Novel drug targets in 2023

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.

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, eight of the novel MoA targets are addressed by drugs for treating rare diseases.