In 2021, regulatory agencies in the United States, European Union and Japan licensed 59 novel drugs in total, of which 50 have well-established mechanism-of-action (MoA) targets for their approved indication (Nat. Rev. Drug Discov. 16, 19–34; 2017). Continuing the annual series, here we briefly summarize the 14 novel MoA targets (Table 1) — that is, the targets that had not previously been modulated by an approved drug —based on analysis of the drug labels and primary literature on the new drugs.
Table 1 | Drugs with novel mechanism of action targets approved in 2021
Drug |
Properties |
Mechanism of action target (gene name) |
Target class |
Indication |
Agency |
Regdanvimaba,sotrovimab,casirivimab,imdevimab |
mAb |
SARS-CoV-2 Spike protein (S)b |
Viral protein |
COVID-19 |
EMA, PMDA |
Evinacumabc |
mAb |
Angiopoietin-related protein 3 (ANGPTL3) |
Cytokine |
Homozygous familial hypercholesterolaemia |
FDA, EMA |
Tezepelumab |
mAb |
Thymic stromal lymphopoietin (TSLP) |
Cytokine |
Severe asthma |
FDA |
Bimekizumab |
mAb |
Interleukin-17F (IL17F) |
Cytokine |
Psoriasis |
EMA |
Tralokinumab |
mAb |
Interleukin-13 (IL13) |
Cytokine |
Atopic dermatitis |
FDA, EMA |
Efgartigimod alfac |
mAb |
Neonatal Fc receptor (FCGRT) |
Transcytosis receptor |
Myasthenia gravis |
FDA |
Maribavirc |
Small-molecule inhibitor |
CMV serine/threonine protein kinase UL97 (UL97) |
Enzyme |
Post-transplant CMV infection/disease |
FDA |
Sotorasibc |
Small-molecule inhibitor |
GTPase KRas (KRAS) |
Enzyme |
Non-small-cell lung cancer |
FDA, EMA |
Belzutifanc |
Small-molecule inhibitor |
Hypoxia-inducible factor 2 alpha (HIF2α) |
Transcription factor |
von Hippel–Lindau disease |
FDA |
Tisotumab vedotin |
ADC |
Tissue factor (TF) |
Tumour-associated antigen |
Cervical cancer |
FDA |
Pabinafusp alfac |
Fusion protein |
Transferrin receptor protein 1 (TFRC) |
Transcytosis receptor |
Hunter syndrome |
PMDA |
Fosdenopterinc |
Synthetic substrate |
Molybdenum cofactor biosynthesis protein 1 (MOCS1) |
Enzyme |
Molybdenum cofactor deficiency type A |
FDA |
Vosoritidec |
Peptide |
Natriuretic peptide receptor 2 (NPR2) |
Enzyme |
Achondroplasia |
FDA, EMA |
Pegcetacoplanc |
Peptide |
Complement C3 (C3) |
Macroglobulin |
PNH |
FDA, EMA |
Six targets are blocked by monoclonal antibodies (mAbs). The first target in Table 1 is the Spike protein of SARS-CoV-2, for which multiple mAbs have been developed for the treatment and prevention of COVID-19. Other targets include three cytokines involved in inflammatory diseases (TSLP, IL-17F and IL-13), a cytokine involved in dyslipidaemia (ANGPTL3), and the neonatal Fc receptor, which is targeted by efgartigimod alfa to reduce circulating immunoglobulin G.
Three targets are inhibited by small molecules. One is another viral target: the cytomegalovirus kinase UL97. The other two are the anticancer drug targets KRAS, a GTPase that for many years was considered ‘undruggable’, and the transcription factor HIF2α. The antibody–drug conjugate tisotumab vedotin, which targets tissue factor on tumour cell surfaces to deliver a microtubule inhibitor, was also approved for a cancer indication.
Two of the drugs are replacement therapies for rare diseases. Pabinafusp alfa harnesses transferrin receptor protein 1 to deliver the enzyme iduronate-2-sulfatase across the blood–brain barrier to treat Hunter syndrome, while fosdenopterin is a cyclic pyranopterin monophosphate that activates molybdenum cofactor biosynthesis to treat molybdenum cofactor deficiency type A.
Two peptidic drugs were also approved for rare diseases. Vosoritide is a positive regulator of natriuretic peptide receptor 2 that results in endochondral bone growth and received approval for achrondroplasia. Pegcetacoplan is a cyclic peptide inhibitor of complement protein C3 conjugated to polyethylene glycol, which was approved for the treatment of paroxysmal nocturnal haemoglobinuria.
Overall, from a therapeutic standpoint, 9 of the 14 novel targets (64%) are for drugs that treat rare diseases of various types.
