GAITHERSBURG, MD. — Clinical vigilance for early signs of progressive multifocal leukoencephalopathy is a cornerstone of the mandatory risk minimization plan that will be in place for natalizumab's return to the market for treating patients with relapsing forms of multiple sclerosis.
The Food and Drug Administration is expected to follow the recommendation of its advisory panel this month to approve the supplemental application for natalizumab, with a stringent risk management plan in place that includes mandatory enrollment of physicians and patients in a registry, and a monthly pre-infusion checklist with questions designed to pick up any neurologic symptoms that could be signs of progressive multifocal leukoencephalopathy (PML).
Natalizumab, an immune-modulator marketed as Tysabri, was taken off the market in February 2005—3 months after its approval for management of relapsing MS—after it was linked to PML, a rare, usually fatal demyelinating CNS infection, in three patients. Immunosuppression in transplant recipients or other patients with compromised immune systems is associated with activation of the usually latent human polyomavirus—JC virus—that can cause PML.
At a meeting of the Food and Drug Administration's Peripheral and Central Nervous System Drugs Advisory Committee, members unanimously agreed that natalizumab should become available again—considering the currently available safety data—and that its use should be limited to patients with relapsing features of the disease, and only as monotherapy. Although the two cases of PML were in MS patients on interferon beta-1a (Avonex), and the third was in a patient with Crohn's disease who had recently been on immunosuppressive agents, the panel was not convinced that the risk was limited only to patients who were taking or had recently been taking another immunosuppressive drug..
The panel did not specify a minimal or maximal degree of disability that would be required for use, but panel members supported plans for the risk minimization program, with some caveats and differences of opinion about certain elements of the program. The panel also unanimously agreed that the manufacturers had demonstrated that natalizumab was effective in reducing the frequency of relapse and the accumulation of physical disability through 2 years. The FDA usually follows the advice of its advisory panels.
Administered in a monthly infusion, natalizumab—a selective adhesion-molecule inhibitor—is thought to work by inhibiting the migration of leukocytes to sites of inflammation within the CNS. In February 2005 the drug was taken off the market, and ongoing trials in MS, rheumatoid arthritis, and Crohn's disease were halted, when the two PML cases were reported. The third case was then identified in a patient in a Crohn's disease trial; the patient had died of what was thought to be an astrocytoma, but was discovered to be PML on follow-up.
At that time, the degree of risk was uncertain. More than 3,000 patients who had been exposed to a mean of 18 monthly doses of natalizumab underwent evaluations, which included MRIs and testing of CSF for JC virus DNA. No new cases of PML were found, and the risk of PML was estimated at 1 in 1,000. But whether the risk changes after 3 years of treatment is not clear; this uncertainty will be addressed in the mandatory registry of all patients and prescribing physicians, which is aimed at determining the incidence and risk factors for PML and other serious opportunistic infections.
During a press conference held at the meeting, Dr. Russell Katz, director of the FDA's neuropharmacological drug products division, pointed out that very little is known about the risk of PML after 3 years of treatment. The hope is that by enrolling patients in the risk management program, “we'd quickly learn if [the risk] increases after 3 years.” Currently, there is no solid evidence that detecting PML early will affect outcome, although there are good reasons to detect it early, he added.
“We believe clinical vigilance by the neurologist is the most important means of screening,” and that monthly interactions between the health care provider and patients before infusions will enhance this vigilance, Dr. Michael Panzara, vice-president of neurology at Biogen Idec, told the panel. He said that the three patients with PML had clinical signs early in the course that had been noticeable to them, or to family members or their clinicians, but that the symptoms had been attributed to MS.
Under the terms of the proposed registry, enrolled physicians will be required to report any PML case to Biogen Idec immediately, and physicians will be queried every 6 months by the company about any patient deaths, discontinuations of treatment, or PML cases. If physicians do not comply, their enrollment in the program and access to natalizumab will be discontinued, according to Dr. Carmen Bozic, senior director of drug safety and risk management at Biogen Idec.
Other elements of the risk minimization plan include mandatory registration of infusion centers and physician offices where infusions are administered; a controlled centralized distribution system, which would ship Tysabri vials only to the registered and compliant infusion centers and physicians; and a mandatory patient-physician informed consent form. Before each infusion, the administering nurse is required to give the patient a medication guide explaining the risk of PML and other safety issues and instructions to report any new or continuously worsening neurologic symptoms.
The nurse is also to review a checklist with questions designed to detect any new or worsening neurologic symptoms that could be early signs of PML or other opportunistic infections, which would prompt immediate discontinuation of treatment and evaluation for PML.
Under the risk minimization plan, any clinical change in a treated patient “will be viewed as PML until proven otherwise,” and will result in stopping treatment and a full evaluation, Dr. Panzara said.
However, whether early identification can affect the course of PML remains unclear. There is some evidence from experience with the HIV population and transplant patients that suggests that early recognition and discontinuation of immunosuppressive therapies can improve survival, he said.
Despite some initial optimism that plasma JC viral DNA levels would be useful in detecting PML early, its sensitivity and positive predictive values are uncertain, and while CSF testing for JC virus is specific at the time of diagnosis, the literature indicates that it tends to be negative in early disease and it is invasive; so it is not considered to be a good screening tool, he explained.
The company will also conduct an observational cohort study of a subset of patients in the registry. The cohort study will enroll 5,000 MS patients who will be followed for 5 years, to collect data on PML and rare events.
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