2023 Novel Small Molecule FDA Drug Approvals

The FDA recently released its summary of the 55 novel drugs approved in 2023. This was the second-highest number of approvals in the last 10 years, after the 59 approved in 2018. Other notable statistics include:

• 36% of the approvals were considered first-in-class by the FDA

• 51% received Orphan Drug Designation for treating rare indications

• 45% were granted Fast Track Designation 

• 16% were designated Breakthrough Therapies (including 2 small molecules)

• 16% were granted Accelerated Approval

• 84% received approval on their first review cycle

Among the 55 approvals, the majority (34) were small molecules (62%). A poster highlighting the structures, mechanisms of action, originators (& marketers), and indications of these small molecule drugs is provided below, along with more information with links about each drug below the poster. 

Oncology Small Molecule Drug Approvals

Eight small molecule drugs were approved for oncology indications, including:

1. pirtobrutinib (Jaypirca): The first approved non-covalent BTK inhibitor. This oral BTK inhibitor for relapsed or refractory mantle cell lymphoma was discovered by UK biotech RedX Pharma and made its way to Eli Lilly via Loxo Oncology. Pirtobrutinib was granted accelerated approval based on response rate; full FDA approval is pending based on the results of confirmatory trials. You can read our in-depth case study on pirtobrutinib and why it’s significant here.

2. elacestrant (Orserdu): The first approved oral ER degrader. This oral SERD/SERM for ER+, HER2-, ESR1-mutated breast cancer was discovered by Eisai and ultimately marketed by Stemline (acquired by Menarini). Our in-depth case study on elacestrant and why it’s significant is here.

3. quizartinib (Vanflyta): An oral FLT3 inhibitor for acute myeloid leukemia discovered by Ambit Biosciences and marketed by Daiichi Sankyo. 

4. momelotinib (Ojjaara): An oral JAK1/2^WT, JAK2^V617F, ACVR1 inhibitor with a surprising mechanism for treating myelofibrosis with anemia discovered by Cytopia and acquired by GlaxoSmithKline for $1.9B after a winding journey through multiple companies. See our in-depth look at momelotinib and its significance here. You can also check out Andrew Wilks’ and Chris Burns’ discussion on the history of momelotinib in their Flash Talk linked here.

5. nirogacestat (Ogsiveo): This oral molecule is the first approved γ-secretase inhibitor for the treatment of progressing desmoid tumors, discovered by Pfizer and developed by Pfizer spinout Springworks Therapeutics. Nirogacestat received Breakthrough Therapy designation. Check out our in-depth review of nirogacetstat, its history in Alzheimer’s disease, and more here.

6. repotrectinib (Augtyro): This oral ROS1 and TRKA/B/C inhibitor for ROS1+ non-small cell lung cancer was discovered by Turning Point Therapeutics and acquired by and marketed by Bristol Myers Squibb. Our in-depth case study on repotrectinib, BMS’s $4.1B acquisition, and why the molecule is significant here.

7. fruquintinib (Fruzaqla): An oral VEGFR1/2/3 inhibitor for refractory, metastatic colorectal cancer discovered by Hutchison Medipharma and marketed by Takeda.

8. capivasertib (Truqap): A first-in-class, oral AKT1/2/3 inhibitor for HR+/HER2- breast cancer discovered by AstraZeneca in a collaboration between Astex Therapeutics, the Institute of Cancer Research, and marketed by AstraZeneca. 

Hematology Small Molecule Drug Approvals

Two small molecule drugs were approved for hematology indications, including:

1. motixafortide (Aphexda): A subcutaneous CXCR4 inhibitor for stem cell mobilization in multiple myeloma discovered by Kyoto University and marketed by Biolinerx.

2. daprodustat (Jesduvroq): This first-in-class oral HIF-PH1/2/3 inhibitor is the first and only HIF prolyl hydroxylase inhibitor approved in the US for the treatment of anemia in chronic kidney disease, discovered and developed by GlaxoSmithKline. You can read our in-depth case study on daprodustat and why it’s scientifically notable here.

Endocrinology Small Molecule Drug Approval

One small molecule drug was approved in endocrinology:

1. bexagliflozin (Brenzavvy): An oral SGLT2 inhibitor for type 2 diabetes mellitus discovered and marketed by Theracosbio.

Cardiology Small Molecule Drug Approval

One small molecule drug was approved in cardiology:

1. sotagliflozin (Inpefa): An oral dual SGLT1/2 inhibitor for reducing the risk of CV death, heart failure hospitalization, and urgent heart failure visits discovered and marketed by Lexicon.

Gastroenterology Small Molecule Drug Approval

One small molecule drug was approved in gastroenterology:

1. etrasimod (Velsipity): An oral S1P receptor modulator for ulcerative colitis discovered by Arena Pharmaceuticals and marketed by Pfizer. You can read more about the acquisition here.

Dermatology Small Molecule Drug Approval

One small molecule drug was approved in dermatology:

1. ritlecitinib (Litfulo): This deceptively simple molecule has a fascinating discovery story, mode of selectivity, and mechanism of action. The oral JAK3/TEC-family kinase inhibitor for severe alopecia areata was discovered and developed by Pfizer. Our in-depth case study on ritlecitinib and its significance is here.

OB/GYN Small Molecule Drug Approval

One small molecule drug was approved in obstetrics and gynecology:

1. fezolinetant (Veozah): A first-in-class oral NK₃ receptor antagonist for hot flashes in menopausal women discovered by Euroscreen and marketed by Astellas.

Infectious Disease Small Molecule Drug Approvals

Four small molecule drugs were approved for infectious diseases, either as single chemical entities or in combination, including:

1. sulbactam, durlobactam (Xacduro): Intravenous β-lactamase inhibitors for hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) caused by Acinetobacter baumannii-calcoaceticus, discovered by AstraZeneca and marketed by Entasis.

2. taurolidine, heparin (Defencath): A combination of taurolidine, which damages microbial cell walls, and heparin, which is an antithrombin III activator for reducing the incidence of catheter-related bloodstream infection (CRBSI), administered via a central venous catheter (CVC), developed by Cormedix. 

3. nirmatrelvir, ritonavir (Paxlovid): This 2021 Drug Hunter Molecule of the Year is a first-in-class, oral combination of nirmatrelvir, a SARS-CoV-2 main protease (M^pro) inhibitor, and ritonavir, a CYP3A inhibitor for COVID-19. Nirmatrelvir was discovered and developed in record time by Pfizer. Paxlovid was authorized for emergency use by the FDA in December 2021 and was granted full approval in May 2023. You can read our in-depth case study on Paxlovid and why it’s significant here.

4. rezafungin (Rezzayo): An intravenous 1,3-β-D-glucan synthase inhibitor for candidemia and invasive candidiasis, discovered by Seachaid and developed by Melinta. You can read more about rezafungin here.

Rare Disease Small Molecule Drug Approvals

Nine small molecule drugs were approved for rare diseases, including:

1. sparsentan (Filspari): This old oral ET_AR and AT₁R antagonist, discovered by BMS, was developed for reducing proteinuria in IgAN by Travere Therapeutics, is interesting for its association with Martin Shkreli. You can read our in-depth case study on sparsentan and its importance here.

2. omaveloxolone (Skyclarys): This oral reversible covalent Nrf2/KEAP1 modulator is a first-in-class treatment for Friedreich’s ataxia was discovered by Reata after a long history rooted at Dartmouth and the University of Texas. Our in-depth case study on elacestrant and why it’s significant is here.

3. trofinetide (Daybue): A first-in-class, oral GPE tripeptide for Rett syndrome discovered by Neuren and marketed by Acadia.

4. zilucoplan (Zilbrysq): A subcutaneous C5 inhibitor for myasthenia gravis discovered by RA Pharmaceuticals and marketed by RA’s acquirer, UCB. This molecule is notable as the first approved drug to be derived (a 15-mer of the peptide) from mRNA display screening.

5. leniolisib (Joenja): This molecule was the first PI3K inhibitor with a first approval outside of oncology. The oral PI3Kδ inhibitor is approved for activated phosphoinositide 3-kinase delta syndrome (APDS) and was discovered by Novartis and marketed by Pharming. You can read our in-depth case study on leniolisib and why it’s significant here.

6. palovarotene (Sohonos): An oral RARγ agonist for fibrodysplasia ossificans progressiva discovered by Syntex (acquired by Roche) and marketed by Ipsen.

7. vamorolone (Agamree): An oral glucocorticoid receptor agonist for Duchenne muscular dystrophy, discovered by Reveragen and marketed by Santhera.

8. iptacopan (Fabhalta): This 2020 Molecule of the Year candidate (LNP023) is an oral complement factor B inhibitor for paroxysmal nocturnal hemoglobinuria that received Breakthrough Therapy Designation, discovered and marketed by Novartis. You can read more about LNP023 here.

9. Birch triterpenes (Filsuvez): A topical formulation of birch triterpenes that modulates inflammation, keratinocytes, and wound healing for wounds associated with dystrophic and junctional epidermolysis bullosa, discovered by Amryt Pharma and developed by Chiesi Global Rare Diseases.

Ophthalmology Small Molecule Drug Approvals

Two small molecule drugs were approved for ophthalmology indications, including:

1. perfluorohexyloctane (Miebo): A first-in-class eye drop that reduces evaporation from the eye for dry eye disease, discovered by Novaliq and marketed by Bausch & Lomb.

2. lotilaner (Xdemvy): A first-in-class, intraocular mite GABA-gated Cl^- channel inhibitor for Demodex blepharitis discovered by Novartis and marketed by Tarsus. 

Neurology Small Molecule Drug Approvals

Three small molecule drugs were approved for neurology indications, including:

1. zavegepant (Zavzpret): An intranasal CGRP receptor antagonist for migraine discovered by BMS and marketed by Pfizer. You can read our in-depth case study on zavegepant and why it’s significant here.

2. zuranolone (Zurzuvae): an oral GABA_A-positive allosteric modulator for postpartum depression by Sage Therapeutics. The FDA did not approve zuranolone for major depressive disorder due to lack of efficacy. 

3. gepirone (Exxua): An oral selective 5HT_1A agonist for major depressive disorder discovered by BMS and marketed by Fabre-Kramer.

Diagnostic Small Molecule Drug Approval

One small molecule was approved for diagnostic purposes:

1. flotufolastat F-18 (Posluma): An intravenous binder to PSMA expressed on cells for PET imaging of prostate cancer discovered by TU Munich and marketed by Blue Earth Diagnostics.