sold by a pharmaceutical company. To further limit the market potential for antibiotics, physicians began hoarding the newest drugs, reserving them only for the very sickest patients with antibiotic‐resistant infections. This practice continues today as one component of antibiotic stewardship. The pharmaceutical industry needed more reliable sources of income, and chronic disease was an area of focus and growth.
At the same time as antibiotics were swiftly changing medical practice in the treatment of infection, the Framingham Heart Study was launched in 1948 with the goal of identifying risk factors for cardiovascular disease. It would not be until the early 1960s that reliable data would be reported from this epidemiological study, but drug development that would impact cardiovascular disease was already underway, although initial efforts were not focused there. In the 1950s, Merck was researching carbonic anhydrase (CA) inhibitors for the purpose of reducing blood acidity. The CA inhibitor class of drugs being studied resulted in the side effect of more frequent urination, and soon became known as “diuretics.” Eventually, Merck saw potential in this side effect and marketed Diuril® for the treatment of edema in 1958. Soon after, physicians started using it to treat the newly identified risk factor for stroke, now known to be hypertension. Physicians were prescribing Diuril® off‐label (meaning it was approved for treating edema but being used for the unapproved indication of hypertension treatment). While it was not the intent of their initial efforts, Merck had just invented the first antihypertensive. Competition soon followed and within a few years more than six thiazide drugs were approved by the United States Food and Drug Administration (FDA).5
Antihypertensive drugs had only moderate uptake until the Framingham Heart Study reported potential links to hypertension and stroke and public health epidemiologists were seeing reduced stroke due to antihypertensive drug use in the broader population. There was tremendous market potential, and drug companies were searching for more effective antihypertensives with fewer side effects to increase their competitive advantage. In 1964, the first beta‐blocker was identified in Britain and rapidly became one of the best‐selling drugs in the world. Beta‐blockers would continue to be researched and improved in the upcoming years; however, they still carried concerning side effects such as fatigue and nausea. In the early 1980s, scientists at Squibb started researching pit viper venom as it was known then to lower blood pressure. They found the venom's most active ingredient, teprotide, and identified the enzyme it works on which is angiotensin converting enzyme (ACE). Since teprotide is a peptide and cannot be given orally, the scientists researched the biochemistry and pharmacodynamics and sought to synthesize other compounds that could inhibit ACE while given orally. Little by little they tweaked and tested their new chemical structures based on their insights into how the modified chemicals would affect the enzyme. This process is called “rational design,” and in this case it led to the approval of the first commercial ACE‐inhibitor, captopril, being approved in the United States in 1981. This drug generated more than one billion dollars in sales in its first full year of being marketed.5
Table 3.1 Best‐selling drugs ranked by sales volume.
Source: Adapted from https://www.fiercepharma.com/pharma/from‐old‐behemoth‐lipitor‐to‐new‐king‐humira‐u‐s‐best‐selling‐drugs‐over‐25‐years.6
| Drug | Lifetime sales (billions) | Clinical uses | Manufacturer | Classification | |
|---|---|---|---|---|---|
| 1 | Lipitor® (atorvastatin) | $94.67 | Elevated cholesterol | Pfizer | Small molecule |
| 2 | Humira® (adalimumab) | $75.72 | Inflammatory diseases | AbbVie | Biologic |
| 3 | Nexium® (esomeprazole) | $72.45 | GERD | AstraZeneca | Small molecule |
| 4 | Advair® (fluticasone/salmeterol) | $69.08 | COPD | GlaxoSmithKline | Small molecule |
| 5 | Enbrel® (etanercept) | $67.78 | Inflammatory diseases | Amgen | Biologic |
| 6 | Epogen® (epoetin Alfa) | $55.63 | Cancer | Amgen | Biologic |
| 7 | Remicade® (infliximab) | $54.67 | Inflammatory diseases | Johnson & Johnson | Biologic |
| 8 | Abilify® (aripiprazole) | $51.34 | Mental health | Otsuka/Bristol‐Myers Squibb | Small molecule |
| 9 | Neulasta® (pegfilgrastim) | $47.40 | Cancer | Amgen | Biologic |
| 10 | Plavix® (clopidogrel) | $46.48 | Cardiovascular | Sanofi/Bristol‐Myers Squibb | Small molecule |
GERD, gastroesophageal reflux disease; COPD, chronic obstructive pulmonary disease.
Drugs that generate revenue of $1 billion in a given year are commonly referred to as “Blockbuster Drugs.” Table 3.1 lists the top 10 all‐time best‐selling prescription drugs in the United States between 1992 and 2017.6
Five of the top 10 drugs are small molecule drugs and the other five are biologics.6 By 2019, the original patents for all the top 10 small molecule and biologic drugs have expired in the United States and many other countries. Most are available in generic or biosimilar form, respectively, in 2019. All but one of the top 10 drugs can be self‐administered by the patient (meaning they do not require health professionals to administer the drug).
Figure 3.1 Relative molecular mass of small molecule and biologic drugs.
