In 2013, seven out of the top ten drugs by revenue were biopharmaceuticals rather than traditional small-molecule, chemically synthesized, drugs. What’s more the top three drugs were all biologics and for the treatment of the autoimmune disease rheumatoid arthritis. Most of these biopharmaceuticals are based upon monoclonal antibodies, utilizing the immune system’s natural defenses to treat disease and, as an immunologist, I’m all in favor of such an approach. However, why has there been this rush over the past decade to switch to biopharmaceuticals when in the past small molecules have been generating significant revenues for pharmaceutical companies? Here is what I think. I believe the push in to biopharmaceuticals is two-fold: the first being the improved performance of biologics, and the second being more financial and the ability to maintain revenues over a longer period. I will explain my thinking in more detail below.
In the past, most small molecules were designed to treat the symptoms of disease, rather than going after the actual cause of the disease itself. This has begun to change with the huge developments in genomics that allow a greater understanding of the molecular basis of disease with the subsequent improvements in the design and targeting of chemical based drugs. Biopharmaceuticals on the other hand, especially antibody-based therapeutics, are more focused on treating the disease - mainly because that is what antibodies evolved to do! Treating the disease rather than the symptom is obviously more advantageous as it offers a quicker and complete resolution. Added to this is the fact that antibodies offer greater specificity which aids in targeting the correct disease-causing biomolecule and also reduces the risk of side-effects to some degree and damage to other bystander cells. Having said all that though, harnessing the power of the immune system to fight your battles, especially if it is trained on other elements of the immune system, is not without its risks and side-effects; knocking-out part of the inflammatory response to prevent conditions, such as rheumatoid arthritis, can leave you exposed to otherwise innocuous infections.
By the time a drug reaches market, it only has a short time to payback the substantial costs of its development before its patent expires and generic, much cheaper alternatives come on to the market and swallow its market share. It’s not that difficult to copy a chemically synthesized small molecule and certainly doesn’t cost that much to manufacture with the added advantage of not having to incur the development costs incurred by the original developer. So when the much cheaper generic hits the market, the revenues from the original plunge. With a biopharmaceutical generic or, as they are known, a biosimilar or biobetter this situation is nowhere near as severe. That’s because a biosimilar is a complex molecule that needs extensive characterization prior to release, meaning that the cost saving is only about 20-30% compared to the original. This is likely to mean that biopharmaceutical revenues are slowly eroded rather than dropping off a cliff as seen with small molecules, making the balance sheet look better and long-term planning easier.
So it seems that biopharmaceuticals are here to stay as they offer greater efficacy, a more targeted approach and more financial security. However, they do present greater challenges in their development and manufacture than small molecules. That’s because they are large and complex molecules. Typically, they are proteins that undergo post-translational modifications, such as glycosylation as I discussed in my previous blog post, titled, Why I Turned From Phosphorylation to Glycan Analysis, (link to post), and this means that all biopharmaceuticals must adhere to the guidelines set out by the European Medicines Authority and Federal Drug Agency (FDA) to ensure the biomolecule is characterized and does not change over time. Even small changes on the biomolecule can drastically alter that biopharmaceutical’s efficacy, safety, and metabolism. This then requires that the analytical techniques used to characterize and quantitate the biopharmaceutical offer high precision, reproducibility, robustness and speed to ensure the analysis is carried out accurately and quickly to minimize costs. This biopharmaceutical analysis is usually performed using the UHPLC technique (Thermo Scientific Vanquish UHPLC System) which provides high retention-time precision and the ability to run fast gradients, often coupled with mass spectrometry with highly accurate mass resolution (Thermo Scientific Q Exactive Focus). Biopharmaceuticals are challenging to characterize, but the analytical technologies available to do this fast and reproducible characterization are also keeping pace with the increasing demands and growth of biopharmaceuticals.
If you would like to expand your knowledge in this area, I suggest the following:
Do you agree with my thinking as to why the market is moving to biopharmaceuticals? Has the genomic revolution been a large factor in the move to biopharmaceuticals? Do you have concerns about harnessing the body’s own weapons (antibodies) as therapeutics? I would like to hear your thoughts.