Small molecules or biologics?

Small molecules or biologics? That is the question


Ever since it became clear that recombinant proteins and monoclonal antibodies would be a medical and commercial success, the leaders of the biopharmaceutical industry have faced a core strategic issue. Which is the better technology: the new biologic entities or traditional small molecule drugs?

Up until a decade ago, only a handful of companies were in a position to manage the entire value chain of biologic development which starts with gaining access to specific cell lines and then progresses to managing discovery, laboratory production and manufacturing, to handling the detailed requirements of the drug regulatory authorities.

This has dramatically changed in recent years, and now every single company can, by itself or through partnerships, become a key player in the biologics field. In addition, the field itself has substantially grown with the development of many new product types. Whereas biologics used to be limited to large peptides and recombinant proteins, the range of therapies has since expanded to include antibodies and monoclonal antibodies, and more recently, nanobodies and related object, soluble receptors, recombinant DNA, fusion proteins, immunoconjugates, immunotherapeutics and synthetic vaccines. All of these later products have emerged from technologies that are based on a better understanding of cell-line production and of protein identification, expression and engineering, with the aim of mitigating or correcting some of the limitations of the original products.

Why have biologics attracted so much attention?

The first reason is that they can interact with challenging targets which have thus far eluded small molecule drugs. The best examples of this are protein-protein interactions which are characterised by large and often flat surfaces with few charged pockets.

Second, the commercial potential of biologics is very promising. A study published in the spring of 2012 by Evaluate Pharma showed that the share of biologics in total sales of prescription and over-the-counter medicines grew from 12% in 2004 to 19% in 2011. The researcher estimates that biologics could reach 23% of total sales by 2016. Even more interesting is the fact that biologic products accounted for 17% of sales of the top 100 pharma products in 2004; 34% in 2011 and are forecast to represent 50% by 2016.

Third, biologics appear to be delivering a better overall economic return than small molecule drugs. Proponents put several arguments forward in making this claim. Biologic manufacturers typically charge $10,000 and upwards for a single yearly treatment which means that the financial return per patient is very high. Studies also show that the rate of attrition for biologics is less than that for small molecules. According to a 2009 report by the KMR Group, 24.4% of biologics that enter preclinical testing eventually reach the market compared with a success rate of only 7.1% for small molecule drugs. Biologics performed better than small molecules at all stages of development with an astonishing 116% rate of success at Phase 2. 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. Moreover, once the patents expire, these developers face less fierce competition from biosimilars, than small molecule producers do from chemical generics.

But this is not the whole story. Returning to the scientific question, small molecule drugs have been, and still are, very effective ligands which can interact with membrane receptors, enzyme cavities and ion channels. There is still a promising future for the small-molecule paradigm. This is illustrated by the relatively high number of new small-molecule drug approvals by the US Food and Drug Administration. In 2012, the agency approved 27 small molecule drugs versus 13 biologics. And while biologic producers ask high prices for their drugs, they are facing increasing resistance from reimbursement bodies that do not want to pay the premium prices.

Weighing up the evidence, developers should see a bright future for both small molecule drugs and biologics. For the large player it would be a strategic mistake to massively favour or disfavour one over the other. Both paradigms have proven their value and are still destined to bring novel, valuable agents to patients. This is especially true with the emergence of synthetic biology and the novel approach of antibody-drug conjugates (ADCs). ADCs, or so-called immunoconjugates, combine state-of-the-art chemical synthesis with biologics engineering. The later technology transforms antibodies into powerful and well-targeted cancer killing compounds.

The recent approval of Roche’s Kadcyla (trastuzumab emtansine) for HER2-positive breast cancer could pave the way for a new hybrid approach consisting of newly defined chemical entities with biological activity and structural diversity. Kadcyla is an immunoconjugate of the highly cytotoxic maytansine and the monoclonal antibody, Herceptin (trastuzumab).

Similarly, it is worth assessing an approach underway at Ensemble Therapeutics Corp in Cambridge, Massachusetts which is building synthetic macrocycles. These mid-sized cyclic structures share many features of the small molecule while at the same time being able to interfere with protein-protein interactions. They could, in future, become valuable biologic surrogates or mimics. Ensemble recently disclosed that it has discovered an antagonist for interleukin-17 (IL 17), a cytokine target thought to be outside the range of the capabilities of small molecule drugs.


Biologics have revolutionised the treatment of diseases such as cancer and rheumatoid arthritis. Small molecules have driven progress in the management of chronic diseases such as hypertension and hypercholesterolemia. Both approaches still massively contribute to new drug development. But there is now an opportunity to explore hybrid structures that combine biologics with well-defined chemical entites. This novel paradigm will only be accessible to those who master, at the same time, the art of chemical synthesis and the new biological technologies. Undoubtedly these novel hybrids will be designed and prepared in biological chemistry departments.

Published in MedNous, April 2013


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Author : Jean-Claude MULLER, Special Advisor,Innovation & International Relationship (I&IR)


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