Small molecule or biologics?

Leslie Cui

Sep 24, 2024 — 5 min read

Small molecules (small molecules, peptides of up to 40 amino acids in length and oligonucleotides, approved as new molecular entities, NMEs) have been the dominant type of drug since the beginning of modern medicine, but large molecules (biologics, often protein-based candidates, approved through biologics license applications, BLAs) are quickly gaining popularity due to their targeted effects for treating complex diseases. Currently, 90% of all marketed drugs are small molecules.¹ However, 7 out of the top 10 global best-selling drugs were biologics in 2023 ranging from monoclonal antibodies (mAb) to RNA (see list below).² Biologics approval have been witnessing a boom fueled by extensive R&D in the last decade (average of 12.8 annual BLA approvals from 2014-2023 compared to 4.1 from 1994 to 2013).³ It’s estimated that the sales of biologics will slowly surpass small molecule drugs in the near future.⁴

Among biologics, antibody is the most approved drug class (22%) with 12 (8 mAb and 4 bispecifics) approved of a total of 55 new drugs approved in 2023.⁵ This number was 24% in 2022. Although there was no antibody-drug conjugate (ADC) approved in 2023, 14 such drugs were approved in 2022.⁵ The other approved protein-based drugs include 3 enzymes, 1 fusion protein and 1 hormone.³

Although oligonucleotides and peptides (TIDES) are classified under NME due to their smaller size compared to protein-based drugs and chemical synthesis and characterization similar to small molecules, they often show structural complexity similar to that of biologics. There has been a steady trend of importance of TIDES, accounting for ~15% share of new drugs approved in 2022 and 2023.⁵Peptides like tirzepatide (Mounjaro by Eli Lilly) and semaglutide (Ozempic by Novo Nordisk) have been the trending topics recently due to their drastic effect in treating obesity, widespread popularity and potential blockbuster sales. There are more new peptide drugs like retatrutide by Eli Lilly (novel triple agonist of GLP-1, GIP, and GCGR receptors, tirzepatide as double agonist of GLP-1 and GIP) targeting similar receptors are near completion of clinical phases and expecting approval soon.⁶

Oligonucleotide drugs have the therapeutic potential to treat a myriad of genetic and rare diseases with high specificity due to their use in modulating gene expression. They offer potent alternatives as some protein targets are thought to be hardly druggable by protein or small molecule drugs as long as a target sequence of the disease pathogenesis can be identified. Despite their great potential, oligonucleotide drugs also face the challenges of toxicity, susceptibility to degradation thus poor uptake and requiring specific and efficient delivery.⁷In this landscape in 2023, RNA aptamer (1 approved), small interfering RNA (siRNA, 2 approved) and antisense oligonucleotide (ASO, 2 approved) have roughly equal share with ASO being the most dominant type of drug.³

The cell and gene therapy field has gained strong momentum in recent years with 38 approvals since 2017 (as of 8/2/24) and strong results in clinical phases due to its specificity, efficiency and applicability to different diseases with known target sites. 7 new cell and gene therapies have been approved by the FDA in 2023 alone.⁸ It might be thought that these therapies only provide life-changing impacts for the treated patients. These therapies can offer broader impact as the technology associated with these therapies can be translated to treating many other diseases. For example, developing better control of the human immune response to reduce immunity to the gene delivery vectors can be translated to advancements in immunosuppression drugs. The development of non-viral delivery nanoparticles for gene therapy and the delivery vessels used in oligonucleotide drugs can mutually benefit each other. Gene editing technologies are also emerging as new modality for treatments due to their precision like CRISPR-based gene editing for sickle cell disease. The advancements in next-generation gene editing technologies and greater understanding of functional genomics are driving great successes in clinical trials and leading to new classes of therapeutic targets.⁹

Growth of biologics are not without barriers. Manufacture of biologics are more complex and less straightforward compared to that of small molecule drugs as the former is produced in living cells, making the process more susceptible to minute changes in the operation conditions and more costly. Due to the complexity of therapeutic proteins (glycosylation, methylation or phosphorylation), more rigorous quality control measures are put in place to ensure product consistency, causing more extensive testing and greater hurdle to regulatory approval of BLAs. Many of these biologics are beyond affordable for the majority of population at a staggering list price of about 4 or 5 figures for a single dose without insurance coverage to cover the R&D, clinical and administrative cost and ensure profitability within the short patent period. Daily dose of a biologic is 22 times more costly than that of a small molecule.¹⁰ Many factors are involved in the prescription drug affordability issue that deserves a separate chapter for discussion. Biologics are often less stable than small molecules (not in pill form), complicating the storage and distribution conditions and limiting patient access as some require specialized equipment and trained medical professionals for administration in hospitals or outpatient facility.¹¹

Top 10 products by sales in 2023 (biologics/BLA, small molecule/NME, ↑ = increase in sales compared to 2022, ↓ = decrease in sales, ~ = similar sales)

Keytruda (Merck) ↑
1. Humanized antibody, a PD-1 Inhibitor, used in cancer immunotherapy to treat many cancers
Humira (AbbVie) ↓
1. Monoclonal antibody to human tumor necrosis factor (TNF) alpha which has potent antiinflammatory activity and is used in the therapy of severe rheumatoid arthritis and inflammatory bowel disease
Ozempic (Novo Nordisk) ↑
1. Semaglutide that acts as glucagon-like peptide-1 (GLP-1) receptor agonists used for the treatment f type 2 diabetes and an anti-obesity medication for long-term weight management
Eliquis (BMS/Pfizer) ~
1. Pyrazole derivative, factor Xa inhibitor, an anticoagulant medication used to treat and prevent blood clots and to prevent stroke
Biktarvy (Gilead Sciences) ~
1. Three-drug combination that contains bictegravir (bridged bicyclic ring, HIV integrase inhibitor), emtricitabine (cytosine analog with a fluorine substitution, nucleoside reverse transcriptase inhibitor) and tenofovir alafenamide (prodrug, functionally related to adenine, nucleoside reverse transcriptase inhibitor) to treat HIV
Dupixent (Sanofi/Regeneron) ↑
1. Monoclonal antibody acting as interleukin-4 (IL-4) receptor alpha antagonist to block IL-4 and IL-13 pathways to reduce inflammation and treat allergic diseases and COPD
Comirnaty (Pfizer/BioNTech) ↓
1. COVID mRNA vaccine (mRNA in lipid nanoparticle)
Stelara (Johnson&Johnson) ~
1. Human IgG1κ monoclonal antibody that blocks IL-12 and IL-23 to reduce the symptoms of plaque psoriasis, psoriatic arthritis, Crohn's disease and ulcerative colitis
Darzalex (Johnson&Johnson) ~
1. Human monoclonal IgG1κ antibody against CD38 antigen to kill cancer cells directly and recruits immune cells to kill cancer cells
Opdivo (BMS/Ono) ~
1. Monoclonal antibody, a PD-1 antagonist to help body’s immune system to fight cancer