PML Complicating Treatment with Natalizumab (Tysabri) for MS

Abstracts & Commentary

By Brian R. Apatoff, MD, PhD, Director, Multiple Sclerosis Clinical Care and Research Center, Department of Neurolgy and Neuroscience, NewYork-Presbyterian Hospital, Cornell Campus. Dr. Apatoff is on the speaker’s bureau of Biogen and Teva.

Synopsis: These 2 cases demonstrate a tragic complication of natalizumab therapy in this promising novel immune modulatory therapy, and the difficulties of predicting late stage drug failures in the difficult and costly process of drug development.

Sources: Langer-Gould A, et al. Progressive Multifocal Leukoencephalopathy in a Patient Treated With Natalizumab. N Engl J Med. 2005;353:375-381; Kleinschmidt-DeMasters BK, et al. Progressive Multifocal Leukoencephalopathy Complicating Treatment With Natalizumab and Interferon Beta-1a for Multiple Sclerosis. N Engl J Med. 2005;353: 369-374.

Two case reports of progressive multifocal leukoencephalopathy (PML) complicating treatment of multiple sclerosis (MS) with natalizumab were studied in a phase III clinical trial that had led to the early FDA approval on the basis of one year safety-efficacy data. Natalizumab is a monoclonal antibody against an alpha-4 integrin adhesion molecule on lymphocytes that prevents normal attachment on the vascular endothelium of the blood brain barrier and limits trafficking into the central nervous system. It was shown to be highly effective in phase II and phase III clinical trials in reducing clinical and MRI measures of MS disease activity (see Neurology Alert. February, 2005)

The first patient was a 45-year-old man with relapsing-remitting MS diagnosed in 1983, treated interferon beta-1a since 1998, who was treated with monthly infusions of natalizumab for 28 months. The first PML lesion seen on MRI was thought to be indistinguishable from a MS lesion, but PML was confirmed ultimately by brain biopsy. The patient deteriorated quickly, becoming quadraparetic and minimally responsive despite treatment with corticosteroids, IVIG, and cidovir. Three months after discontinuing natalizumab, he developed changes thought to be consistent with an immune-reconstitution inflammatory syndrome. Two additional months after treatment with cytarabine, his condition had improved.

The second patient was a 46-year-old woman diagnosed with relapsing-remitting MS in 1999, treated with weekly interferon beta-1a since 2000, and then treated with 37 monthly doses of natalizumab. She developed a rapidly progressive right hemiparesis and aphasia that was treated with IV corticosteroids. PML was confirmed on autopsy.

Commentary

These 2 cases demonstrate a tragic complication of natalizumab therapy in this promising novel immune modulatory therapy, along with the difficulties of predicting late stage drug failures in the difficult and costly process of drug development. PML is typically a consequence of profoundly impaired cellular immunity, such as seen in AIDS, leukemia, or chronically immunosuppressed organ-transplant recipients. The only effective treatment for PML is immune-reconstitution, for example, with strong anti-retroviral therapy, in the case of HIV infection, to allow for recovery of T-cells.

Questions remain about the potential use of natalizumab in the future, given that the drug was shown to be safe and highly effective in clinical trials in which several hundred patients were dosed. Could the drug be used with relative safety, with more limited dosing regimens of possibly 12 months, since both PML cases were treated for over 2 years before their adverse event was detected? However, a third case of PML occurred in a patient that received just 8 doses of natalizumab for Crohn’s disease, but who was on additional immunosuppressives including azathioprine (N Engl J Med. 2005; 353:362-368). Both MS cases of PML were detected in a clinical trial combining natalizumab and interferon beta-1a, but none in a monotherapy trial for MS with natalizumab alone. Did interferon beta-1a increase the relative risk of acquiring PML, possibly inducing mild lymphopenia, or by additional reduction of T-cells trafficking across the blood-brain barrier? If the drug is allowed to be given in limited dosing regimens, for example in patients with severe MS refractory to other treatments, could it be re-dosed after an acceptable period of time to allow for immune recovery? These and other complicated questions will be addressed by the FDA in the months ahead.