Biologics: New Miracle Drugs - AARP Magazine

Special Report

Biologics: New Miracle Drugs

By Mary A. Fischer, November & December 2009

These new medicines—which target diseased cells while leaving healthy cells alone—are transforming the way doctors treat cancer, arthritis, and MS. But are the benefits worth the risks, both physically and financially?

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In January 2006 Richard Oropeza Jr., now 60, was making coffee in the kitchen of his California home when he felt a sudden tingling in his legs. The sensation went away within 20 minutes, but over the next several weeks it came back twice, along with excruciating headaches and complete paralysis on his left side. Emergency surgery revealed that Oropeza had a malignant tumor the size of an apricot on his brain, and doctors gave him less than a year to live. He underwent six weeks of conventional cancer treatment—radiation and chemotherapy—that sapped his energy and caused debilitating nausea. But the tumor kept growing.

"There's nothing more I can do for you," his doctor told him in September 2006, eight months after his initial symptoms.

"Isn't there anything else we could try?" Oropeza pleaded. "Any clinical trial?"

In fact, there was. The University of Virginia, as part of a Phase II clinical trial, was testing a new "biologic" drug called Avastin—the first drug that could fight his type of aggressive cancer by attacking the blood supply that fed the tumor. But there was also a potential downside: the drug could cause blood clots, hypertension, and joint pain.

"In the long run, we're going to have patients who do better for longer with fewer side effects, and to me that's very exciting."

Oropeza signed the liability waiver. "I didn't care what the treatment was or its side effects," he recalls. "To me it was worth it."

Almost immediately after Oropeza started intravenous Avastin therapy, his tumor stopped growing. He could walk again and hold things without dropping them. He went back to work part-time, and now, every two weeks—for the rest of his life—he will take Avastin. Without it, he says, "I wouldn't be alive today."

Radical recoveries like Oropeza's are giving biologics a much-hyped reputation as miracle drugs. Biologic medicines are now the fastest-growing class of drugs in the pharmaceutical world; Avastin alone garnered nearly $3 billion in sales in 2008. Many patients today survive cancers once considered a death sentence, and those who suffer from autoimmune diseases such as multiple sclerosis or rheumatoid arthritis can regain full use of limbs once racked by crippling pain and immobility.

So why aren't biologic drugs prescribed more frequently? Two reasons: the drugs are expensive—Avastin can cost up to a staggering $100,000 per year—and their side effects can be devastating. Some biomedical experts question whether our current health care system, with its prescription-drug pricing protocols, is equipped to handle the flood of new biologic drugs coming on the market. Most patients rely on private insurance or Medicare to pay for them (Medicare spent roughly $13 billion on biologics in 2007). A few also qualify for subsidies from the biotech companies that develop the drugs. But many patients simply cannot afford the medicines.

HOW THEY'RE MADE

Gene is spliced
The genes for a disease-fighting protein are inserted into the cells of a living organism.

Cells extracted
The cells with that new protein are then removed from the organism.

Copies made
The cells multiply, slowly at first, then in increasingly larger quantities.

Harvested
The desired proteins are extracted from the rest of the cells, purified, and made into biologic medicines.

Illustration by Daniel Marsiglio

"We cannot ethically defend our system of payment and access the way it is now," says Ruth Faden, Ph.D., director of the Johns Hopkins Berman Institute of Bioethics. "We have a class of expensive drugs that can prolong life, improve quality of life, or, in the case of Herceptin [a biologic used to treat breast cancer], possibly be a cure for some patients. It is indisputable that any patient should have access to these drugs, regardless of income or insurance status."

What makes biologic medicines unique is this: unlike conventional chemical drugs, biologics are produced by living organisms and specifically target human proteins that are involved in disease.

One class of biologics—known as monoclonal antibody biologics—are similar to the antibodies that the human immune system uses to fight off bacteria and viruses, only these antibodies are genetically engineered to target specific cancers. Avastin, which proved so effective against Richard Oropeza's brain tumor, is now also widely used to treat lung, breast, colon, and rectal cancers. Other monoclonal antibody biologics are designed to attack certain proteins (or protein receptors) on the surface of cancer cells and stop their growth. Examples of such protein inhibitors include Rituxan, which is used to treat lymphomas, and Herceptin.

Other biologics alter the function of the immune system by either suppressing or enhancing certain responses. In autoimmune diseases such as rheumatoid arthritis and psoriasis, for example, the immune system overproduces a protein that triggers a buildup of white blood cells, which leads to excessive inflammation and joint damage. Enbrel, Humira, Remicade, and other biologics in this class target that protein, called the tumor necrosis factor, and block its action. Tysabri, a biologic used to treat multiple sclerosis and Crohn's disease, blocks the passage of inflammatory cells into the brain and the spinal cord—and, in the case of Crohn's disease, into the intestines.

"These biologic agents provide a degree of selectivity not achievable with conventional chemotherapy drugs," explains oncologist Oliver Press, M.D., Ph.D., of the Fred Hutchinson Cancer Research Center in Seattle. "Many of [the biologics] can produce dramatic antitumor effects without the toxicity that historically has been associated with chemotherapy and radiation."

Biologic treatments date back to 1982, when recombinant insulin was first approved in the United States for the treatment of diabetes. (A hormone originally derived from the pancreas of animals, insulin is today made synthetically from genetically engineered human bacteria.) Since then, more than 300 biologic drugs, most of them developed in the past five years, have flooded the pharmaceutical market. Today they constitute roughly 25 percent of all new drugs approved by the FDA; by 2014, industry insiders predict, more than half of the top 100 drugs will be biologics.

The growth is fueled in part by their effectiveness. Two 2005 studies sponsored by the National Cancer Institute showed that adding Herceptin to standard chemotherapy reduced the risk of recurrence by 52 percent. A 2004 study published in the New England Journal of Medicine found that adding Avastin to chemotherapy extended life by 4.7 months for those with colorectal cancers. And studies have established that the addition of Rituxan to the standard chemotherapy regimen for certain types of chronic leukemia doubled complete remission rates.

The benefits aren't limited to cancer patients. In a 2008 clinical trial of Enbrel (with the chemical-based drug methotrexate) conducted by the developers of the drug—Amgen and Wyeth Pharmaceuticals—half of patients with moderate to severe rheumatoid arthritis were in remission after one year, compared with 28 percent of patients treated with methotrexate (brand names Rheumatrex and Trexall) alone.

When Pat Novak Nelson of Basking Ridge, New Jersey, was diagnosed with rheumatoid arthritis in 1976, available treatments provided little relief for the inflammatory disease. Starting with a single swollen finger, Nelson developed such overwhelming pain that she had to give up her passions: tennis, volleyball, and softball. She couldn't even play Frisbee with her young son. Back then, treatment for the roughly 1.3 million sufferers of rheumatoid arthritis was aspirin and anti-inflammatory drugs such as Naprosyn (naproxen)—which worked "for a while," Nelson recalls.

Then, in 1998, the FDA approved Enbrel, a biologic drug that blocks the protein receptors that trigger inflammation, swelling, and joint damage. "Without question, biologic agents have had a profound impact on improving the treatment of rheumatoid arthritis," says John Howard Klippel, M.D., president and CEO of the Arthritis Foundation. "It can't cure the disease, but it stops it from progressing."

As promising as Enbrel sounded, Nelson had reservations. "I thought about it for a couple of months because the possible side effects [infections, tumors, headaches] can be nasty," she says. But with no alternatives in the offing, she decided to take the plunge, and now, twice a week, she self-injects Enbrel. "It made a huge improvement in the quality of my life," she says. "I can't remember a day when I woke up with pain."

For all the stories of miraculous recoveries and pain-free lives, biologics represent a quandary in modern medicine. The drugs are typically prohibitively expensive—Rituxan can cost $60,000 a year; Enbrel, $32,000—partially because the FDA has no process for approving generic versions of biologics (see "What Price a Miracle?"). And, as patients such as Pat Nelson know, the drugs can also trigger serious side effects, ranging from heart attacks to infections.

Chicago oncologist Mark Kozloff, M.D., who has been treating cancer patients for 30 years, does not dispute the effectiveness of the drugs for his patients, but he often wonders "who bears the cost and how does society pay for it." Even when patients are covered by health insurance or Medicare, many of them face high costs. Richard Oropeza Jr. is okay for now, but his future is uncertain. With his brain cancer stable, Oropeza continues to take Avastin, but he doesn't pay for the drug—yet. Oropeza receives his biweekly IV infusions courtesy of Genentech, the biotech company that developed Avastin. All other costs—doctor fees, MRI scans—are covered under Oropeza's private insurance plan, but only after he pays a deductible. And Genentech's coverage of his treatment may end next year.

"I'm not going to worry about the cost now," Oropeza says. "I live day by day, and right now I'm doing well and feeling good. I'm hoping that less expensive generic versions of these drugs will come along soon."

The safety of biologics is another area of concern. Roughly 13 percent of the drugs, including Herceptin, Enbrel, and Rituxan, have received FDA black-box-label warnings—the most severe kind—for their potential serious side effects, including not just infections and heart attacks but also lymphoma and disorders of the central nervous system and immune system. Adverse effects sometimes do not surface for five or more years after drugs have been on the market. "The human body is in a constant state of change," wrote the editors of The Journal of the American Medical Association in an editorial accompanying a 2008 report on biologics, "and the effects of some drugs will manifest only after exposure over time."

In clinical studies 6 out of 39 patients receiving Avastin for colorectal and other types of cancer had bleeding complications and delayed wound healing.

And while some patients such as Nelson have had no side effects from Enbrel, others haven't been as lucky. "We know that the drug mediates the immune system's response, which in some cases can have grave consequences," says Debra Lappin, president of the Council for American Medical Innovation and an Enbrel user herself (she has a rheumatic disease that causes arthritis of the spine and sacroiliac joints). "The drug reduces the inflammatory response, thereby preventing serious joint damage, but it can also decrease the immune system's ability to fight infection." In a 2007 report in the Archives of Internal Medicine that analyzed adverse events reported to the FDA, Enbrel ranked tenth in the number of deaths: 1,034 from 1998 to 2005.

Such alarming reports do not dissuade Lappin. "When you have drugs like Enbrel that are so powerfully transformative in changing the course of a disease," she says, "you have to weigh this extraordinary life benefit against the real likelihood of risk. This is a drug that took me off disability and gave my family back a wife and a mother."


Reducing side effects is one of the top goals for scientists developing new biologics. At the Fred Hutchinson Cancer Research Institute, oncologist Oliver Press is leading research on improved antibodies and gene modification "that will allow the patients' own immune systems to recognize and kill their lymphomas more effectively, with less toxicity." New research also suggests that side effects may be determined by genetic factors. "If this proves to be true," says Arthritis Foundation president Klippel, "then in the future people might have genetic testing to select a biologic that would have the least likelihood—ideally, zero—of having a side effect."

Other research is focused on designing biologics that will deliver proteins and enzymes involved in DNA repair inside cells, where disease begins. "Currently, nearly all biologics target protein receptors that lie on the outside of cells, but the source of disease is inside," says University of Washington bioengineering professor Patrick Stayton, Ph.D. "If we can achieve better delivery of biologic drugs to intracellular targets, I think there's little doubt they'll have a big impact on the pharmaceutical world."

"In the long run," says oncologist Mark Kozloff, "we're going to have patients who do better for longer with fewer side effects, and to me that's very exciting."

Mary A. Fischer is a journalist based in Los Angeles.

For more information on biologic drugs visit aarp.org/biologics


Comment

The biologics work to stop almost all new growth of a tumor but do not reduce the size of the tumor. As I understand it the biologics stop 95%+ of new growth by restricting new blood supplies. If they could reduce the size of the tumors with surgery and then give the biologics it would seem to be the best outcome possible. especially for brain tumors because at a certain size they impinge on nearby nreves and cells that the brain needs to function. Althogh if the surgical reduction isnt possible, or risky, giving the biologics would at least stop most of the new growth.
The other question is the cost. My Mom went thru 4 courses of chemo, 8 or 10 episodes each, and each episode in the doctors clinic cost $1800 each. If you are not involved in a research study, who can afford these trteatments? Avastin was available to her in Orlando, but the cost was incredible. My Mom had to decide whether to drain her savings out completely, before Medicare would consider paying for it, or to discontinue the treatments and live out her remaining days as comfortably as she could. "I am too old to be a bag lady", she said. So she stopped the Avastin and let Nature take its course. the other reason she didnt continue the treatments was because she wanted to have some money to pass on to her heirs.