In 2023, 49 new drugs (excluding vaccines and gene therapies) received their first approval in the United States, the European Union, and Japan. Among them, 40 drugs have specific mechanism of action targets. Among them, there are 12 novel targets that have not been previously approved for drug modulation. See Table 1 

Table 1  Drugs approved in 2023 with novel mechanism of action targets (source: nature). 

Of the nine drugs with novel targets, five are small-molecule drugs. These include one G Protein-Coupled Receptor (GPCR) antagonist and four enzyme inhibitors, which collectively target seven new sites (four of which are kinases). 

The first Neurokinin 3 Receptor antagonist, Fezolinetant, has gained approval for managing menopausal hot flashes. By inhibiting the binding of neurokinin B in the hypothalamus, this medication modulates body temperature, representing the first non-hormonal treatment for the specific indication. Fezolinetant (VEOZAH), developed by Astellas Pharma Inc., is intended for the treatment of moderate to severe vasomotor symptoms (VMS) or menopausal hot flashes. Blocking NK3R-mediated signaling in the central nervous system serves as a non-hormonal approach to modulate the activity of neurons associated with thermoregulation, ultimately leading to a reduction in the frequency and severity of VMS. Fezolinetant was first approved in the United States in May 2023 for the treatment of moderate to severe VMS caused by menopause. 

Iptacopan, by inhibiting Factor B in the alternative complement pathway, serves as the first oral monotherapy for patients with paroxysmal nocturnal hemoglobinuria. Iptacopan (FABHALTA?) is an orally administered Factor B inhibitor formulated by Novartis Pharmaceuticals. On December 5, 2023, iptacopan received approval in the United States for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH). 

Nirogacestat, a γ-secretase inhibitor capable of preventing protein activation of Notch receptors, serves as the first approved drug for the treatment of desmoid tumor and is formulated by SpringWorks Therapeutics, Inc. Development. Nirogacestat can cleave multiple transmembrane protein complexes, including Notch and membrane-bound B-cell maturation antigen (BCMA). Inhibition of γ-secretase may result in growth inhibition of tumor cells that overexpress Notch, while retaining membrane-bound BCMA may increase the target density for BCMA-targeted therapies. In November 2023, nirogacestat was approved in the United States for use in adult patients with progressive desmoplastic tumors requiring systemic treatment. 

Two additional drugs are also have been approved for cancer treatment, both of which are kinase inhibitors. Capivasertib, an oral small-molecule pan-AKT inhibitor developed by AstraZeneca, is used to treat various cancers, including breast cancer and prostate cancer. In November 2023, Capivasertib received its initial approval in the United States for adult patients with one or more locally advanced or metastatic breast cancers. Capivasertib is also undergoing regulatory review in the European Union and several other countries for the treatment of HR-positive, HER2-negative breast cancer, and is in Phase III clinical development for the treatment of triple negative breast cancer, castration-resistant prostate cancer, and hormone-sensitive prostate cancer (combined with other anticancer drugs). 

Momelotinib, which has been approved for use in patients suffering from myelofibrosis accompanied with anemia, is the fourth Janus kinase 1/2 (JAK1/2) inhibitor approved for myelofibrosis. However, it is also the first drug that inhibits activin A receptor type 1 (ACVR1), enabling an increase in red blood cell production to alleviate anemia. In September 2023, Momelotinib gained approval in the United States for treating moderate or high-risk myelofibrosis (MF), including primary MF or secondary MF with anemia in adult patients. 

Two approved antibody-based therapies utilized novel drug targets. Talquetamab is a bispecific antibody that can bind to GPRC5D on the surface of multiple myeloma cells and CD3 on T cells, thus facilitating T cell-mediated killing of cancer cells. In early August 2023, Talquetamab received accelerated approval in the United States for the treatment of adult patients with relapsed or refractory MM. Later in August 2023, Talquetamab obtained a conditional marketing authorization in the European Union for the treatment of adult patients with RRMM. Concizumab is the only drug approved by the Japan Pharmaceutical and Medical Device Agency on this list, suitable for patients with hemophilia A and B. This monoclonal antibody functions by binding to the tissue factor pathway inhibitor (TFPI), disrupting its inhibition of activated factor X, and thereby enhancing hemostasis. In March 2023, Canada granted approval for concizumab to be used in the treatment of adolescent and adult patients (aged 12 and above) suffering from hemophilia B, those who use FIX inhibitors and require routine prophylaxis therapy to prevent or minimize the occurrence of bleeding events. 

There are also two new oligonucleotide drugs targeting novel targets, both of which have been approved for rare diseases. Tofersen, an antisense oligonucleotide (ASO), promotes the degradation of superoxide dismutase 1 mRNA and has been approved for the treatment of patients with amyotrophic lateral sclerosis. Nedosiran (RIVFLOZA), being developed by Dicerna Pharmaceuticals, a subsidiary of Novo Nordisk, is for the treatment of primary hyperoxaluria (PH). It works by inhibiting the expression of liver lactate dehydrogenase (LDH) to reduce excessive oxalate production. On September 29, 2023, Nedosiran was first approved in the United States for reducing urinary oxalate levels in children over 9-year-old and adults with PH1 type and relatively preserved renal function. 

In general, drugs for the treatment of rare diseases have addressed eight new mechanism of action targets. 

[1] https://www.nature.com/articles/d41573-024-00057-9