One of the most talked about issues in multiple sclerosis circles is the role of Tysabri (natalizumab) and its association with progressive multifocal leukoencephalopathy (PML). The benefits of the drug are clear, as evidenced by some of the pleas from patients to bring it back after the FDA temporarily sidelined it briefly last decade. But what remained less apparent is when physicians could confidently administer the drug with diminished odds of MPL.

The New England Journal of Medicine recently published research from Biogen Idec and Elan’s global risk management program that updates the risk of Tysabri (natalizumab)-associated PML, an infrequent but serious brain infection that usually leads to death or severe disability, in people with multiple sclerosis (MS). The researchers looked at three risk factors associated with a patient’s PML risk: anti-JC virus (JCV) antibody status, use of immunosuppressant (IS) therapy prior to Tysabri initiation, and longer duration of treatment with Tysabri.

They concluded that the risk of PML increased with longer duration of Tysabri treatment, with the greatest increase in risk observed after two years of natalizumab therapy. Data beyond four years of therapy were limited. Prior immunosuppressant (IS) use was more common in patients who developed PML (34.5 percent) compared to patients in the global TYGRIS study (20.3 percent), indicating that prior IS use was associated with an increased risk of PML.

The prevalence of anti-JCV antibodies in the general MS population was 54.9 percent (95% confidence interval [CI], 53.7 – 56.2) and differed from the 100 percent anti-JCV antibody positivity observed in the 54 MS patients who developed PML and had known pre-PML anti-JCV antibody status. Because all 54 MS patients with known pre- PML anti-JCV antibody status tested positive, a sensitivity analysis assuming one hypothetical anti-JCV antibody negative PML patient was used to estimate the PML risk in antibody negative patients. Anti-JCV antibody status, combined with prior IS use and Tysabri treatment duration were used to stratify patients at lower or higher risk for the development of PML. “There was an approximately 120-fold difference between patients in the lowest and highest risk groups,” the companies noted in a release. “Patients who were anti-JCV antibody negative were at the lowest risk for PML with an estimated risk of 0.09 cases or fewer per 1,000 patients (95% CI, 0 to 0.48).”

The highest risk of PML was found in patients who had received 25 to 48 months of TYSABRI treatment, had been treated with an IS therapy before TYSABRI treatment was initiated, and were positive for anti-JCV antibodies. The PML incidence in this group was estimated to be 11.1 cases per 1,000 patients (95% CI, 8.3 to 14.5).

Practical Neurology recently spoke with Robert J. Fox, MD, a Staff Neurologist and Medical Director of the Mellen Center for Multiple Sclerosis at Cleveland Clinic, about the study. Dr. Fox did not have a role in the NEJM publication.

What should neurologists take away from the update published in the New England Journal of Medicine? Can you talk about the quantitative risk stratification algorithm?

RJF: The main take-away is that natalizumab is a different drug for different patients. When the risk of PML is 11.1 per 1000 (or 1 in 90) in one patient, and <0.09 in 1000 (or 1 in 10,000) in another patient, it’s clearly a different drug to different patients. Of note, I think the numbers in the NEJM paper are a little hard to interpret the way they’re presented. We created a display (Neurology; 78:436- 437), which I think is easier for neurologists (and patients) to appreciate. With these three risk factors, we can tailor the risk of PML to an individual patient, which can help guide treatment recommendations. This provides us with a clear pathway towards personalized medicine: tailoring treatment recommendations to the specific patient sitting in front of me. It’s not what we traditionally think about in personalized medicine: “Which drug will work best in this specific patient?” But instead is tailoring based on risk: “Which drug has less risk in this specific patient?”

The risk factor of “duration of therapy” may pose challenges for some patients and physicians. What should physicians and patients make of this and how should it affect patients’ approach to their MS treatment regimen?

RJF: Well, it is what it is: with this drug, the risk of PML in the first year (regardless of risk factors) is extremely low. The risk in later years gradually increases, until it plateaus around three years. There are many patients who may go it in initially, and then they turn out to be JCV seropositive, and so after 18-24 months decide (with a discussion with their care provider) that they want to transition to an alternative therapy.

Where do you think Tysabri fits in given the approval of Gilenya and other drugs in the pipeline? Given known, though apparently predictable, risks with Tysabri, will it be worth using when other options emerge?

RJF:Each patient is evaluated separately, factoring in the severity of disease (most believe natalizumab is more effective than other currently-available therapies); response to previous therapies; risk factors for the different drugs (immunosuppression and JCV serology for natalizumab; heart arrhythmia and diabetes for fingolimod; uncontrolled depression for interferons, etc.); and the patient’s (and clinician’s) tolerance for risk.

Clearly, natalizumab has an important role, and so does fingolimod, and so will the future oral drugs in development.

Tysabri’s timeline is accentuated by market removal and thoughts that it might be finished for good, but now has been called “the model for facing a drug safety crisis.” To what do you attribute the drug’s revival and success?

RJF:That’s easy: natalizumab is a highly effective therapy— the most effective therapy currently available. When the therapy is highly effective, without equivalent alternatives, and the disease is as destructive as MS is, then there’s interest among patients and physicians to tolerate risks for the benefits of the treatment.

I don’t know who said natalizumab was finished for good, but I don’t think it was either neurologists or patients.