If you watch network prime-time news programs at all, you can’t help but be impressed by the number of direct-to-consumer (DTC) ads that dominate the commercials. It seems the demographics of the viewers of these programs are older folks, ideal targets for all manner of medication-focused commercials. The conditions that dominate the DTC ad space are inflammatory disorders—Crohn’s disease, rheumatoid arthritis, psoriasis, psoriatic arthritis, and eczema. The ads tout remarkable results and urge viewers to ask their doctors if certain drugs are “right” for them.
Of course, the goal is to get physicians to “write” prescriptions. Most physicians think of themselves as being immune from such pressures. But, apparently, the pharmaceutical companies have reason to think otherwise—which is why these ads are prevalent. In the United States, DTC advertising expenditures were about $6.13 billion in 2017.
DTC ads are banned everywhere except in the United States and New Zealand—and there are processes under way in New Zealand to ban them again. The New Zealand Medical Association has opposed the law allowing DTC ads since 2006. The American Medical Association has opposed DTC advertising only since 2015.
The focus of most DTC advertising centers on the psychosocial aspects of the various targeted diseases. Ads for psoriasis depict embarrassment when a patient’s involved skin is exposed to the public on the beach. Ads for monoclonal antibodies against Crohn’s disease depict the unexpected and socially inconvenient urge to go to the bathroom. Generally, the focus is curing the pathology in order to deal with the embarrassment and limitations these conditions impose on patients and not just the clinical symptoms.
Meet the “Mabs”
Let’s take a look at anti-inflammatory monoclonal antibodies, which many of us now casually refer to as “mabs.” In the past, steroids were used to suppress inflammation, but they had widespread effects that were often problematic. Over time, scientists were able to develop anti-inflammatory drugs that had more dominant effects on certain organs or tissues. The analogy to steroids is important in that, although they target certain organs, mabs still can have some systemic effects, just like steroids.
As of 2017 there were 73 mabs approved by the US Food and Drug Administration (FDA). Ten new ones were approved in 2017, up from one in 2010 and three in 2013. Since then, a total of 33 new mabs have been approved in the United States. Of the 73, 34 are for cancer, 26 are for immune disorders, four are for infections, three are for cardiovascular disease, and six are for other problems. It is anticipated that worldwide sales of mabs will approach $125 billion by 2020.
The names of the specific mabs and their relatives are infamously unpronounceable, but there is a method to the apparent madness of how they are named. The original source of the mab is established by the letters before “mab.” Specifically:
- -o-: mouse (all mouse)
- -xi-: chimeric (part human, part nonhuman)
- -zu-: humanized (mostly human, part nonhuman)
- -u-: human (all human)
The target for the mab in the body is usually determined by one or two letters before the source:
- -b(a)-: bacterium
- -s(o)-: bone
- -c(i)-: circulatory system
- -f(u)-: fungus
- -gr(o)-: growth factor
- -k(i)-: interleukin
- -l(i)-: immune system
- -n(e)-: nervous system
- -tox-: toxin
- -t(u)-: tumor
- -vi(r)-: virus
What do emergency clinicians need to know about mabs? First, these drugs cause immunosuppression, predisposing patients to infections. All of the TV ads warn that patients must be checked for latent infections such as tuberculosis or deep fungal infections before starting a mab. Risks of bacterial infections and sepsis are also increased.
Unfortunately, mabs can occasionally cause an array of other side effects, many of which are not likely to be anticipated when only considering their anti-inflammatory effects. These can include:
- New or worsening heart failure
- Blood problems (anemia and pancytopenia)
- Nervous system problems (new or worsening multiple sclerosis and Guillain-Barré syndrome, depression, headaches)
- Paradoxical development of immune disorders, which are often unrelated to the disorder being treated (psoriasis, inflammatory bowel disease, and lupus-like syndromes)
- Weight loss
- Liver abnormalities
- Allergy/anaphylaxis
- Cancer (lymphomas)
- The usual assortment of minor side effects associated with (but not definitively caused by) most drugs (rash, itching, diarrhea, you name it)
Mabs to Combat Cancer
By far, one of the most miraculous aspects of mabs is their ability to treat cancer. In 2015, former President Jimmy Carter announced that he had malignant melanoma that was in his liver and brain. I figured he was a dead man walking. But four years on, Jimmy Carter is alive and well and still teaching Sunday school in Plains, Georgia. He was treated with a drug called Keytruda (pembrolizumab, a mab from mostly human sources that modulates the immune system). The drug was fast-tracked by the FDA and approved in 2014, and Jimmy Carter got it in 2015.
What do emergency clinicians need to know about mabs? First, these drugs cause immunosuppression, predisposing patients to infections.
Keytruda and another heavily marketed competitor, Opdivo (nivolumab), are the only intensively DTC-marketed drugs for the treatment of cancer. Their commercials don’t talk about cures but rather imply a better (and perhaps longer) quality of life in people with advanced cancer. Commercials typically focus on happy family gatherings. Keytruda had sales reaching $919 million in the first nine months of 2016 alone.1
How do they work? Keytruda and Opdivo are cancer cell uncloaking agents (also called checkpoint inhibitors). Many cancer cells have the ability to “hide” from the immune system, and as such, the body’s own defenses are inhibited from destroying them. More specifically, there are molecules on immune cells that need to be turned on to recognize and attack foreign cells. Cancer cells have the ability to prevent these molecules from being activated. The cancer cells activate what are called checkpoints, and these checkpoints prevent the immune cell from being mobilized. These two drugs inhibit these checkpoints and allow the body’s own immune system to detect and then attack the cancers. Checkpoint inhibitors are often used in conjunction with drugs that boost the immune system, in essence providing a one-two punch. Yervoy (ipilimumab) is one such drug.
The side effect profile of checkpoint inhibitors is markedly different from the anti-inflammatory mabs. Checkpoint inhibitors side effects include:
- Immune-mediated pneumonitis
- Immune-mediated colitis
- Immune-mediated hepatitis
- Immune-mediated endocrinopathies (thyroid disorders, type I diabetes, hypophysitis)
- Immune-mediated nephritis
- Immune-mediated adverse skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis
- Infusion-related reactions
Then There’s the Cost
Most people have no idea how expensive mabs are. For example, the psoriasis pill Otezla (apremilast) costs $4,067 for 60 30-mg pills at Walmart. Once on a maintenance program, the dose is two tablets a day—totaling about $50,000 a year for a chronic disease that may last a lifetime.
That pales in comparison to the price tag for Keytruda, which is given as an infusion of 200 mg every three weeks. Costco sells a 50-mg vial for $2,171. If the drug were taken for half a year, it would cost $75,261. According to a Reuters article from April 3, 2017, the combination of Opdivo and Yervoy costs $256,000 for a year’s treatment.2
With more and more patients taking immune-modulating mabs, it will just be a matter of time until emergency clinicians see the diverse range of side effects that can be caused by these medications. And given that it will be impossible to remember all of the side effects of these drugs, clinicians should have a low threshold for considering patient’s symptoms to be manifestations of the mabs in the ever-growing number of patients who are, and will be, taking them.
Dr. Bukata is medical director for The Center for Medical Education.
References
- McCaffrey K. Merck launches DTC campaign for Keytruda. MM&M website. Accessed June 19, 2019.
- Beasley D. The cost of cancer: new drugs show success at a steep price. Reuters website. Accessed June 10, 2019.
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