 | Since August, the alpha-4-integrin inhibitor natalizumab (TYSABRI) is again on the market for monotherapy of multiple sclerosis (MS). The monoclonal antibody is licensed only for patients with severe remitting-relapsing MS who have suffered at least two relapses with progressive disability or one relapse despite beta-interferon treatment and who have evidence of distinct MS-specific MRI.
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| Restriction of indication and limitation to monotherapy were imposed because cases of progressive multifocal leukoencephalopathy (PML) occurred, sometimes with fatal outcome, in clinical studies of combined use of natalizumab with interferon beta-1a (AVONEX) or when there was previous treatment with various other immunosuppressants.
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| The narrowing of the indication ordered now and not planned originally means that there are no clinical studies showing efficacy or evidence of benefit of natalizumab for the therapeutic indications which are licensed now.
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| Natalizumab was tested as single agent in MS patients, over 90% of whom had not been treated before with any immune modulator drug and who most often show only minimal to moderate disability after an average disease duration of five years. In these patients, the drug reduces the relapse rate as well as the progression of disability.
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| Prescribing and treatment with natalizumab is restricted to experienced doctors in centres with MRI access and linked to regular monitoring for early identification of PML. However, it is unknown whether these measures are suitable to protect against the dangerous effect of the drug.
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| Further severe infections (including opportunistic infections with fatal outcome) are to be expected. Antibodies to natalizumab and systemic hypersensitivity reactions are common. A carcinogenic risk cannot be ruled out.
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| As proof of efficacy for the licensed indication is lacking and the observed deadly risks cannot be foreseen, the use of the toxic drug cannot - in our view - be allowed for an uncontrolled field trial.
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| For ethical reasons, we regard its use as justified only in the framework of valid randomised controlled studies to elucidate the efficacy and safety of the monotherapy with the drug in patients for whom it is licensed.
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