MAJOR MECHANISMS OF ACTION
The top selling drugs of 2013 were Abilify (Otsuka Pharmaceuticals; $6.9 billion), Nexium (AstraZeneca; $6.3 billion), and Humira (AbbVie; $5.9 billion). Anyone who follows biopharmaceuticals—and plenty of people who do not—are familiar with these drugs.
How do they actually work?
In this issue, we will take a look at the diverse mechanisms of action (MOA) of these top-selling drugs.
Otsuka’s Abilify is a small molecule drug first approved in 2002 used to treat schizophrenia, a disease which is not fully understood but involves irregularities in dopamine signaling.
Schizophrenics typically have elevated levels of dopamine signaling in the mesolimbic system—the part of the brain associated with reward and desire. These elevated levels are thought to be responsible for the positive symptoms of schizophrenia: visual or auditory hallucinations, distress, and agitation. At the same time, they exhibit lower dopamine levels in the mesocortical pathways—the part of the brain involved in emotional response, motivation, and cognitive control. These lower mesocortical levels are thought to be responsible for the negative symtoms of schizophrenia: lack of motivation and emotional response.
Abilify works by modulating this complex dopamine system. It is a partial agonist of the dopamine D2 receptor, meaning it activates the receptor, but not to the same extent that dopamine does. In the regions of the brain where there is too much dopamine activity, Abilify competes with dopamine for receptor binding, resulting in less activation. In regions of the brain where there is too little activity, Abilify provides at least some activation. Earlier anti-psychotics simply blocked the activation of dopamine receptors, and thereby did little to ameliorate the negative symptoms of schizophrenia.
Abilify has also been approved for acute manic episodes associated with bipolar disorder (October 2004), as an adjunct therapy for major depressive disorder (November 2007), and to treat irritability in children with autism (November 2009).
AstraZeneca’s Nexium is a small molecule drug prescribed primarily for the treatment of gastroesophageal reflux disease (acid reflux) and ulcers.
Nexium reduces the acidity of the stomach by inhibiting an enzyme called a proton pump which is present on the surface of the cells that line the stomach.
Proton pumps do exactly what their name implies—they pump protons, or positively charged hydrogen atoms (H+) into the stomach where they combine with chloride ions (Cl-) to make hydrochloric acid (HCl).
HCl plays an important role in the digestion of food, helping to break down proteins and other nutrients so they can be absorbed in the intestine. However, in individuals with defects in the barrier between the esophagus and the stomach, acid moves into the esophagus, causing heartburn and food regurgitation, sometimes accompanied by nausea, pain with swallowing, and chest pain. Decreasing stomach acid production relieves these symptoms. Likewise people with ulcers—open sores in the stomach or intestine usually caused by infection with the bacteria H. pylori—find relief from pain with decreased stomach acid.
AbbVie’s Humira, the third top-selling drug of 2013, is a monoclonal antibody designed to target the pro-inflammatory signaling molecule tumor necrosis factor alpha (TNF-alpha).
TNF-alpha’s normal function is to turn on the body’s inflammatory response which is the migration of several different types of white blood cells towards a site of infection or injury within the body. Symptoms such as swelling, heat, and pain occur, but it ultimately rids the body of the infectious agent or repairs damaged tissue.
In a healthy individual, this inflammatory response goes away after the infection or injury is resolved. In people with autoimmune disorders, this response is activated by the patient’s own tissues – thus the inflammation doesn’t resolve on its own, leading to chronic pain and loss of function.
Humira works by binding TNF-alpha and preventing it from activating its receptor on the surface of white blood cells, thereby “turning down” the inflammatory response. Humira has been approved for a wide range of autoimmune disorders including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, and ulcerative colitis.
Emily Burke, PhD has worked in biopharma for 20 years, gaining science writing experience at The Scripps Research Institute and Ionis Pharmaceuticals. As a Ph.D. molecular biologist, she is passionate about advancing the public’s understanding of science. In addition to being a self-proclaimed “science geek,” she is regularly asked to speak at international scientific meetings. When not teaching and writing the WEEKLY for Biotech Primer, Dr. Burke swims with her swim club and performs regularly on the improv circuit in San Diego.