In 2023, 49 novel drugs (excluding vaccines and gene therapies) were approved for the first time in the United States, European Union and Japan. Of these, 40 have well-defined mechanism of action (MoA) targets (Nat. Rev. Drug Discov. 16, 19–34; 2017) based on the package inserts and primary literature. Among these, there are 12 novel MoA targets; that, is, targets not previously modulated by approved drugs. We briefly outline these targets and the corresponding nine drugs in Table 1.

Drug

Properties

Mechanism of action target (gene name)

Target class

Indication

Agency

Fezolinetant

Small-molecule inhibitor

Neurokinin 3 receptor (NK3R)

GPCR

Vasomotor symptoms due to menopause

FDA

Iptacopana

Small-molecule inhibitor

Complement factor B (CFB)

Enzyme

Paroxysmal nocturnal haemoglobinuria

FDA

Nirogacestata

Small-molecule inhibitor

γ-Secretase (PSEN1 and PSEN2)

Enzyme

Desmoid tumours

FDA

Momelotiniba

Small-molecule inhibitor

Activin receptor type 1 (ACVR1)b

Kinase

Myelofibrosis

FDA

Capivasertib

Small-molecule inhibitor

RAC-serine/threonine-protein kinase 1, 2, and 3 (AKT1, AKT2 and AKT3)

Kinase

Breast cancerc

FDA

Talquetamaba

mAb

G-protein-coupled receptor family C group 5 member D (GPRC5D)d

GPCR

Multiple myeloma

FDA, EMA

Concizumaba

mAb

Tissue factor pathway inhibitor (TFPI)

Protease inhibitor

Haemophilia A/B

PMDA

Tofersena

ASO

Superoxide dismutase 1 mRNA (SOD1)

Enzyme

Amyotrophic lateral sclerosis

FDA

Nedosirana

siRNAe

l-Lactate dehydrogenase A mRNA (LDHA)

Enzyme

Hyperoxaluria type 1

FDA

Five of the nine drugs with novel targets are small molecules. These include one G-protein-coupled receptor antagonist and four enzyme inhibitors, which have seven novel targets in total (four of which are kinases).

The first-in-class neurokinin 3 receptor antagonist fezolinetant was approved for treating menopausal hot flashes. This drug, which modulates thermoregulation by blocking the binding of neurokinin B in the hypothalamus, is the first non-hormonal treatment for this indication. Iptacopan, which inhibits complement factor B in the alternative complement pathway, is the first oral monotherapy for patients with paroxysmal nocturnal haemoglobinuria. Nirogacestat, a γ-secretase inhibitor that prevents the proteolytic activation of Notch receptors, is the first approved treatment for desmoid tumours. Two other drugs were also approved for cancer therapy, both of which are kinase inhibitors. Capivasertib, an inhibitor of all three isoforms of the serine/threonine kinase AKT, was approved in combination with fulvestrant for locally advanced or metastatic breast cancer. Momelotinib, approved for myelofibrosis patients with anaemia, is the fourth Janus kinase 1/2 (JAK1/2) inhibitor to be approved for myelofibrosis, but the first to also inhibit activin A receptor type 1 (ACVR1), promoting increased red blood cell production to ameliorate anaemia.

Two approved antibody-based therapies harness novel drug targets. Talquetamab is a bispecific antibody that binds to GPRC5D (G-protein coupled receptor family C group 5 member D) on the surface of multiple myeloma cells and CD3 on T cells, promoting T-cell mediated killing of the cancer cells. Concizumab, the only drug approved by Japan’s drug agency in the list, is indicated for haemophilia A and B. This monoclonal antibody binds to tissue factor pathway inhibitor (TFPI), disrupting the inhibition of activated factor X and thus facilitating haemostasis.

There were also two new oligonucleotide drugs with novel targets, both of which were approved for rare diseases. Tofersen, an antisense oligonucleotide (ASO) that promotes the degradation of the mRNA for superoxide dismutase 1 (SOD1), was approved for treating patients with amyotrophic lateral sclerosis with SOD1 mutations. Nedosiran, a small interfering RNA (siRNA) that targets the mRNA for lactate dehydrogenase A (LDHA), was approved for primary hyperoxaluria type 1. Overall, six of the novel MoA targets are addressed by drugs for treating rare diseases.

Acknowledgments

This article is part of a series from the NIH Common Fund Illuminating the Druggable Genome (IDG) programme. The goal of IDG is to catalyse research on understudied proteins from druggable gene families by providing reagents, phenotypes and a mineable database; focusing on GPCRs, kinases and ion channels. This work was funded by NIH grant U24 CA224370. For more information, see https://druggablegenome.net/

Competing Interests

T.I.O. is a full-time employee of Expert Systems Inc. He previously worked for Roivant Sciences Inc. and AstraZeneca R&D. The other authors declare no competing interests.