Question

How did the regulatory agencies (EMA, FDA) handle natalizumab-associated Progressive multifocal leukoencephalopathy (PML) cases?

Answer 1

Ans.

Natalizumab, a monoclonal antibody directed against >4 integrins, has, to date, been associated with 399 cases of progressive multifocal leukoencephalopathy (PML) worldwide in patients receiving treat- ment for multiple sclerosis (MS).

Progressive multifocal leukoencephalopathy is a rare infection of the brain that is caused by the JC (John Cunningham) virus. People with a weakened immune system are most likely to get the disorder. People may become clumsy, have trouble speaking, and become partially blind, and mental function declines rapidly.

What are the symptoms of progressive multifocal leukoencephalopathy (PML)?

• Clumsiness or loss of coordination.
• Difficulty walking.
• Facial drooping.
• Loss of vision.
• Personality changes.
• Trouble speaking.
• Weak muscles.

Treatment of multiple sclerosis with natalizumab is complicated by rare occurrence of progressive multifocal leukoencephalopathy (PML). Between July, 2006, and November, 2009, there were 28 cases of confirmed PML in patients with multiple sclerosis treated with natalizumab. Assessment of these clinical cases will help to inform future therapeutic judgments and improve the outcomes for patients.

Recent developments: The risk of PML increases with duration of exposure to natalizumab over the first 3 years of treatment. No new cases occurred during the first two years of natalizumab marketing but, by the end of November, 2009, 28 cases had been confirmed, of which eight were fatal. The median treatment duration to onset of symptoms was 25 months (range 6-80 months). The presenting symptoms most commonly included changes in cognition, personality, and motor performance, but several cases had seizures as the first clinical event. Although PML has developed in patients without any previous use of disease-modifying therapies for multiple sclerosis, previous therapy with immunosuppressants might increase risk. Clinical diagnosis by use of MRI and detection of JC virus in the CSF was established in all but one case. Management of PML has routinely used plasma exchange (PLEX) or immunoabsorption to hasten clearance of natalizumab and shorten the period in which natalizumab remains active (usually several months). Exacerbation of symptoms and enlargement of lesions on MRI have occurred within a few days to a few weeks after PLEX, indicative of immune reconstitution inflammatory syndrome (IRIS). This syndrome seems to be more common and more severe in patients with natalizumab-associated PML than it is in patients with HIV-associated PML. WHERE NEXT?: Diagnosis of natalizumab-associated PML requires optimised clinical vigilance, reliable and sensitive PCR testing of the JC virus, and broadened criteria for recognition of PML lesions by use of MRI, including contrast enhancement. Optimising the management of IRIS reactions will be needed to improve outcomes. Predictive markers for patients at risk for PML must be sought. It is crucial to monitor the risk incurred during use of natalizumab beyond 3 years.

Symptoms can progress quickly over weeks and include mental deterioration, vision loss, speech disturbances, lack of coordination, paralysis, and coma. Specific symptoms relate to the affected areas of the brain by PML. Seizures can occur in 1 out of 5 people. How is PML diagnosed