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In the first half of 2023 (as of June 27), the FDA approved 26 new drugs, including 14 small molecule compounds. MCE provides an FDA listing library (2,700+ FDA- approved compounds).
Table 1. FDA-approved Drugs in the First Half of 2023.
1.Pirtobrutinib (Jaypirca™)
In January 2023, Pirtobrutinib (Jaypirca™) was approved in the USA for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL)[1].
Covalent BTK inhibitors (BTKi) are efficacious in multiple B-cell malignancies, but patients discontinue these agents due to resistance and intolerance. Non-covalent BTKi have alternative mechanisms of binding to BTK than covalent BTKi and therefore offer a therapeutic alternative for patients with B-cell malignancies[2].
Pirtobrutinib is a non-covalent, reversible Bruton's tyrosine kinase (BTK) inhibitor. Pirtobrutinib inhibits WT BTK (Y223) autophosphorylation with an IC50 of 3.68 nM.
Fig 1. B-cell receptor (BCR) complex-covalent and non-covalent BTKi mechanism of action[3].
2.Elacestrant (Orserdu®)
Elacestrant (Orserdu®) is a selective estrogen receptor degrader. Elacestrant is an orally available selective estrogen receptor degrader (SERD) with IC50s of 48 and 870 nM for ERα and ERβ, respectively. In vitro, Elacestrant (0-1 µM; 24 or 48 h) results in a dose-dependent and marked decrease in estrogen receptor protein expression. In addition, Elacestrant inhibits breast cancer cell proliferation in vivo[4][5].
Elacestrant was approved by FDA on January 27, 2023, for the treatment of estrogen receptor-positive, human epidermal growth factor receptor 2-negative, ESR1-mutated, advanced or metastatic breast cancer[6].
Fig 2. The mechanism of Elacestrant.
3.Daprodustat (Jesduvroq)
Daprodustat (Jesduvroq) was officially approved by the FDA on February 1, 2023, for the treatment of anemia due to chronic kidney disease.
Decreased erythropoietin (EPO) production, shortened erythrocyte survival, and other factors reducing the response to EPO contribute to anemia in patients with a variety of underlying pathologies such as chronic kidney disease (CKD). The transcription factors hypoxia-inducible factor (HIF)1α and HIF2α control the physiological response to hypoxia and invoke a program of increased erythropoiesis. Daprodustat is a small molecule HIF-prolyl hydroxylase (HIF-PH) inhibitor that stabilizes HIF1α in cell lines, resulting in the production of increased levels of EPO[7].
Fig 3. Schematic diagram of oxygen-dependent transcriptional regulation of HIFα[7].
4.Sparsentan (FILSPARI™)
Sparsentan (FILSPARI™) is a highly potent dual angiotensin II and endothelin A receptor antagonist with Ki values of 0.8 and 9.3 nM, respectively.
Sparsentan is approved by the FDA on February 17, 2023 to reduce proteinuria in adults with primary immunoglobulin A nephropathy at risk of rapid disease progression[8].
Fig 4. Progression of Sparsentan[8].
5.Omaveloxolone (Skyclarys™)
Omaveloxolone (SKYCLARYS™) is an orally active, small molecule semi-synthetic triterpenoid drug that increases antioxidant activity, for the treatment of Friedreich's ataxia.
In patients with Friedreich's ataxia, the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway is suppressed, which is associated with oxidative stress, mitochondrial dysfunction and damage to cells, including central and peripheral neurones. Omaveloxolone activates the Nrf2 pathway by blocking the ubiquitination and degradation of Nrf2[9].
Omaveloxolone was approved in February 2023 in the USA for the treatment of Friedreich's ataxia in adults and adolescents aged 16 years and older.
Fig 5. The mechanism of Omaveloxolone.
6.Zavegepant (ZAVZPRET™)
Migraine is a common neurobiological disorder. Release of the potent vasodilatory neuropeptide calcitonin gene-related peptide (CGRP) in the trigeminovascular system is believed to be crucial for migraine generation[10].
Zavegepant (ZAVZPRET™) is a third generation, small-molecule, calcitonin gene-related peptide (CGRP) receptor antagonist. Zavegepant exhibited potent inhibition (Ki = 23 pM) of CGRP binding to human CGRP receptor expressed in cell membranes and demonstrated potent and full reversal of CGRP-induced dilation of ex vivo human intracranial arteries (EC50=880 pM).
In March 2023, Zavegepant nasal spray received its first approval in the USA for the acute treatment of migraine with or without aura in adults.
Fig 6. Molecular Signaling Pathways in Migraine[11].
7.Trofinetide (Daybue™)
Trofinetide (DAYBUE™), an oral, small molecule, synthetic analog of glycine-proline-glutamate. Trofinetide has neuroprotective in animal models of brain injury[12].
Trofinetide was approved in March 2023 in the USA for the treatment of Rett syndrome in adult and pediatric patients 2 years of age and older.
8.Rezafungin (Rezzayo™)
Rezafungin (Rezzayo™) is a kind of white spines, inhibits1, 3-β-D-glucan synthase.
On March 22, 2023, Rezafungin was approved by the US FDA for the treatment of candidemia and invasive candidiasis. Rezafungin at present is also developing used to prevent blood and bone marrow transplant recipients of invasive fungal disease[13].
9.Leniolisib (JOENJA®)
In March 2023, Leniolisib (JOENJA®) received its first approval for the treatment of activated PI3Kδ syndrome (APDS) in adult and paediatric patients 12 years of age and older.
Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) is an inborn error of immunity with clinical manifestations including infections, lymphoproliferation, autoimmunity, enteropathy, bronchiectasis, increased risk of lymphoma, and early mortality. Hyperactive PI3Kδ signaling causes APDS[14].
Leniolisib is an oral selective PI3Kδ inhibitor with an IC50 value of 11 nM for the treatment of immunodeficiency disorders.
Fig 7. Effective Targeted Therapies for APDS[15].
10.Fezolinetant (Veozah)
Menopause is a normal, natural change in a woman’s life when her period stops, usually occurring between ages 45 and 55. During menopause a woman’s body slowly produces less of the hormones estrogen and progesterone. Hot flashes occur in around 80% of menopausal women and can include periods of sweating, flushing and chills lasting for several minutes. Hormone replacement therapy (HRT) is effective at alleviating menopausal symptoms, but some women cannot or prefer not to take HRT[16].
The FDA approved Fezolinetant (Veozah), an oral medication for the treatment of moderate to severe vasomotor symptoms, or hot flashes, caused by menopause. Fezolinetant is the first neurokinin 3 (NK3) receptor antagonist approved by the FDA to treat moderate to severe hot flashes from menopause. It works by binding to and blocking the activities of the NK3 receptor, which plays a role in the brain’s regulation of body temperature[17].
Fig 8. Relationship between KNDy neurons, GnRH neurons, and the heat-defence pathway[16].
11.Sulbactam, Durlobactam (Xacduro)
Sulbactam, Durlobactam (Xacduro) is composed of Sulbactam and Durlobactam. It is a β-lactam/β-lactamase inhibitor combination for the treatment of infections caused by Acinetobacter[18].
Sulbactam kills A. baumannii whereas Durlobactam protects Sulbactam from being degraded by enzymes that may be produced by A. baumannii. Sulbactam, Durlobactam is administered by intravenous infusion.
Sulbactam, Durlobactam (Xacduro) was officially approved by the FDA on May 23, 2023, for the treatment of pneumonia caused by certain difficult-to-treat bacteria.
Fig 9. Antimicrobial agents for carbapenem-resistant[19].
12.Ritonavir, Nirmatrelvir (Paxlovid™)
On May 25, 2023, The U.S. FDA approved the oral antiviral Ritonavir, Nirmatrelvir (Paxlovid™) (Nirmatrelvir tablets and Ritonavir tablets, co-packaged for oral use) for the treatment of mild-to-moderate COVID-19 in adults who are at high risk for progression to severe COVID-19, including hospitalization or death. Nirmatrelvir (Paxlovid™) is the fourth drug--and first oral antiviral pill--approved by the FDA to treat COVID-19 in adults.
Nirmatrelvir is a peptidomimetic inhibitor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease, while Ritonavir is a human immunodeficiency virus type 1 (HIV-1) protease inhibitor and CYP3A inhibitor. Ritonavir is also a SARS-CoV 3CLpro inhibitor with an IC50 of 1.61 μM[20].
Fig 10. Therapeutic agents to prevent and treat COVID-19[21].
13.Sotagliflozin (Inpefa)
Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure or death from cardiovascular causes among patients with stable heart failure[22].
Sotagliflozin (Inpefa) is a novel oral dual small-molecule inhibitor of SGLT1 and SGLT2. SGLT1 inhibition can delay and reduce glucose absorption in the proximal gut, thereby improving postprandial glucose control, and SGLT2 inhibition can reduce renal glucose reabsorption[22].
Sotagliflozin was officially approved by the FDA for the treatment of heart failure on May 26, 2023.
Fig 11. Dual SGLT1 and SGLT2 inhibitions with Sotagliflozin[23].
14.Ritlecitinib (Litfulo™)
Ritlecitinib (Litfulo™) is a kind of effective oral, selective JAK3 / TEC covalent kinase inhibitor. Ritlecitinib inhibits JAK3 activity with an IC50 of 33.1 nM[24].
Ritlecitinib (Litfulo™) on June 23, 2023 formally approved by the FDA as a treatment for serious peeling hair loss. It is also the world's first drug approved for the treatment of adolescent alopecia areata.
Fig 12. The immune mechanisms of alopecia areata and potential targeted therapies[25].
Elacestrant (RAD1901) is an orally available and selective estrogen receptor degrader (SERD) with IC50s of 48 and 870 nM for ERα and ERβ, respectively. Elacestrant also can inhibit growth of ER+ breast cancer cell lines in vitro and in vivo.
PD-LTrofinetide (NNZ-2566), a synthetic analogue of the endogenous N-terminus tripeptide, Glycine-Proline-Glutamate (GPE), has been shown to be neuroprotective in animal models of brain injury.
Rezafungin (Biafungin) is a next-generation, broad-spectrum, and long-lasting echinocandin. Rezafungin shows potent antifungal activity against Candida spp., Aspergillus spp., and Pneumocystis spp.
Tofersen (BIIB067) is an antisense oligonucleotide that mediates RNase H-dependent degradation of superoxide dismutase 1 (SOD1) mRNA to reduce the synthesis of SOD1 protein. Tofersen can be used for the research of amyotrophic lateral sclerosis (ALS).
