Kari Antin, a 40-year-old financial analyst in Minneapolis, knows she’s taking a life-or-death risk with every monthly infusion of Biogen (BIIB:US) Idec Inc.’s Tysabri.
She is among the 55 percent of multiple sclerosis patients who harbor a potentially lethal virus that can be reactivated by the drug, allowing it to creep from the kidneys to the brain, where it destroys nerve-protecting cells. The risk soars after two years of treatment. Still, Antin insists on sticking with the drug she credits with restoring her health.
It’s a dilemma faced by almost 60,000 multiple sclerosis patients worldwide who continued on Tysabri beyond the recommended two years. It’s also new territory for Biogen, as the number of patients pushing the time limit increases, and a concern for prescribing doctors who increasingly find patients resolute about staying on the potent medicine that reduces the risk of relapse by 68 percent.
“I dread the thought of being in a wheelchair,” said Antin, who has had only one relapse on Tysabri and just returned from sailing a 50-foot catamaran with a group of friends in the British Virgin Islands. “If the alternative is that I die, I would rather that than lose the quality of life. To me, it all comes down to personal choice and what you’re willing to risk.”
Tysabri is the most effective MS medicine available, generating (BIIB:US) $1.1 billion annually for Weston, Massachusetts-based Biogen. The company dominates the market for MS and its latest treatment, Tecfidera, helped push up shares (BIIB:US) 31 percent since its March approval. That’s outpaced the 17 percent increase in the Nasdaq Biotechnology Index and the 5.5 percent gain in the Standard & Poor’s 500 Index. (SPX) Biogen fell less than 1 percent to $232.62 at the close in New York.
While Tecfidera has shown none of the same risks of Tysabri, it may also not control the disease as well. Yet with Tysabri’s greater efficacy comes the chance of disability or death caused by a brain infection. The two-year warning was added to the drug’s prescribing label in 2011.
More than 2.1 million people worldwide have multiple sclerosis. The chronic disease develops when a person’s immune system inexplicably attacks the brain, spinal cord or optic nerves. Symptoms range from mild numbness or loss of coordination to paralysis and blindness. The most common form is marked by terrifying relapses were symptoms surge, followed by quiet periods of remission. There is no cure.
Stopping the Descent
The goal of treatment is to stop the relentless descent into disability.
“That’s something only the patient can understand,” said Al Sandrock, Biogen’s chief medical officer. “They knew what it was like before they were on Tysabri, and how they did on the drug. We don’t have any good ways of repairing the brain right now. All we can do is prevent MS lesions from forming and Tysabri is very good for that.”
Uncertainty has surrounded Tysabri since its beginning. The drug was pulled off the market after just three months of sales in 2005 when three patients developed the brain disorder, called progressive multifocal leukoencephalopathy. Two of the three subsequently died. The drug’s effectiveness, however, drew passionate appeals from patients and doctors that led regulators to allow sales to resume the following year with strict rules governing its use.
Now regulators in the U.S. and Europe recommend taking Tysabri for no longer than two years. It is approved only after other treatments fail and for patients with highly active disease. All must enroll in a registry and are closely monitored.
As of April 2013, 347 people have contracted PML while taking Tysabri, designed to block the abnormal immune response that causes MS. The virus targets the cells that make myelin to protect the nerves. PML also occurs in people with conditions that suppress the immune system and make it harder to fight infection, such as cancer and HIV. In those cases, it is almost always fatal.
For MS patients, however, about 20 percent die from the condition, with the remainder suffering from a range of disabilities that have been likened to the worst possible multiple sclerosis relapse. Intense MRI monitoring to catch and treat the virus early seems to help limit the damage.
James Stankiewicz, a neurologist at Brigham and Women’s Hospital in Boston, always advises his Tysabri patients to come off the drug after two years if they have antibodies to the germ, known as JC virus. While he’s never run into a situation where he and a patient can’t agree on continued Tysabri use, he said he might have to recommend another physician if a particularly high-risk patient insists on staying on the drug.
“If they are positive, I’m not thrilled with them remaining on the drug,” Stankiewicz said. “The risk is real. In general, especially after two years, you get more and more concerned with them being positive.”
Now that more patients have taken Tysabri for longer periods of time, Biogen’s statistics point out the drug’s increased risk over time. While PML was originally thought to develop in 1 in 1,000 patients, the data shows a risk of getting the PML infection in the first year of 0.05 in 1,000, jumping to 4 in 1,000 after one year or more of monthly infusions.
New medicines will eventually cut into Tysabri’s revenue growth, including Biogen’s own entrants, said Marko Kozul, an analyst at Leerink Swann & Co. in San Francisco. In March, Biogen won U.S. approval of its first pill for MS, Tecfidera, and sales have exceeded analysts’ initial estimates (BIIB:US). It is also developing MS medicines with Roche Holding AG (ROG) and AbbVie Inc. (ABBV:US) that are more potent without the same dangers of PML.
“There are other drugs that are coming to the market that might start to fill the void of alternatives after Tysabri,” said Kozul. “As Tecfidera launches and starts to gain legs, we have decelerating revenues for Tysabri.”
Biogen’s Sandrock said he considers that “a great problem to have.” Just 20 years ago, there were no medicines for multiple sclerosis. “To have multiple options, not just ours, is a great place to be,” he said.
All PML cases have occurred in patients who test positive for the JC virus, and Biogen introduced a test for it in January 2012. Still, about 2 percent to 3 percent of people can have a false negative report, said J. William Lindsey, a professor of neurology at the University of Texas Medical School at Houston. Another 1 percent may contract the virus each year, he said.
Patients who are negative can remain on the drug “indefinitely,” as long as regular tests show they remain unexposed, he said. In some cases, taking patients off Tysabri can trigger a worsening of MS symptoms, he said. There is no way to know which patients are most likely to suffer relapses after they go off the drug, Lindsey said.
Some evidence, however, suggests the risk of PML doesn’t climb with successive years of use, said David Clifford, a professor of neuropharmacology at Washington University School in St. Louis.
The risk appears to peak after 24 infusions, when there were 5.13 infections for every 1,000 patients. The number of cases fell over each subsequent six infusion, until there were 2.54 cases for every 1,000 patients on Tysabri for five years. Still, the data aren’t definitive since the number of patients who have taken the drug for more than four years is small, and the difficult choice for patients remains.
“I might have a greater chance of dying in an airplane crash than dying from PML,” said Antin, whose doctor is running MRI scans on her every three months. “I have nothing to lose.”
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