Tysabri® (natalizumab)

FDA-Approved Medications: Administered by Intravenous (IV) Infusion

Company: Biogen and Elan Pharmaceuticals, Inc.

  • Administered via intravenous infusion every four weeks in TOUCH program-authorized infusion centers; dose is 300 mg
  • Approved for individuals with relapsing types of MS

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This drug was originally recommended for patients who have not responded adequately to, or who cannot tolerate, another treatment for MS, although its use is evolving through new study findings as specified in the FDA’s label changes, described later in this section.

This laboratory-produced monoclonal antibody acts against a molecule involved in the activation and function of lymphocytes (immune-system cells produced to fight infection and disease) and their migration into the central nervous system (CNS).

A pivotal trial of Tysabri showed that this agent substantially reduces clinical and MRI activity in relapsing MS. Recent studies with Tysabri indicate that the drug may achieve a sustained improvement in disability for individuals with relapsing-remitting MS (RRMS). At 18 months and up to 24 months of treatment with Tysabri, 87 percent of RRMS patients previously treated with Avonex showed stable or improved MRI scans. In this same group, disability scores as measured by the Expanded Disability Status Scale (EDSS) were stable or improved in 59 percent of patients.

A Phase IV trial, The Randomized Treatment Interruption of Natalizumab (RESTORE)22 study, evaluated the impact of stopping Tysabri and switching to other disease-modifying therapies. This study enrolled 175 patients and found a high rate of recurrence of MS disease activity, both in terms of relapses and new lesions on MRI, beginning about three months after Tysabri was stopped. This study provides important information, especially for people on Tysabri who are weighing the risks and benefits of stopping this drug – particularly in light of PML risk.

Progressive Multifocal Leukoencephalopathy (PML)

Tysabri has been increasingly utilized as a disease-modifying therapy in RRMS, though clinical use of this drug has been limited from the outset by the risk of progressive multifocal leukoencephalopathy (PML). PML is a viral brain infection caused by the JC virus, which, when not discovered and treated early, can typically lead to severe disability or death. Many people are exposed to the JC virus (JCV), which typically remains dormant; however, it may become activated and infect the brain when one’s immune system becomes weakened, a condition that may result from immunosuppressive drugs.

Once projected as a universal risk of approximately 1 in 1,000, based on Tysabri’s pivotal trial data, new data presented and published in 2012 allow for the risk of Tysabri-associated PML to be estimated for each individual with increasing precision.

Three risk factors for Tysabri-associated PML have since been identified, allowing for the classification of individuals according to their relative risk of PML.23 The most important risk factor is the presence of JC-virus antibodies. Roughly 50-to-60 percent of adults carry the JCV antibodies, which can now be determined by a simple blood test.

The JCV Antibody Program (STRATIFY-2) began in April 2010, enrolling more than 30,000 people with MS, and will continue for several more years. Testing for JCV antibodies was added to the FDA label for Tysabri in 2012. The JCV antibodies assay is available through Quest Diagnostics, at no charge to patients if ordered with the “STRATIFY JCV™” test form (available from Quest and Biogen). People testing negative for JCV antibodies are at risk for becoming JCV-positive by approx-imately 2-to-3 percent per year. Current recommendations are to re-test JCV antibodies status every six months in JC-virus negative people on Tysabri therapy. Some neurologists may opt to test JC-virus status more frequently, though this goes beyond the current FDA guidance.

The second risk factor for the development of Tysabri-associated PML is the duration of Tysabri treatment. Risk for PML in JCV-positive people increases the longer Tysabri is used. The risk is small in the first year of treatment with Tysabri, likely less than 1 in 1,000. In the second year, this increases to approximately 1 in 500, and beyond two years on Tysabri, the risk increases further.

The third risk factor for the development of Tysabri-associated PML is prior treatment with immune-suppressing medications such as Cytoxan® (cyclophosphamide), Novantrone (mitoxantrone), or other chemotherapy agents. Standard injectable MS disease-modifying therapies (interferons and Copaxone, listed earlier) are not considered immune suppressants, and use of these prior to Tysabri does not increase the risk of PML.

As of Fall 2014, approximately 517 cases were reported of PML24 with Tysabri, while more than 130,000 people have been treated with this medication. The FDA labeling of Tysabri has been updated to further quantify the risk. The new labeling also notes the increased risk from previous use of immunosuppressive medications.

Although PML is always serious, it is no longer always fatal. Early recognition and the quick removal of Tysabri using a procedure called plasmapheresis have improved the outcomes. Early PML diagnosis and treatment increases the survival rate to 80 percent (although often with disability).

In December 2013, the FDA approved a label change for Tysabri. Some of the more notable changes include: indications of approval for first, second, and third-line therapy are the decision of the provider; updated data includes patients on treatment for up to six years; an increased risk of developing herpes encephalitis and meningitis – patients need to be instructed by the provider to immediately report if they experience fever, headache, or confusion; and one patient with acute liver failure is noted.

Current Study Information

As the use of Tysabri in early MS has not been widely studied, 300 individuals with early RRMS who are JC virus antibody-negative will be followed over the course of four years while undergoing treatment with Tysabri.25 One purpose of the study is to find out how effective Tysabri is at keeping patients who are in the early stages of RRMS free of disease. This study is expected to run through the end of 2016.

Final results of the Tysabri 24 PLUS study were presented in 2013. In this observational study, the clinical course of patients with RRMS receiving Tysabri for more than two years was assessed. Patients experienced reductions in relapse rates of more than 90 percent compared to their status before treatment. Eighty percent of patients experienced no relapses during the entire observation period after baseline. The mean EDSS scores remained stable at the level observed before the start of treatment. Safety data, including the number of cases of progressive multifocal leukoencenphalopathy (PML) were consistent with the known safety profile of Tysabri.

A small Phase II clinical trial, Natalizumab Treatment of Progressive Multiple Sclerosis (NAPMS), was performed at Copenhagen University Hospital to study the safety and efficacy of Tysabri treatment of PPMS and secondary-progressive MS (SPMS).26 It enrolled 24 patients and showed a reduction in markers of inflammation in the spinal fluid, as well as evidence of protection of brain tissue on modern MRI measures. This proof-of-concept study provides encouraging evidence that Tysabri may have beneficial effects in progressive forms of MS.

To continue this line of investigation, a large, randomized trial of Tysabri in SPMS called ASCEND27 is ongoing, and will evaluate the effects on the accumulation of disability in people with SPMS. As of Fall 2013,28 all 889 SPMS patients have been enrolled. This trial is expected to conclude in 2015.

A small study of 20 individuals with RRMS29 is evaluating the role of Tysabri on cognition and neurodegeneration (the breakdown or cell death of nerve cells). Its objective is to further establish the role of Tysabri in preventing neurodegeneration in MS and to establish new markers for such damage. This study is expected to conclude in 2016.

Other studies are exploring the effects of Tysabri on ambulation (walking and mobility), cognition, fatigue, depression, bladder function, sexual function, disability, and health-related quality of life. Some of these studies are completed with generally favorable results. One study indicated that Tysabri-treated patients had fewer MS-related hospitalizations and emergency-room visits over one year of treatment, suggesting that it may reduce the economic burden of MS.

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