TNF-α: The shape of small molecules to come?

In 2020, the anti-tumor necrosis factor (TNF) monoclonal antibody Humira (R) generated US$165.8 billion in cumulative sales and snatched the crown for the industry's most successful drug from Lipitor (atorvastatin). TNF-alpha is a major component in beneficial and disease-related inflammation and TNF-alpha-ainhibitor biologics have gained widespread use in autoimmune diseases, such as rheumatoid arthritis (RA). Many more diseases could benefit from TNF-alpha inhibitors, such as Alzheimer's disease (AD) or major depression. However, the nature of TNF-alpha-inhibitor biologics prohibits central nervous system (CNS) applications. Moreover, high drug production costs and pricing, together with antidrug immune reactions and insufficient patient coverage, argue for the development of small-molecule drugs. Recently, drug-like orally available small molecules were described with high activity in animal disease models with activities comparable to those of antibodies.

Automated summary

In 2020, the anti-TNF monoclonal antibody Humira generated a huge cumulative sales, surpassing Lipitor as the most successful drug in the industry. However, due to limitations in CNS applications, small-molecule drugs are being developed to benefit a wider range of diseases.