Natalizumab
This drug is an important addition to the therapies available for treating serious, active MS, although there are still safety concerns despite its approval for use by the FDA in the United States in 2006. It was originally marketed under the trade name of Antegren, but more recently Tysabri. Natalizumab works by specifically targeting and inhibiting a protein, alpha 4 integrin, which is present on the surface of immune system cells and helps them attach to blood vessel walls and get into the brain. It has been used in the animal model of MS where it is effective and in studies in humans. Recent animal work shows that inhibition of alpha integrin allows remyelination to occur, as well as inhibiting demyelination.1 The difficulty with using drugs of this type is that they don’t just affect the immune response in MS, but in all conditions where the immune response is required. As a result, they tend to cause other problems related to underactivity of the immune system.
Initially, a RCT published in 2003 in the New England Journal of Medicine2 randomly assigned 213 patients to receive a low dose or high dose of natalizumab, or placebo. The drug was given IV and administered once every four weeks for six months. Patients were followed with MRI scanning and clinical assessment. The placebo patients had on average nearly 10 new brain lesions at the end of the six months, compared with 0.7 for the low dose group and just over 1 new lesion for the high dose group. Twice the number of patients in the placebo group had relapses than in either of the treatment groups. Those taking the drug generally reported improvement in their sense of well-being, and those in the placebo group the reverse. This suggests the drug is quite well tolerated and side effects are not too unpleasant.
At the meeting of the American Academy of Neurology in Honolulu in 2003, findings were presented on a number of related drugs, which also proved beneficial for people with MS. The drug alemtuzumab was shown to have significant benefit for relapsing-remitting MS although not secondary progressive MS. Unfortunately side effects were a major problem, with a third of patients treated developing a severe thyroid disorder, Graves Disease. Nevertheless, a large international trial of this drug in combination with Rebif, one of the interferons, is now underway. Another related drug, daclizumab, looked a more promising option. Two US groups reported results in 10 and 11 patients with relapsing-remitting and secondary progressive MS, either alone or in combination with interferon beta, with dramatic effects on MRI-demonstrated disease activity. One group found no new lesions and the other an over 70% reduction in the number of lesions.
The natalizumab story has been soured however by the events which led to the FDA in America fast tracking the drug to general use in November 2004, only to be forced to remove it three weeks later because of safety concerns. Unexpectedly, two patients who had taken natalizumab in combination with an interferon in MS trials developed a condition called progressive multifocal leukoencephalopathy (PML), an illness similar to very aggressive MS, and previously only ever reported in AIDS patients. Shortly after, a third patient, taking natalizumab alone in a trial for inflammatory bowel disease, also died of the illness. Following suspension, there was very careful investigation of all patients who had taken the drug in clinical trials to see if there were other cases of PML which had not been reported.3 This detailed review revealed no new cases, and concluded that the risk of PML was about 1 in 1,000 for patients treated for about 18 months. The longer term risk was unknown.
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At the meeting of the American Academy of Neurology in Honolulu in 2003, findings were presented on a number of related drugs, which also proved beneficial for people with MS. The drug alemtuzumab was shown to have significant benefit for relapsing-remitting MS although not secondary progressive MS. Unfortunately side effects were a major problem, with a third of patients treated developing a severe thyroid disorder, Graves Disease. Nevertheless, a large international trial of this drug in combination with Rebif, one of the interferons, is now underway. Another related drug, daclizumab, looked a more promising option. Two US groups reported results in 10 and 11 patients with relapsing-remitting and secondary progressive MS, either alone or in combination with interferon beta, with dramatic effects on MRI-demonstrated disease activity. One group found no new lesions and the other an over 70% reduction in the number of lesions.
The natalizumab story has been soured however by the events which led to the FDA in America fast tracking the drug to general use in November 2004, only to be forced to remove it three weeks later because of safety concerns. Unexpectedly, two patients who had taken natalizumab in combination with an interferon in MS trials developed a condition called progressive multifocal leukoencephalopathy (PML), an illness similar to very aggressive MS, and previously only ever reported in AIDS patients. Shortly after, a third patient, taking natalizumab alone in a trial for inflammatory bowel disease, also died of the illness. Following suspension, there was very careful investigation of all patients who had taken the drug in clinical trials to see if there were other cases of PML which had not been reported.3 This detailed review revealed no new cases, and concluded that the risk of PML was about 1 in 1,000 for patients treated for about 18 months. The longer term risk was unknown.
At around the same time, two further papers were published on the benefits of natalizumab in MS, one with natalizumab in combination with an interferon, the other alone. The former was the trial in which the two cases of PML were initially discovered.4 It showed that the combination of natalizumab and interferon was significantly better than interferon alone, with the annual relapse rate dropping to 0.34 per year on the combination, compared with 0.75 on the interferon alone, and less progression to disability. In the latter study, 627 patients receiving natalizumab alone had a 68% reduction in annual relapse rate, as well as less progression to disability than those receiving placebo.5 More recent MRI studies confirm that natalizumab is highly effective at preventing new MRI lesions, with between 76% and 92% fewer lesions (depending on lesion type) in those on natalizumab versus placebo.6
Recent updates from the company, reported through the National Multiple Sclerosis Society website late October 2009 (http://www.nationalmssociety.org/news/news-detail/index.aspx?nid=2308) reveal that, out of the 60,700 people worldwide receiving the drug, there have now been 24 cases of PML occurring in both men and women receiving Tysabri from one year to three and a half years, with an average of two years. It was reported that 16 cases occurred in Europe, and 8 in the United States, and 4 of the 24 died. The degree of disability in the 20 survivors ranges from some who have recovered enough to return to work, and at the other extreme, some markedly disabled and confined to bed, requiring extensive assistance with activities of daily living.
It is important that people taking this drug and their doctors be vigilant for any occurrence of new, unusual symptoms that might indicate PML. It is currently impossible to predict who will get PML, although half of the people who developed PML had histories of having been on immunosuppresive therapies, such as mitoxantrone, azathioprine or methotrexate.
When PML was suspected, Tysabri infusions were stopped. There is no treatment for PML, but once the drug is stopped, as the immune system begins to recover, a condition called IRIS (immune reconstitution inflammatory syndrome) usually occurs about 4 weeks later.
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Recent updates from the company, reported through the National Multiple Sclerosis Society website late October 2009 (http://www.nationalmssociety.org/news/news-detail/index.aspx?nid=2308) reveal that, out of the 60,700 people worldwide receiving the drug, there have now been 24 cases of PML occurring in both men and women receiving Tysabri from one year to three and a half years, with an average of two years. It was reported that 16 cases occurred in Europe, and 8 in the United States, and 4 of the 24 died. The degree of disability in the 20 survivors ranges from some who have recovered enough to return to work, and at the other extreme, some markedly disabled and confined to bed, requiring extensive assistance with activities of daily living.
It is important that people taking this drug and their doctors be vigilant for any occurrence of new, unusual symptoms that might indicate PML. It is currently impossible to predict who will get PML, although half of the people who developed PML had histories of having been on immunosuppresive therapies, such as mitoxantrone, azathioprine or methotrexate.
When PML was suspected, Tysabri infusions were stopped. There is no treatment for PML, but once the drug is stopped, as the immune system begins to recover, a condition called IRIS (immune reconstitution inflammatory syndrome) usually occurs about 4 weeks later.
- Piraino PS, Yednock TA, Messersmith EK, et al. Spontaneous remyelination following prolonged inhibition of alpha(4) integrin in chronic EAE. J Neuroimmunol 2005
- Miller DH, Khan OA, Sheremata WA, et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2003; 348:15-23.
- Yousry TA, Major EO, Ryschkewitsch C, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med 2006; 354:924-933
- Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 2006; 354:911-923
- Polman CH, O\‘Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006; 354:899-910
- Miller DH, Soon D, Fernando KT, et al. MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS. Neurology 2007; 68:1390-1401
- Engelhardt B, Briskin MJ. Therapeutic targeting of alpha4-integrins in chronic inflammatory diseases: tipping the scales of risk towards benefit? Eur J Immunol 2005
- Schipper JP. [Natalizumab in multiple sclerosis: unclear patient benefits]. Ned Tijdschr Geneeskd 2007; 151:852-855
- Vermeulen M. [Still no evidence on the efficacy of immunomodulatory therapy in reducing functional impairment in multiple sclerosis]. Ned Tijdschr Geneeskd 2007; 151:850-851
- Chen Y, Bord E, Tompkins T, et al. Asymptomatic reactivation of JC virus in patients treated with natalizumab. N Engl J Med 2009;361(11):1067-74
- Piraino PS, Yednock TA, Messersmith EK, et al. Spontaneous remyelination following prolonged inhibition of alpha(4) integrin in chronic EAE. J Neuroimmunol 2005
- Miller DH, Khan OA, Sheremata WA, et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2003; 348:15-23.
- Yousry TA, Major EO, Ryschkewitsch C, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med 2006; 354:924-933
- Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 2006; 354:911-923
- Polman CH, O\‘Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006; 354:899-910
- Miller DH, Soon D, Fernando KT, et al. MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS. Neurology 2007; 68:1390-1401
- Engelhardt B, Briskin MJ. Therapeutic targeting of alpha4-integrins in chronic inflammatory diseases: tipping the scales of risk towards benefit? Eur J Immunol 2005
- Schipper JP. [Natalizumab in multiple sclerosis: unclear patient benefits]. Ned Tijdschr Geneeskd 2007; 151:852-855
- Vermeulen M. [Still no evidence on the efficacy of immunomodulatory therapy in reducing functional impairment in multiple sclerosis]. Ned Tijdschr Geneeskd 2007; 151:850-851
- Chen Y, Bord E, Tompkins T, et al. Asymptomatic reactivation of JC virus in patients treated with natalizumab. N Engl J Med 2009;361(11):1067-74