Biologic Drugs: From Crohn’s Disease to Cancer

            Biologics are a wide class of drugs that in recent decades, have become incredibly common and desirable due to their specificity and subsequent decreased potential for side effects. All biologics originate from or are modified forms of biomolecules. In contrast to traditional small molecule drugs such as lipitor or aspirin, biologics are quite large and are substantially more specific in the treatment of small groups of diseases through targeted modification of cellular pathways (Chan and Chan, 2017). This is by design, as most new biologic drugs are synthetic and rely on exploiting the principles of established physiological actions. Many believe that the healthcare industry is only just beginning to understand and utilize this powerful class of drugs and in fact they may allow for the treatment of many diseases that current lack effective therapies (Riley, 2018).

            One common example of a disease that is preferentially treated with biologic drugs is Crohn’s disease or CD for short. CD is a chronic inflammatory disease of the gastrointestinal tract that is caused by dysregulation of inflammatory pathways within the walls of the digestive system (Binion, 2019). This disease has been on the rise in recent decades.  It is now estimated that more than 1.6 million individuals have been diagnosed with CD in the United States (Shivashankar et al, 2017). Prior to the advent of biologics, CD was treated in much the same way as other inflammatory conditions, with repeated administration of corticosteroids and eventual surgery. The corticosteroids would down regulate and maintain low levels of inflammation, while surgery would remove the areas of the GI tract that were inevitably destroyed by the disease (Binion, 2010). It is not difficult to imagine that the prospects for life with CD were not great at that time. Now, CD is treated using biologics such as infliximab and adalimumab which modulate tumor necrosis factor or TNF which is a major cytokine that is crucial for maintenance of the inflammatory pathway. By binding and removing TNF, inflammation is halted in patients with CD and remission is commonly achieved and maintained (Jauregui-Amezaga et al, 2017).

            Despite the success of biologics, however, it is not uncommon for some patients to become unresponsive to the drug or to develop resistance over time (Riley, 2018). Because of this, a patient may have to switch between drugs throughout the course of their lifetime. Interestingly, more and more biologics are made each year, and the newest generation of biologics are designed to be more efficient and less likely to lose effectiveness. One such CD drug is ustekinumab which was originally used for psoriatic arthritis but is now evaluated for other applications like CD. In CD, ustekinumab, a monoclonal antibody, targets the p40 subunits of cytokines IL-12 and IL-23 to downregulate the immune response and shut down inflammation. Of note, these pathways also prohibit TNF and their downstream activity in the Th17 and Th1 response pathways (Jauregui-Amezaga et al, 2017).

Figure 1. An illustration of the action of ustekinumab on p40 and cytokine activation (Jauregui-Amezaga et al, 2017)

            Many patients with CD benefit from biologics, but the applications of these drugs are far more diverse with uses in treating several forms of arthritis, asthma, lupus, diabetes, heart attack, cystic fibrosis, osteoporosis, and several more. Several more diseases have the potential to benefit from future biologics that are not even yet made such as multiple sclerosis and cancer (Riley, 2018). Cancers are of particular interest because of the horrible side effects that are typically associated with chemotherapy, the current standard of cancer treatment. The principles that are guiding research efforts into the development of biologic cancer drugs rely on targeting markers specific to a cancerous cell using antibodies.  These antibodies may then arm immune cells to destroy cancer cells directly using the host immune system. They can also act to destroy cancer cells by introducing cytotoxic agents by binding a target marker and entering the cell with the toxin (NIH National Cancer Institute, 2018). Regardless, this could be far more specific than traditional chemotherapy that indiscriminately destroys cells and tissues leading to side effects like hair loss, soft tissue damage, and neuropathies.

Figure 2. An illustration of endocytosis of biologic drugs conjugated to cytotoxic agents in cancer cells (Riley, 2018).

             There is now a sort of mad dash to develop these drugs because of how potentially lucrative producing biologics can be. More than 37% of net drug spending since 2014 was on biologics, and more than 93% of the drug market growth can be attributed to an increase in their sales and production (Forbes, 2019). It is quite easy to forecast that the market will continue to demand more biologics as time goes on. More importantly, many diseases that could not be managed before will likely have biologics developed for them to improve the quality of life for patients and enrich our knowledge about disease processes and treatment at large. As such, the healthcare industry and patients will no doubt continue to benefit from biologic drugs as they evolve and improve.

By Bradley Wright, Master's of Medical Science Student, University of Kentucky

References:

Binion, D. G. (2010). Biologic Therapies for Crohn's Disease Update from the 2009 ACG Meeting. Gastroenterology and Hepatology, 6(1), 4–16. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2886448/

Riley, M. (2018, March 13). The ever-increasing attraction of biologics. Retrieved October 26, 2019, from https://www.chemistryworld.com/health-tech/the-ever-increasing-attraction-of-biologics/3008719.article.

Chan, J. C., & Chan, A. T. (2017). Biologics and biosimilars: what, why and how? ESMO Open, 2(1). doi: 10.1136/esmoopen-2017-000180

Jauregui-Amezaga, A., Somers, M., Schepper, H. D., & Macken, E. (2017). Next generation of biologics for the treatment of Crohn’s disease: an evidence-based review on ustekinumab. Clinical and Experimental Gastroenterology, Volume 10, 293–301. doi: 10.2147/ceg.s110546

NIH National Cancer Institute. (2018, April 26). Biological Therapies for Cancer. Retrieved October 26, 2019, from https://www.cancer.gov/about-cancer/treatment/types/immunotherapy/bio-therapies-fact-sheet.

Forbes. (2019, July 3). Biologic Medicines: The Biggest Driver Of Rising Drug Prices. Retrieved October 26, 2019, from https://www.forbes.com/sites/theapothecary/2019/03/08/biologic-medicines-the-biggest-driver-of-rising-drug-prices/#61afc63718b0.

Shivashankar, R., Tremaine, W. J., Harmsen, W. S., & Loftus, E. V. (2017). Incidence and Prevalence of Crohn’s Disease and Ulcerative Colitis in Olmsted County, Minnesota From 1970 Through 2010. Clinical Gastroenterology and Hepatology, 15(6), 857–863. doi: 10.1016/j.cgh.2016.10.039