The temporary withdrawal of natalizumab (Tysabri) from the market in February 2005 in response to 3 cases of progressive multifocal leukoencephalopathy (PML) among clinical trial participants was a wake-up call for the neurology community about the risks of therapies for multiple sclerosis (MS). Although natalizumab returned to the market under a restricted distribution program in June 2006, the impact of the withdrawal remains evident in the more guarded optimism now being expressed by clinicians and researchers about the agent and about other immunosuppressive therapies for relapsing- remitting MS (RRMS) in the absence of longterm safety data.

Such caution was readily apparent at the annual meeting of the American Academy of Neurology (AAN) that took place in Boston from April 28 to May 5. Phase 2 trial results suggesting dramatic reductions in relapse rates and disability associated with the monoclonal antibody alemtuzumab (Campath)^1,2 were offset by presentations on the risks of thyroid abnormalities³ and immune thrombocytopenic purpura (ITP)⁴ for patients taking the drug. Phase 2 trial evidence in support of another monoclonal antibody, rituximab (Rituxan),⁵ seemed somewhat less encouraging in light of the eerily familiar December alert issued by the FDA regarding 2 cases of PML in patients with systemic lupus erythematosus who had been treated with the drug. In several symposia on MS therapy, speakers cited the therapeutic potential of other immunosuppressive agents but cautioned that it is still too soon to know just what types of adverse effects the agents might have.

“We are looking . . . [at] some very exciting times for being able to treat these patients,” said Elliot M. Frohman, MD, PhD, director of the Multiple Sclerosis Program and the Multiple Sclerosis Clinical Center at the University of Texas Southwestern Medical Center in Dallas, who spoke during a symposium titled “Hot Topics in Multiple Sclerosis” at the AAN meeting. “But we may be reaching the ceiling of our ability to treat patients without compromising surveillance,” he said.

RISKY BUSINESS
Not only must clinicians who treat patients with MS wrestle with the uncertainties about drug-related complications, they must do so on behalf of patients who have a prognosis so daunting that they may be willing to accept a high degree of risk in exchange for therapeutic benefit. In an attempt to quantify patients’ risk tolerance, researchers from the Cleveland Clinic surveyed 128 patients who had planned to begin taking natalizumab before its withdrawal. Because 2 of the aforementioned PML cases in natalizumab trials were fatal, the survey focused on what patients considered an acceptable risk of death in exchange for symptom relief, delayed disease progression, or cure.⁶ The survey results, presented at the AAN meeting, confirm what many neurologists have reported anecdotally. Although 18% of patients said that they were unwilling to accept any risk of death, 14% said that they would accept a risk as high as 1-in-2 in exchange for a cure. Patients in the Cleveland Clinic study said they would be willing to accept a risk of death of 1 in 1000 in exchange for a two-thirds reduction in relapse rate and a 42% slowing of disability rate, which were the mean response rates that were reported in the phase 3 AFFIRM (Natalizumab Safety and Efficacy in Relapsing-Remitting MS) trial.⁷ Those who expressed the highest levels of risk tolerance were those with high levels of disability, low self-reported quality of life, and no dependents at home. The Cleveland Clinic study, of course, was focused on a single potential complication of a particular drug in patients who had reason to believe that the drug would help them; other patients with MS may have different levels of risk tolerance for other drugs associated with other adverse effects. But physicians acknowledge that they don’t always see eye to eye with patients about what constitutes an acceptable level of risk.

“I think it depends on the patient’s perception of how they’re doing,” said Patricia K. Coyle, MD, professor and acting chair of neurology at Stony Brook University Medical Center and director of the Stony Brook Multiple Sclerosis Comprehensive Care Center in Stony Brook, New York. “A patient with MS who is clearly deteriorating as far as she’s concerned and is not responding to treatment is generally willing to take greater risk than someone who is feeling well.”

NEW RULES FOR NATALIZUMAB
Since its withdrawal in 2005, natalizumab has come to symbolize the risks associated with immunosuppressive MS therapy—although interestingly, some researchers suspect that the risk of PML associated with natalizumab actually may not be related to diminished immunosurveillance.⁸ The FDA authorized the drug’s return to market in June 2006 under specific conditions.

Because the clinical trial in which PML developed in 2 patients involved combination natalizumab and interferon beta 1a (IFN-β-1a, Avonex) therapy,⁹ natalizumab was to be used solely as a monotherapy. It was approved only for use in patients who had failed or who were ineligible for first-line treatment with interferons or glatiramer acetate (Copaxone), and it only may be used by physicians and patients who enrolled in the Tysabri Outreach: Unified Commitment to Health (TOUCH) risk-management program, which emphasizes physician training, patient education, and periodic monitoring. Beyond the 3 cases that led to the drug’s withdrawal (1 of which occurred in a patient with Crohn disease rather than with MS), no additional cases of PML have been reported in patients taking natalizumab.

Meanwhile, evidence of the drug’s clinical benefits continues to accumulate. The AFFIRM trial investigators recently reported10 on 2-year MRI outcomes for patients taking natalizumab versus outcomes for those taking placebo. This report provided more detail than the initial report on the AFFIRM trial.

Among the more recent findings were a 76% decrease in number of new lesions that were hypointense on T1-weighted scans relative to the number of new lesions in patients taking placebo, a 9.4% decrease in median T2-weighted hyperintense lesion volume (vs an 8.8% increase in the placebo group), and a 23.5% decrease in median T1-weighted hypointense lesion volume (vs a 1.5% decrease in the placebo group).

Researchers from the AFFIRM and SENTINEL (Safety and Efficacy of Natalizumab in Combination with Avonex) trials reported that natalizumab was associated with significantly reduced levels of vision loss.¹¹ In the AFFIRM patient population, those taking natalizumab were 35% less likely than those taking placebo to experience clinically significant vision loss (defined as a 2-line worsening of visual acuity score) at a contrast level of 1.25%. In the SENTINEL study population, the risk was reduced by 28% for those taking natalizumab plus IFN-β-1a compared with those taking IFN-β-1a alone.

Further analysis of the AFFIRM vision data, presented at the AAN meeting,12 found that even patients considered treatment failures—those who experienced 12 weeks of sustained disability progression as measured using the Expanded Disability Status Scale—were significantly less likely to suffer concurrent vision loss if they were treated with natalizumab than with placebo.

The clinical benefits associated with natalizumab, in turn, improve patients’ quality of life, according to another analysis of both the AFFIRM and SENTINEL data presented at the AAN meeting.¹³ In the AFFIRM trial, patients treated with natalizumab were significantly more likely than those in the placebo group to experience clinically important improvement (a change of 0.5 SDs) on the physical component summary of the Short Form-36 (SF-36) health survey after 104 weeks. In the SENTINEL trial, those who received combination therapy were more likely to experience a similar degree of improvement than those treated with IFN-β-1a alone. Natalizumab also was associated with trends toward significant improvement on the mental component summary of the SF-36. Contributing to improvements in quality of life may be issues of convenience; natalizumab is administered only once per month, whereas other drugs require several injections or more per week.

Still, despite all of the positives, any professional discussion of natalizumab inevitably returns to the risk of PML—which is of particular concern because the differential diagnosis of PML in patients with MS is so difficult.

“PML produces lesions of brain and neurological abnormalities that can be very hard to sort out from MS, at least early on,” Coyle said.

Frohman, for one, said he does not consider natalizumab to be the best treatment option for patients who have failed interferons or glatiramer acetate.

“I’m very cautious,” he said. “I have to ask myself, if this were my wife or my daughter, would I treat them with this drug?”