Enbrel and the Autoimmune Era

How a banner biotech drug made in Chinese hamster ovary cells is changing disease even as it treats it. An Object Lesson.
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Enbrel is one of the top ten drugs in the U.S. by sales, garnering the pharmaceutical giants who co-market the drug, Amgen and Pfizer, billions of dollars in revenue annually. People take Enbrel for inflammatory conditions like rheumatoid arthritis and psoriasis, at prices of tens of thousands of dollars per year.

Enbrel is a biotech drug, or as the industry calls it, a "biologic." This means that Enbrel is made in living cell cultures rather than in a chemistry lab. It was one of the first successful products to emerge from the flourishing of innovations in cell biology since the 1990s.

We normally think of pharmaceutical manufacture as a chemical process, but biologic engineers are more like Dr. Frankenstein than like Walter White: biotech's beakers and vats hold living tissues instead of chemical compounds. Enbrel is a fusion protein, a molecule produced from recombinant DNA (rDNA)-a kind of molecular graft that combines multiple genetic properties like a horticultural graft joins vascular tissues. Biologic manufacture is thus also reminiscent of one of the most ancient forms of production: agriculture. Like the production of meat or vegetables, biologic manufacture requires the careful management of living, nonhuman things. In the case of Enbrel, genetically-modified Chinese hamster ovary cells churn out the desired proteins. Chinese hamster ovary cells are the go-to mammalian cell line for protein manufacture in the biotech industry, the biopharmaceutical equivalent of chicken.

While the public may not be used to thinking of pharmaceutical manufacture as a process akin to food engineering, they are nevertheless accustomed to ingesting pharmaceutical products like food. But from a consumer's perspective, drugs made from living matter are actually less like food than traditional chemical-based drugs are. Like biologics generally, Enbrel cannot be taken orally: your gut would kill it, so instead it must be injected below the skin.

Most biologics are administered in hospitals, but patients can get Enbrel at a pharmacy, store it in their refrigerators at home, and self-inject. Enbrel's first mode of packaging, available since 1998, is a kit with powder and solvent, which a patient (or a caregiver) mixes at home. This process brings the final step of pharmaceutical fabrication home: a carefully measured amount of sterile liquid is drawn from a vial into a syringe, injected into a vial of powder, mixed, and drawn back into the syringe. The resulting liquid is injected just below the skin. In so doing, the Enbrel patient participates in the creation and administration of the drug to a remarkable degree. When a consumer pops a tablet from a blister pack and swallows it whole, they don't have to think about what the tablet's components are, or how it is made. Indeed, it is difficult to see the tablet as components at all. In contrast, this Enbrel packaging enrolls the patient as compiler.

Obviously, people with moderate to severe rheumatoid arthritis may find this mixing and self-injection process particularly difficult. And so, a new form of packaging was released in 2004: an autoinjection pen.

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Types of Enbrel injector, from the manufacturer's website.

This delivery mode reduces the patient's participation in biotech production, and the self-inject pen is in that sense more like taking a pill. Yet since relatively few Enbrel patients have prior experience with self-injection - with the exception of those who have personal experience with, say, insulin-dependent diabetes, or with illicit intravenous drugs - for the overwhelming majority of patients, self-injection is still a new mode of intimacy with drugs.

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Compared to pills and even injections from a doctor or nurse, the process is unusual and unfamiliar. Enbrel's website offers a series of videos to help patients learn the process. In it, the science fiction futurism of Star Trek-style medical magic meets the humdrum reality of an ordinary den recliner. With the Enbrel pen, the futuristic and the ordinary are combined, like the drug itself is grafted from rDNA sequences.

Enbrel's most prominent spokesperson is pro golfer Phil Mickelson, and he is an appropriate icon not only for his wholesomeness and perseverance but also for his wealth. Enbrel's high price effectively limits its use to the first world, and so does its vulnerability to heat, since easy and reliable access to refrigeration is assumed. Even so, Enbrel still poses a challenge for the developed world's affluent, mobile lifestyle, since it can't simply be tossed in a bag or purse like a pill or an inhaler. Luckily, for patients on the go, EnbrelSupport™ offers a travel pack-including bubble wrap, a cooler packed with ice, and a thermometer-at no additional cost. Such are the perks of being a customer worth annual revenues in the five-figures.

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One of Pro Golfer Phil Mickelson's Enbrel endorsements (Enbrel.com)

It may be tempting to conclude that Enbrel is just a luxury drug, but it actually does improve quality of life for many people suffering from severe joint pain. Moreover, it provides a more general lesson about our contemporary experience of health and disease in the post-industrial economy. Until the twentieth century, infectious diseases were the most urgent ones, and the antibiotics that treated them were a major breakthrough in building the modern pharmaceutical industry. Antibiotics helped to cure many diseases that previously had been deadly, which allowed the industry to thrive even as it posed a risk to its future sustainability. Quick cures make for difficult business, because your customers no longer need your product.

After World War II, pharmaceutical development shifted from infectious diseases to chronic "degenerative diseases," especially heart disease. A slew of drugs became blockbusters, including those for high blood pressure and high cholesterol, by promising to reduce the risk of heart disease if you took them every day. In the late 20th century, the pharmaceutical industry extended its reach still further. "Life-style drugs"-pills that promise to enhance life rather than to save or lengthen it-became the dominant form of blockbuster. Think Prozac, think Viagra.

Both risk-reducing drugs and lifestyle drugs have a business advantage over antibiotics, because they are designed to be drugs for life, to be taken routinely by people who are expected to live long lives. There is a fundamental market limit for antibiotics: you stop taking them once you are cured. But for these risk-reducing and lifestyle drugs, a different economic pressure presents itself: generic competition. New blockbusters have yet to be developed to replace the late-twentieth century boom, and so almost all face generic competition.

Biologics like Enbrel represent the next phase of commercial pharmaceutical business models. Many of the most profitable biologics are indicated to prolong life for cancer patients, but Enbrel is a lifestyle drug: it is meant to enhance life rather than extend it. It is also a risk-averting drug, promising to stave off further damage to joints. However, Enbrel is very different from most other lifestyle and risk averting drugs because those drugs are chemicals. Chemical manufacture has its challenges, but biotech manufacture is much more complex. As a biologic, Enbrel is hard to copy. And unlike traditional chemical drugs, it's not clear how generic equivalents could be fashioned for biological things like fusion proteins made in hamster ovary cell lines. The landmark 1984 law that regulated generic drug competition doesn't cover biologics. The health care laws of 2010 were supposed to facilitate competition in the form of "biosimilars," but so far biotech companies have been very successful in staving off that competition. Although Enbrel's main patent was set to expire in 2012, Amgen benefited from complicated vagaries in changing patent law, and a new Enbrel patent is valid until about 2028.

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Chinese hamster ovary (CHO) cells in cell culture flask (Wikimedia Commons)

If Enbrel's business model is a good fit for today's economy, its operation is a good match for the nature of disease today. Rich countries have moved from an infectious era to a degenerative era to a lifestyle era, and now to a new autoimmune era that encompasses the three prior eras all at once.

We can get a sense of what this autoimmune era means by understanding Enbrel's mechanism of action. The drug interferes with a naturally occurring protein called tumor necrosis factor (TNF). Interfering with TNF is not normally something that we would want to do. TNF is released by immune cells for a reason: it binds to receptors on the surface of cells and triggers a cell death pathway. That is, TNF gives the immune system a way to destroy potentially harmful cells by causing them to commit suicide. But, in autoimmune disease, the immune system is not attacking potentially dangerous cellular intruders-it is attacking the body's own cells. In this immune response gone awry, rogue TNF plays a role in excessive inflammation and resulting impairments to mobility and comfort. Enbrel is supposed to interfere with TNF by acting as a decoy. But as with any decoy, Enbrel can trick agents it never intended to snare.

Consequently, Enbrel's immunosuppressant aspect also bears its principal risk. In patients contracting autoimmune diseases, the immune system is so eager to fight absent infection that it attacks the patient's own body. Treating autoimmune diseases requires suppressing the immune system, which in turn compromises the body and thus makes it vulnerable to old-fashioned infections. In 2008, Enbrel and its cousin TNF-inhibitors Remicade and Humira were required to display the FDA's strongest "black box" warning, meaning that the package insert must alert patients that Enbrel can cause death. One reason this warning was added: rare reports of Enbrel patients with the most prominent infectious disease of the 18th and 19th centuries: tuberculosis. In 2009, another risk of death was added: cancer, thanks to new instances of lymphoma and other malignancies in children and adolescents taking Enbrel. "May cause cancer" is obviously a worrying statement, albeit so common that we are perhaps desensitized to it. When cancer risk is combined with risk of TB, Enbrel's black box warning becomes particularly ominous.

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Ernest Hamlin Baker tuberculosis poster, circa 1935 (National Institutes of Health).

Enbrel is a drug that embraces weird recombination. First its engineers assemble unexpected parts of biological systems, parts which in turn churn out the proteins that confuse an overactive immune system when introduced by a patient's unfamiliar, deliberate injections into the skin of a thigh pulled taut. And in so doing, Enbrel also recombines its predecessors by introducing new susceptibilities. Enbrel is a lifestyle drug that promises to enhance life's quality by reducing the impact of arthritis and related conditions. And yet, it can render the body vulnerable to forms of disease that were never really left behind: infections like consumption, degenerations like cancer. The apotheosis of contemporary biotechnical achievement creates a strange loop to the past. Even as we coax hamster ovary cells to emanate life-affirming resilience, we also summon old demons that might otherwise remain shrouded in the shadows.

Yet a Frankenstein narrative can only get us so far. Had Dr. Frankenstein not made the monster in the first place, or had he bolstered and stayed within the walls of his home, he and his bride might have been safe. Like infectious diseases, the danger of Frankenstein's monster is "out there," in public rather than in private. By contrast, the promise and the peril of Enbrel is also within. We need Enbrel precisely because chronic degenerative diseases can make our own bodies unsafe for themselves on the inside. But yet, taking this drug, made Frankenstein-style out of living things, makes those bodies susceptible to the long-forgotten infectious diseases of the outside world. If Enbrel is our monster, killing or exiling it offers no solution. Both the benefit and the risk of Enbrel are found within and without the patient, bound together like the rDNA from which the drug is fashioned.

Enbrel illustrates a fundamental characteristic of pharmaceuticals: we are seldom more intimately connected to anything or anyone like we are to our drugs. Pills and injectable drugs are tangible objects that are external to us, but upon consumption, they transform us and even constitute us. They are simultaneously embedded in huge economic processes and literally vanishingly small-scale. Pharmaceuticals are made to cross the boundaries of the body, to calibrate or modify it. Our drugs don't simply "cure" us. They transform both our bodies and our diseases in ways we can't predict or understand by looking at either in isolation.

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Anne Pollock is is an assistant professor of science, technology, and culture at Georgia Tech. She is the author of Medicating Race.

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