. The most frequent AE were
headache, diarrhea, fever, and nausea (Hoy 2023e).
Another drug approved by the FDA in 2023 for treating
generalized myasthenia gravis is zilucoplan. Zilucoplan is a
small, synthetic macrocyclic peptide inhibitor of the comple-
ment component 5 (Shirley 2023b), by preventing the cleav-
age of C5 into C5a and C5b and also by inhibiting the bind-
ing of C5b to C6 (Tang etal. 2023). Thus, zilucoplan has
been suggested to have a dual mechanism of action prevent-
ing complement activation (Tang etal. 2023). Zilucoplan has
been approved for use in adult patients who are positive for
anti-AChR antibodies (Shirley 2023b) and granted orphan
drug status (Menon and Bril 2022). The most common AE
are bruising and pain at the injection site, headache, diar-
rhea, and exacerbation of the disease (Shirley 2023b).
Postpartum depression is a major form of depression,
and the effects of fluctuations in neurosteroid levels on the
expression of gamma-aminobutyric acid (GABA)A receptors
are thought to play a role in its pathogenesis (Gunduz-Bruce
etal. 2022). Therefore, GABA modulators have been investi-
gated in the treatment of postpartum depression. Zuranolone
is an oral, synthetic neuroactive steroid and a positive
allosteric modulator of the GABAA receptor (Heo 2023b).
Zuranolone is the first therapy approved for the treatment
of postpartum depression that is given orally (Heo 2023b).
Zuranolone received priority review and fast track designa-
tion. The most common AE are drowsiness, headache, dizzi-
ness, sedation, nausea, urinary tract infections, fatigue, and
diarrhea (Heo 2023b).
Gepirone has been in development for several decades
against major depressive disorder (Jenkins etal. 1990).
Gepirone is an oral, selective serotonin 5HT1A receptor
agonist, and its extended-release formulation is the first
approval for the treatment of major depressive disorder in
adults (Keam 2023a). Gepirone has shown good tolerability
in clinical trials, with the most frequent AE being dizziness,
pain, drowsiness, insomnia, gastrointestinal upset, upper res-
piratory tract infections, xerostomia, and enhanced appetite
(Keam 2023a).
Hereditary transthyretin amyloidosis with polyneuropa-
thy is a rare, progressive disease that causes damage to the
peripheral nerves because of the accumulation of transthyre-
tin amyloid fibrils (Adams etal. 2021). Eplontersen is an
N-acetylgalactosamine-linked antisense oligonucleotide that
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2958 Naunyn-Schmiedeberg's Archives of Pharmacology (2024) 397:2949–2970
inhibits transthyretin production and decreases the serum
and tissue transthyretin levels (Coelho etal. 2023). Eplont-
ersen is similar to inotersen, which was approved by the
FDA in 2018 to treat hereditary transthyretin amyloidosis
(Benson etal. 2018). Eplontersen has been approved for pol-
yneuropathy of hereditary transthyretin-mediated amyloido-
sis in adults and received orphan drug designation. The most
common AE were reduced vitamin A levels and vomiting.
Cardiovascular andendocrine disorders
Bexagliflozin is the fifth sodium-glucose transporter 2
(SGLT-2) inhibitor, administered orally to diabetic patients
to enhance glycemic control. Bexagliflozin has undergone
investigation both as monotherapy (Halvorsen etal. 2019a,
2020) and in combination with metformin (Halvorsen etal.
2019b, 2023a, 2023b), demonstrating its effectiveness in
improving glycemic control by lowering HbA1C levels
(Halvorsen etal. 2019a, 2020, 2023a, 2023b). The most
commonly observed AE associated with bexagliflozin treat-
ment include female genital mycotic infections, urinary tract
infections, and increased urination and are typical for this
drug class. It is important to note that bexagliflozin is con-
traindicated in patients undergoing hemodialysis and is not
recommended for individuals with type 1 diabetes or those
with a low glomerular filtration rate (Hoy 2023a).
Sotagliflozin is a dual SGLT1 (intestinal) and SGLT2
(renal) inhibitor of glucose absorption and reabsorption,
respectively. Clinical studies have revealed that initiating
sotagliflozin therapy before discharge following hospitaliza-
tion for worsening heart failure reduces cardiovascular death
and heart failure (HF) events in patients with type 2 diabe-
tes and chronic kidney disease (Bhatt etal. 2021; Pitt etal.
2023). Despite its positive impact on glycemic control, the
FDA has not approved sotagliflozin for diabetes treatment
due to concerns related to diabetic ketoacidosis (Markham
and Keam 2019). The drug is approved to reduce the risk
of cardiovascular death and worsening heart failure events
in (1) patients with type 2 diabetes and chronic kidney dis-
ease with additional risk factors; and (2) patients with HF,
with or without diabetes, regardless of ejection fraction.
The latter approval is inexplicable, as no patients without
diabetes were enrolled in the clinical studies (Packer 2023).
While generally well-tolerated, sotagliflozin has AE similar
to those observed with SGLT2 inhibitors (diarrhea, genital
mycotic infections, volume depletion, and diabetic ketoaci-
dosis) (Bhatt etal. 2021).
On the other hand, in 2023, FDA approved a groundbreak-
ing therapy for the treatment of type 1 diabetes. Donislecel-
jujn is the first allogeneic pancreatic islet cellular therapy
obtained from deceased donors’ pancreatic cells, designed
to address the challenges faced by diabetic patients unable
to control glycated hemoglobin due to repeated episodes of
hypoglycemia. Infused allogeneic islet cells secrete insu-
lin and other pancreatic hormones, mimicking endogenous
glucose control and homeostasis. Administrated through
infusions into the hepatic portal vein, the treatment con-
veys insulin independence after 1–3 infusions (Alam etal.
2023). Moreover, 60% of islet-transplanted diabetic patients
maintained insulin independence 5years post-transplant (Qi
etal. 2014). For optimal efficacy, donislecel should be used
in conjunction with immunosuppressive therapy initiated
before the procedure and continued on a long-term basis.
The most frequently reported AE include nausea, fatigue,
anemia, diarrhea, and abdominal pain.
A novel, first-in-class medication, fezolinetant, is
designed to treat the vasomotor symptoms associated with
menopause. This non-hormonal drug acts as a neurokinin 3
(NK3) receptor antagonist. Studies have shown that fezoli-
netant reduces both the frequency and severity of vasomotor
symptoms compared to placebo (Johnson etal. 2023; Leder-
man etal. 2023). The daily oral administration of fezolin-
etant appears to be well tolerated with infrequent serious AE
(Johnson etal. 2023). Abdominal pain, diarrhea, insomnia,
back pain, hot flush, and hepatic transaminase elevation are
reported as the most common AE of the therapy. Fezolin-
etant has received priority review designation.
Growth hormone deficiency is a rare condition char-
acterized by insufficient growth hormone secretion, lead-
ing to short stature and delayed puberty. A novel recom-
binant human growth hormone, somatrogon-ghla, has
been approved to treat growth failure in pediatric patients
with growth hormone deficiency. This long-acting agent
is injected subcutaneously once a week, thereby reducing
injection frequency compared to currently available drugs.
Clinical trials comparing the efficacy of once-weekly
somatrogon with once-daily analogue of the somatotropin
hormone somatropin have demonstrated similar effects on
height velocity along with comparable safety and toler-
ability profiles for both treatments (Deal etal. 2022; Zadik
etal. 2023). Reported AE include injection site reactions,
nasopharyngitis, pyrexia, anemia, hypothyroidism, and oro-
pharyngeal pain.
Renal andgastrointestinal disorders
Nedosiran is a small interfering RNA designed to achieve
hepatic lactate dehydrogenase (LDH) inhibition through sup-
pression of the LDHA gene. As this enzyme plays a crucial
role in the final step of oxalate synthesis, nedosiran lowers
oxalate production thereby preventing the formation of kidney
stones (Liu etal. 2022). This therapy has been approved for
treating primary hyperoxaluria type 1 (PH1) in adults and high
oxalate levels in children aged 9years and older. Studies have
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2959Naunyn-Schmiedeberg's Archives of Pharmacology (2024) 397:2949–2970
shown that nedosiran injections effectively lower 24-h urinary
oxalate compared to placebo (Baum etal. 2023; Goldfarb etal.
2023). The therapy has proven to be well-tolerated and safe,
with injection site reactions reported as the only common AE
effects. Nedosiran received breakthrough therapy designation.
An orally taken, dual antagonist targeting endothelin and
angiotensin II receptor, sparsentan, has been approved for
lowering proteinuria in adult patients with primary immuno-
globulin A nephropathy at risk of rapid disease progression.
Sparsentan caused a substantial reduction in proteinuria and
maintained kidney function over 110weeks compared to those
receiving irbesartan (Heerspink etal. 2023; Rovin etal. 2023).
Noteworthy, AE associated with sparsentan treatment include
peripheral edema, hypotension, dizziness, hyperkalemia, and
anemia. Due to potential severe AE, such as hepatotoxicity
and embryo-fetal toxicity, sparsentan is exclusively available
through Risk Evaluation and Mitigation Strategies. Sparsentan
received accelerated approval.
Two novel drugs have been approved to treat ulcerative coli-
tis in 2023. Etrasimod is a sphingosine 1-phosphate receptor
modulator that targets receptors that play dominant roles in
immune response, and pathologically particularly in immune-
mediated diseases including ulcerative colitis, where T cells
contribute to mucosal inflammation in the gastrointestinal
tract. Clinical trials have demonstrated the efficacy of etrasi-
mod in both inducing and maintaining treatment for moderate
to severe ulcerative colitis (Sandborn etal. 2023). Etrasimod
therapy has shown good tolerability, with common AE includ-
ing headache, nausea, urinary tract infections, back pain, and
dizziness (Silverberg etal. 2023). Of note, other sphingosine
1-phosphate receptor modulators have been approved earlier
as treatments for multiple sclerosis (Kayki-Mutlu etal. 2022).
Mirikizumab-mrkz, an anti-interleukin (IL)-23 mono-
clonal antibody, has also been approved for the treatment
of moderate-to-severe ulcerative colitis. Patients receiving
mirikizumab demonstrated clinical remission and improved
bowel-movement urgency in both induction and mainte-
nance trials (D'Haens etal. 2023). The achievement of clini-
cal response and remission was associated with an enhanced
quality of life at week 12 and sustained through week 52
(Dubinsky etal. 2023). Opportunistic infections and cancer
were reported in a small number of patients receiving miriki-
zumab (D'Haens etal. 2023). The most frequently observed
AE are upper respiratory tract infections and arthralgia.
Etrasimod is administered orally, while mirikizumab is given
through intravenous infusion or subcutaneous injection.
Infectious diseases
A sulbactam and durlobactam combination has received
approval for the treatment of hospital-acquired bacterial
pneumonia and ventilator-associated bacterial pneumonia
(HABP/VABP) caused by Acinetobacter. Sulbactam has
been used as a β-lactamase inhibitor, but it also has intrin-
sic antibacterial activity against Acinetobacter that is medi-
ated by the inhibition of penicillin-binding proteins 1 and
3. The utility of sulbactam for Acinetobacter infections has
been limited by its susceptibility to cleavage by numerous
β-lactamases present in this species. Durlobactam inhibits
serine β-lactamase, thus restoring sulbactam activity against
Acinetobacter (El-Ghali etal. 2023). Sulbactam and durlo-
bactam were non-inferior to colistin, each given as an add-
on to imipenem with cilastatin. Sulbactam and durlobactam
have demonstrated good tolerability and a lower risk of
nephrotoxicity compared to colistin (Kaye etal. 2023; Wat-
kins etal. 2023). This therapy has been granted fast track,
qualified infectious disease product, and priority review
designations.
In 2023, a novel oral antiviral therapy, comprising nir-
matrelvir and ritonavir, has been approved for the treatment
of COVID-19, marking the fourth drug approved by FDA
for this indication. Nirmatrelvir, a 3C-like protease (3CLPRO)
inhibitor, plays a crucial role in cleaving nonstructural pro-
teins of the virus and inhibiting its replication. The oral
availability of nirmatrelvir is advantageous, allowing for
prescription to patients before the need for hospitalization.
Ritonavir, an obsolete HIV protease inhibitor, increases the
exposure of nirmatrelvir via inhibition of its inactivation
by CYP3A4. Notably, older patients (65years and above)
receiving nirmatrelvir demonstrated lower rates of hospitali-
zation and death due to COVID-19 compared to untreated
ones (Arbel etal. 2022). The nirmatrelvir plus ritonavir com-
bination lowers the risk of disease progression by 89% with
no safety concerns (Hammond etal. 2022). The most fre-
quently reported AE include dysgeusia and diarrhea. How-
ever, it is crucial to note that due to the many potential drug
interactions mediated by CYP3A4, this therapy should be
prescribed after a thorough review of all medications taken
by the patient. Recognizing its present importance, this
therapy has been granted emergency use authorization by
the FDA for the treatment of mild-to-moderate COVID-19.
Nirsevimab-alip, a recombinant human IgG1ĸ monoclo-
nal antibody, has received approval for the prevention of res-
piratory syncytial virus (RSV) lower respiratory tract disease
in newborns and infants. It binds to the pre-fusion conforma-
tion of the RSV F protein. Administered intramuscularly as a
single-dose for the entire RSV season, this long-acting agent
protects infants from hospitalization throughout the 150days
of the RSV season (Griffin etal. 2020; Hammitt etal. 2022).
Common AE include rash and injection site reactions. Nir-
sevimab received a fast-track designation.
Rezafungin has received approval for the treatment of
candidemia and invasive candidiasis in patients aged 18 and
above who have limited alternative treatment options. This
echinocandin antifungal boasts extended pharmacokinetics
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2960 Naunyn-Schmiedeberg's Archives of Pharmacology (2024) 397:2949–2970
and remarkable stability, making it well-suited for infrequent
dosing intervals. With a half-life exceeding 130h, it allows
for weekly administration, presenting a convenient alterna-
tive to daily dosing. It is important to note that rezafungin is
administered exclusively intravenously and does not attain
therapeutic concentrations in the central nervous system,
eyes, and urine. Clinical studies have convincingly demon-
strated the efficacy of rezafungin, showing non-inferiority
to caspofungin for primary endpoints such as day-14 global
cure and 30-day all-cause mortality. Additionally, reports
on the safety of rezafungin further support its use (Thomp-
son etal. 2021, 2023). Common AE include hypokalemia,
pyrexia, diarrhea, anemia, vomiting, nausea, hypomagne-
semia, abdominal pain, constipation, and hypophosphatemia.
The FDA granted rezafungin orphan drug, qualified infec-
tious disease product, and fast track designations.
Genetic disorders
In 2023, FDA approved nine drugs for genetic disorders, pri-
marily rare diseases. Velmanase alfa-tycv which is a recom-
binant human lysosomal alpha-mannosidase is indicated to
treat alpha-mannosidosis. It is the first enzyme-replacement
therapy to target the non-neurological symptoms associated
with the disease. This rare autosomal recessive lysoso-
mal storage disorder arises from genetic mutations in the
MAN2B1 gene, resulting in the inadequate production of
the alpha-mannosidase enzyme. This enzyme plays a crucial
role in breaking down complex sugars. Consequently, its
deficiency leads to the accumulation of mannose-rich oli-
gosaccharides, contributing to progressive neuromuscular
and skeletal deterioration (Guffon etal. 2023). Velmanase
treatment has been demonstrated to be effective in reduc-
ing serum oligosaccharide levels. Notably, best benefits
were observed when therapy was initiated during childhood
(Borgwardt etal. 2018). The treatment involves weekly
injections. Common AE include hypersensitivity reactions,
such as anaphylaxis, as well as nasopharyngitis, pyrexia,
headache, and arthralgia. The FDA granted velmanase
orphan drug designation.
A potent and selective inhibitor of phosphoinositide
3-kinase δ (PI3Kδ), leniolisib, was approved for the treat-
ment of activated phosphoinositide 3-kinase delta syndrome.
Remarkably, it stands as the first therapy to address this
disorder in both adults and pediatric patients aged 12 and
above. The syndrome is caused by mutations in PIK3CD
or PIK3R1 genes, which together encode the heterodimer
PI3Kδ. Consequently, augmented PI3Kδ activity ensues,
leading to immune dysfunction and increased susceptibil-
ity to infections (Duggan and Al-Salama 2023). Clinical
trials have shown that leniolisib, administered twice daily
for 12weeks, enhances parameters such as the lymph node
size and the percentage of naïve B cells in peripheral blood
over placebo (Rao etal. 2023). AE include headache, sinusi-
tis, and atopic dermatitis. Leniolisib received orphan drug
designation, rare pediatric disease designation, and priority
review.
Fabry disease is a rare genetic disorder linked to alpha-
galactosidase A deficiency. Pegunigalsidase α-iwxj is a
recombinant form of human α-galactosidase-A indicated
as long-term enzyme replacement therapy in the treat-
ment of Fabry disease. Notably, its plant cell-based protein
expression system and pegylated structure contribute to
enhanced stability and half-life, decreased immunogenic-
ity, and increased efficacy compared to similar available
agents (Schiffmann etal. 2019). Clinical trials, focusing on
renal and cardiac function, adverse events, and the presence
of IgG antidrug antibodies, have consistently reported the
safety and effectiveness of pegunigalsidase α when adminis-
tered through intravenous infusion every other week (Schiff-
mann etal. 2019; Linhart etal. 2023). The most frequently
observed AE include infusion-associated reactions, naso-
pharyngitis, pain in extremity, and sinusitis. Pegunigalsidase
α has received fast track designation and priority review.
Fibrodysplasia ossificans progressiva (FOP), an excep-
tionally rare genetic disorder, is attributable to mutations
in the ACVR1/ALK2 gene, leading to progressive hetero-
topic ossification. This process entails the transformation of
connective tissues into bone tissue. Palovarotene, a selec-
tive agonist of the retinoic acid receptor gamma (RARγ),
received approval for mitigating heterotopic ossification in
patients afflicted by FOP. It is the first medication approved
for treating FOP with eligibility starting at 8years for
females and 10years for males. Clinical studies assessing
palovarotene have demonstrated its efficacy in reducing
heterotopic ossification by impacting lower vertebral bone
mineral density and content, and strength while increasing
vertebral fracture resistance (Pignolo etal. 2023). The most
commonly reported AE of palovarotene include dry skin, lip
dryness, arthralgia, pruritus, rash, alopecia, erythema, skin
exfoliation, musculoskeletal pain, myalgia, dry eye, hyper-
sensitivity, peripheral edema, and fatigue. FDA granted
palovarotene priority review and orphan drug designation.
Pozelimab-bbfg has been approved for the treatment of
another ultra-rare hereditary disease known as CD55-defi-
cient protein-losing enteropathy also known as CHAPLE
disease. CHAPLE, which stands for CD55 deficiency with
hyper-activation of complement, angiopathic thrombosis,
and severe protein-losing enteropathy, results from CD55
deficiency leading to a hyperactivated complement system
that mediates the formation of the membrane-attacking com-
plex (Ozen etal. 2017). Pozelimab is a human monoclonal
IgG4 antibody targeting the terminal complement protein
C5. It marks the first treatment indicated for CHAPLE dis-
ease and is available for patients starting from 1year of age.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

2961Naunyn-Schmiedeberg's Archives of Pharmacology (2024) 397:2949–2970
The initial dose is administered intravenously, followed by
weekly subcutaneous injections. Clinical evidence has dem-
onstrated that pozelimab administration effectively inhibits
intravascular hemolysis and is generally well-tolerated (Jang
etal. 2021). Common AE to the therapy include upper res-
piratory tract infections, fractures, urticaria, and alopecia.
It is crucial to note that pozelimab carries a boxed warning
for life-threatening and fatal meningococcal infections. The
FDA has granted pozelimab fast track, orphan drug, priority
review and rare pediatric disease designations.
Cipaglucosidase α-atga has received approval for treating
late-onset Pompe disease in adults weighing at least 40kg,
particularly those who do not show improvement on their
existing enzyme replacement therapy. This rare genetic
metabolic disorder is linked to a deficiency of human acid
α-glucosidase. Cipaglucosidase α is a recombinant human
α-glucosidase, modified to enable intracellular uptake via
mannose 6 receptors. The drug is administered every other
week intravenously together with miglustat, a small mol-
ecule that stabilizes the conformation of the enzyme. Cipa-
glucosidase α plus miglustat treatment has been shown to
improve the 6-min walking distance and biomarkers linked
to Pompe disease and has a safe and well tolerated profile
(Byrne etal. 2023). Although this combination was not
found to be superior over alglucosidase α plus placebo group
in week 52 (Schoser etal. 2021), longer treatment with this
combination for up to 104weeks has been reported to main-
tain a durable effect (Blair 2023a). Common AE include
headache, diarrhea, fatigue, nausea, abdominal pain, and
pyrexia. Hypersensitivity reactions, including anaphylaxis,
are also potential risks associated with this treatment. It
received orphan drug and breakthrough designations.
Two gene therapies have been approved in 2023 for the
treatment of sickle cell disease in patients aged 12years or
older with a history of vaso-occlusive events. Sickle cell
disease is an autosomal recessive condition characterized
by a mutation in the β-globin gene, leading to the formation
of hemoglobin S. This abnormal hemoglobin variant causes
the red cells to become rigid and take on a sickle shape.
Lovotibeglogene autotemcel, an autologous CD34+ cell
therapy, involves hematopoietic stem and progenitor cells
encoding a functional copy of the β-globin gene. This inno-
vative therapy aims to address the underlying genetic cause
of sickle cell disease by providing patients with a corrected
and functional version of the affected gene. A single intrave-
nous administration of lovotibeglogene has demonstrated the
ability to sustain the formation of anti-sickling hemoglobin,
known as HbAT87Q. This modified adult hemoglobin
involves an amino acid substitution, specifically threonine
to glutamine at position 87. The therapy has been shown
to mitigate impaired hemolysis and reduce vaso-occlusive
events (Kanter etal. 2022). The most frequently observed
AE include stomatitis, thrombocytopenia, neutropenia,
febrile neutropenia, anemia, and leukopenia. The FDA has
granted lovotibeglogene orphan drug designation, fast track
designation, and rare pediatric disease designation.
The other sickle cell therapy is exagamglogene autotem-
cel, the first treatment utilizing CRISPR/Cas9 genome edit-
ing. Clinical trials have demonstrated a reduction in vaso-
occlusive crises in patients treated with exagamglogene
autotemcel. The therapy has also been reported to be asso-
ciated with an independence from transfusion in the patients
with β-thalassemia (Kingwell 2023), for which it is approved
in the UK. Following myeloablative conditioning, the drug
is administered intravenously as a suspension of hematopoi-
etic stem and progenitor cells capable of producing fetal
hemoglobin. To this end, cells are edited by CRISPR/Cas9 at
the erythroid specific enhancer region of the BCL11A gene.
Neutropenia, thrombocytopenia, leukopenia, anemia, lym-
phopenia, mucositis, and decreased appetite are among the
most common AE. It has received orphan drug, fast track,
and rare pediatric disease designations.
Dermatology
Ritlecitinib has received approval for the treatment of the
immune disorder alopecia areata in adults and adolescents
aged 12years and older. It is a highly selective and irrevers-
ible dual inhibitor targeting Janus kinase 3 (JAK3) and TEC
kinases and has immunosuppressive effects. Notably, it is the
first oral drug in its class. Studies have shown that ritlecitinib
effectively reduces the severity of alopecia and is well toler-
ated (Hordinsky etal. 2023; King etal. 2023). Most common
AE are headache, diarrhea, acne, rash, urticaria, pyrexia,
atopic dermatitis, blood creatine phosphokinase increased,
herpes zoster, red blood cell count decreased, and stomatitis.
A gene therapy, beremagene geperpavec-svdt, has been
approved to treat skin wounds in patients with dystrophic
epidermolysis bullosa. This ultra-rare and life-threatening
genetic disorder stems from mutations in the collagen type
VII alpha 1 chain (COL7A1) gene, which encodes colla-
gen VII (COL7). COL7 plays a crucial role as a compo-
nent of anchoring fibrils essential for dermal-epidermal
cohesion. Consequently, mutations in this gene lead to the
loss of structural integrity in anchoring fibrils in the der-
mis (Dhillon 2023a). Beremagene geperpavec comprises
replication-defective herpes simplex virus type 1 (HSV-
1) carrying a COL7A1 gene, incorporated into an excipi-
ent gel. This gel is topically applied to the wounds once a
week to restore COL7 levels. The repeated administration
of beremagene geperpavec resulted in complete wound heal-
ing at 3 and 6months (Guide etal. 2022). The therapy has
also demonstrated efficacy in reducing wound surface area,
and in improving the duration of and time to wound clo-
sure (Gurevich etal. 2022). AE include pruritus, chills, and
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2962 Naunyn-Schmiedeberg's Archives of Pharmacology (2024) 397:2949–2970
mild systemic effects. Beremagene geperpavec has received
orphan drug designation.
A second drug approved for the treatment of both dys-
trophic and junctional epidermolysis bullosa is birch trit-
erpenes. This therapy is intended for use in patients aged
6months and older and is administered topically. The topi-
cal gel comprises extracts from birch bark containing natu-
ral triterpenes, such as betulin, betulinic acid, erythrodiol,
lupeol, and oleanolic acid. Research has revealed that the
application of topical birch triterpenes enhances wound heal-
ing within 45days. Importantly, the incidence of AE, includ-
ing infections, was found to be similar to that observed with
control gel treatment (Kern etal. 2023). The FDA granted
birch triterpenes orphan drug, fast track, and priority review
designations. The approval of a plant extract as a medicine
and not as a dietary supplement is a rare occurrence for the
FDA, but it is understandable considering the severity of the
medical indication.
A monoclonal antibody bimekizumab-bkzx was approved
to treat plaque psoriasis. This dual inhibitor selectively tar-
gets interleukin 17A (IL-17A) and interleukin 17F (IL-17F),
which play crucial roles in inflammatory processes (Reis
etal. 2019). The efficacy of bimekizumab has been sub-
stantiated through the American College of Rheumatology
response criteria and the Psoriasis Area and Severity Index,
demonstrating consistent maintenance from week 16 to week
52 of treatment (Ritchlin etal. 2023). In another clinical
trial, complete skin clearance was achieved at week 48 and
was sustained at week 96 with bimekizumab therapy favora-
bly comparing to secukinumab. AE include nasopharyngitis,
oral candidiasis, and urinary tract infection (Strober etal.
2023).
Ophthalmology
Three drugs for ophthalmic diseases have received approval
in 2023. Perfluorohexyloctane was approved to address signs
and symptoms of dry eye disease. It is a semifluorinated
alkane—a chemically inert, slightly amphiphilic compound.
Being a completely non-aqueous liquid, it eliminates the
possibility of microbial growth, obviating the need for added
preservatives. Studies have demonstrated that perfluorohexy-
loctane therapy reduces the signs and symptoms of dry eye
disease compared to a hypotonic saline control. Moreover, it
is well-tolerated and exhibits an AE profile similar to that of
saline (Sheppard etal. 2023; Tauber etal. 2023). The most
common ocular AE reported was blurred vision.
Lotilaner, an antiparasitic agent, is indicated for the treat-
ment of Demodex blepharitis caused by Demodex mites.
Originally employed for veterinary purposes to combat flea
and tick infestations, lotilaner operates as a selective inhibi-
tor of the γ-aminobutyric acid-gated chloride (GABA-Cl)
channel specific to insects. The S-enantiomer is the active
component in the drug product which is the first-in-class
medication for this ocular disease. Twice-daily treatment
with lotilaner ophthalmic solution has demonstrated signifi-
cant reduction in collarettes in the upper eyelid and effective
mite eradication (Gaddie etal. 2023; Yeu etal. 2023). This
medication is recognized for its safety and high tolerance
levels, with the most frequent adverse effects reported being
site stinging and burning.
Avacincaptad pegol, a complement C5 inhibitor, is indi-
cated for the treatment of an advanced form of age-related
macular degeneration called geographic atrophy, which leads
to bilateral and irreversible vision loss over time. Intravitreal
injection of avacincaptad was reported to reduce geographic
atrophy in eyes over a 12-month period (Jaffe etal. 2021).
The therapy was also demonstrated to mediate macular neo-
vascularization more frequently compared to sham control
and to be well tolerated over 18months with ocular side
effects (Patel etal. 2023). Most common AE include con-
junctival hemorrhage, increased intraocular pressure, blurred
vision, and neovascular age-related macular degeneration.
The FDA granted avacincaptad pegol fast track, break-
through therapy designations and priority review.
Diagnostic agents
A radioactive diagnostic agent, flotufolastat 18F, has been
approved to be used in positron emission tomography imag-
ing to visualize prostate-specific membrane antigen-posi-
tive lesions in patients with prostate cancer with suspected
recurrence or metastasis. Flotufolastat was reported to have
high specificity and an excellent safety profile (Surasi etal.
2023). It is administered as an intravenous bolus injection.
AE include diarrhea, blood pressure increase, and injection
site pain.
General trends andconclusions
The number of novel drugs approved by the FDA in 2023
was similar to that in the past several years (Kayki-Mutlu
and Michel 2021; Kayki-Mutlu etal. 2022), except the
pandemic-related dent observed in 2022 (Kayki-Mutlu
etal. 2023). The share of small molecules among new drug
approvals has continuously declined in the past 4years
from 70% in 2020 to 49% in 2023. Concomitantly, the
share of antibodies (22–27%) and of peptides and proteins
other than antibodies (15–19%) remained stable. Of note,
the share of nucleic acid, gene, and cell therapy products
increased from 4% in 2020 and 2021 to now 20%. Regard-
ing degree of innovation, we did not observe a consistent
trend with first-in-indication ranging from 2 to 11% and
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

2963Naunyn-Schmiedeberg's Archives of Pharmacology (2024) 397:2949–2970
first-in-class from 28 to 54% over time; the share of next-
in-class medication also did not exhibit a clear trend rang-
ing from 46 to 60% in the past 4years.
By treatment area, rare diseases/orphan drugs (54%)
and cancer drugs (23%) were once again the most preva-
lent (and partly overlapping) therapeutic areas with neither
exhibiting a clear trend over the past 4years. By coin-
cidence, three approvals target major medical problems
predominantly or exclusively found in women. Fezolin-
etant has been approved for menopause-related vasomo-
tor symptoms, zuranolone for postpartum depression, and
elecestrant for advanced or metastatic breast cancer in
postmenopausal women (and less frequently in adult men).
2023 marks the beginning of the availability of immu-
nization options against the RSV-related lower respira-
tory tract disease in newborns and infants. Besides the
passive immunization using nirsevimab, they include two
active vaccines, not covered in this review. The approval
of the sickle cell therapeutic exagamglogene autotemcel
marks the beginning of an entire new treatment era—that
of genome editing.
The various special processing procedures contin-
ued to be used at high rates: In 2023, 41% of approved
drugs were granted fast track status as compared to 32%
in 2020–2022; a breakthrough therapy designation was
provided in 42% in 2020 and has continuously declined
to 22% in 2023. In contrast, priority review (52–57%) and
accelerated approval (16–23%) remained stable over the
past 4years. The availability of these accelerated regula-
tory pathways may also have provided incentives to focus
clinical development projects on conditions where such
designations are likely.
Author contribution GKM and ZSA performed the literature searches
and data extraction. GKM, ZSA and MCM drafted parts of the man-
uscript. LW revised the manuscript for critical intellectual content.
MCM conceptualized the work, supervised the project, and revised the
manuscript for critical intellectual content. All authors have read and
approved the final version of the manuscript.The authors confirm that
no paper mill andartificial intelligence was used.
Funding Open Access funding enabled and organized by Projekt
DEAL.
Data availability No datasets were generated or analysed during the
current study.
Declarations
Ethics approval Not applicable.
Consent to participate Not applicable.
Consent for publication Not applicable.
Competing interests GKM, ZSA, and LW declare no conflict of inter-
est. MCM is a consultant and/or speaker for Apogepha, Astellas, Dr.
Willmar Schwabe, Eli Lilly, GSK, Labatec, MIP Pharma, and Sanofi-
Aventis.
Open Access This article is licensed under a Creative Commons Attri-
bution 4.0 International License, which permits use, sharing, adapta-
tion, distribution and reproduction in any medium or format, as long
as you give appropriate credit to the original author(s) and the source,
provide a link to the Creative Commons licence, and indicate if changes
were made. The images or other third party material in this article are
included in the article’s Creative Commons licence, unless indicated
otherwise in a credit line to the material. If material is not included in
the article’s Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you will
need to obtain permission directly from the copyright holder. To view a
copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
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