Will Biologics Surpass Small Molecules In The Pharmaceutical Race?

by Andrii Buvailo 

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The first biologics drug, humanized insulin (5.8 kDa), became available in 1982 following the advent of biotechnology, and it marked a new era in the pharmaceutical industry. Modern advances in biotechnology enabled large-scale syntheses of biologics in a more or less cost-effective manner. Having once started with large peptides and recombinant proteins, biologics nowadays include a wide range of other entities, such as monoclonal antibodies, nanobodies and related objects, soluble receptors, recombinant DNA, antibody-drug conjugates (ADCs), fusion proteins, immunotherapeutics, and synthetic vaccines.  

RELATED: The Explosion of Therapeutic Modalities: Small Molecules, Biologics, and Everything in Between

The growing promise of biologics drugs has captured the increasing attention of pharmaceutical professionals and industry analysts, as this alternative drug discovery paradigm represents substantial business challenge for a more "traditional" small molecule-oriented research model, dominating the pharmaceutical industry for more than a century.  

So, here is the question: are small molecules losing “attractiveness” as research objects for drug discovery in the modern world of biological advances? Some experts remain optimistic about the potential of small molecules to lead the race in the future pharmaceutical pipelines, others perceive that “money are changing pockets”, and small molecules research will be increasingly neglected by shareholders and investors in favor of biologics and therapies.  

In order to figure out where the industry is heading, let’s first start with a bit of statistics. Over a period of 10 years (2010-2020) U.S. Food and Drug Administration (FDA) approved a total of 421 new molecular entities (NMEs), excluding several diagnostic imaging agents and 1 insulin analog. It appears that 76% of them are small molecules (321) with only a quarter being biologics, with a quite stable distribution ratio year by year since 2017. Interestingly, there is no dramatic growth in biologics NMEs approvals relative to small molecules as both categories of therapeutics are trending in a quite similar fashion, as shown on the diagram below. However, since the biologics are priced very differently from small molecules (they are way more expensive), the picture is different when looking at total sales and revenue growth: for instance, over the period from 2011 to 2017 biologic sales revenue has grown by 70% having reached $232 billion. The share of the total pharmaceutical market that biologics held in that period increased from 16% in 2006 up to 25% in 2016, and according to EvaluatePharma report for top 20 product sales in 2020, biologics had a small edge over small molecules, with biologics accounting for 12 products (60%) and small molecules -- 8 products, respectively (40%). In today's drug market, small molecules constitute as much as 90% of global sales. However, in the United States and other countries, the rate of purchase of biologics is rapidly increasing, by those who can afford them. On average, a daily dose of biologic costs 22 times more than that of a small molecule.

FDA-approved NMEs

While there are distinct advantages of biologics over small molecules in several ways (for example, their profound selectivity), things are not “black-and-white” when comparing these two categories of therapeutics by their attributes, as both of them have substantial pros and cons to consider during strategic decision-making.

A table below summarizes some strong and weak aspects of both categories (ref) illustrating challenges and opportunities available in both “camps” (note colors: gray -- no apparent advantage in neither camp; green -- advantageous situation; yellow -- disadvantageous situation):

Small Molecules


General properties

Low molecular weights (0,1 - 1 kDa); usually chemically and thermally stable, wide range of polarity.

Very large molecular weights >1 kDa; generally polar, sensitive to heat, easily degraded (with the exception of some long-lived types such as monoclonal antibodies)

Selectivity, safety

Rather promiscuous, usually bind to various off-target sites, rendering side-effects or toxicity.

Finally, biologic developers have had an easier time obtaining patents because there is was little or no state-of-art in the field, when current blockbusters were discovered.

Highly specific to the targets, generally of lower toxicity (with one major exception being that of immunogenicity, which may seriously influence efficiency, safety, and disposition of biologics).

Cell permeability

SMs bind with targets like G-protein-coupled receptors (GPCRs), ligand-gated ion channels, and receptor tyrosine kinases on the extracellular or intracellular domains. They can access targets in the intracellular regions, cytosols, nuclei and even CNS targets, separated by the tight blood-brain barrier (BBB).

A large proportion of pharmacological targets are embedded and therefore inaccessible to biologics. Especially, when it comes to the central nervous system (CNS), the presence of the blood-brain barrier is a major obstacle on the way of any molecules larger than 600 Da restricting up to 98% of SMs and practically all biologics.


Largely fall into “Rule of five” for oral absorption, making it suitable for oral delivery. Further permeability via intestinal epithelium is primarily mediated by a combination of passive diffusion and paracellular transport.

Intrinsic instability and high molecular masses render nearly all biologics orally inactive. Mostly, invasive delivery, or alternative non-invasive technologies are in progress.


SMs are distributed via the blood circulation, allowing for achieving pick concentrations quickly.

For larger molecules (e.g. >10 kDa) a slower (by 100–500 times) lymphatic system becomes dominating in the distribution process. Larger biologics distribute via both the blood and the lymphatic systems moving convective transport, receptor-mediated endocytosis, phagocytosis, and pinocytosis. It The result of this situation is that larger biologics have longer half-lives, limited volumes of distribution, and need more time to reach peak concentrations, compared to SMs.

Disposition (metabolism)

Most SMs are disposed of by non-targeted organs -- via cytochrome or non-cytochrome metabolisms, renal filtration, or fecal excretion.

Biologics have tighter interactions with targets, so their dispositions are directly affected by their binding (receptor-mediated drug disposition), including the clearances of biologics by proteases and peptidase.

Drug-drug interactions

SMs are prone to drug–drug interactions that can occur due to the presence of concomitant drugs that affect their transport, metabolism, transport, or elimination pathways.

Biologics are less prone to traditional drug–drug interactions since they undergo metabolism and elimination as the endogenous substrates. However, there are documented cytokine-mediated changes in drug-metabolizing enzymes, therefore drug-biologic interactions have to be assessed in the case the drug might influence the expression of metabolic enzymes.

Business aspects

Low prices for SM drugs.

Typically, very high prices for biologics treatments. This is regarded as one of the reasons biologics appear to be delivering better overall economic returns, compared to SMs.

High rate of attrition (2009 study by KMR Group showed that only 7.1% of SMs entering preclinical testing eventually reached the market).

Relatively low rate of attrition (same KMR Group study revealed 24.4% of preclinical stage biologics survived up to the market stage).

Severe competition from chemical generics after patents expiration.  

Biologics developers face less severe competition from biosimilars, after patents expiration.

Simpler drug discovery/development process.

More expensive and complex drug discovery and development process, compared to biologics.

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  • SH 2021/06/07, 18:00 PM

    Thanks for this overview. It is surprising that small-peptide drugs, which may in some aspects unite the good of both worlds - delivery/cost and targeting undruggable surfaces (PPI), remains unmentioned at all.


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