A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis
Polman CH, O'Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, et al.;
Commented by , 24 Aug 2006
Natalizumab is an a4 integrin antagonist that attenuates the inflammatory process in multiple sclerosis (MS) by inhibiting migration of lymphocytes to the CNS. Furthermore, natalizumab modulates survival, priming and activation of leukocytes that have already gained access to the CNS.
The drug was approved by FDA after 1-year of a phase III clinical trial but was withdrawn three months later caused by 2 cases of progressive mulifocal leukoencephalopathy (PML).
Natalizumab have now been re-approved by the FDA as well as the EMEA and the current study reports the final results of the phase III trial.
To investigate efficacy and safety of natalizumab in relapsing remitting MS (RRMS) in a randomized placebo-controlled trial.
Twenty-nine clinical centers enrolled 942 patients with RRMS, who were randomly assigned (2:1 ratio) to receive monthly doses of 300 mg natalizumab (n=627) or placebo (n=315) i.v. every four weeks for more than two years.
Clinical (EDSS), biochemical and MRI data were collected throughout the study.
Primary endpoints were rate of clinical relapse at 1 year and sustained disability at two years. A number of secondary endpoints were also measured.
Risk of sustained progression of disability in the Natalizumab group was reduced by 42% over two years (HR = 0.58; CI 0.43 – 0.77; p<0.001), and cumulative probability of progression was 17% in the Natalizumab group and 29% in the placebo group. Natalizumab reduced the rate of clinical relapses by 68% during the first year (p<0.001) and accumulation of new or enlarging T2 hyperintense lesions was reduced 83% over two years (p<0.001), Gd+ lesions was reduced 92%.
Adverse events were significantly more frequent in the Natalizumab group compared with placebo (fatigue 27% vs. 21%, allergic reactions 9% vs. 4%). Nine percent had detectable antibodies against natalizumab at some time and persistent antibodies developed in 6%, who also had increase in infusion related adverse events as well as loss of efficacy.
Dr Blinkenberg's comments
Natalizumab significantly reduces the risk of disability progression and relapse rate in patients with RRMS. These results seem more robust and convincing than other approved RRMS standard treatments (interferon-beta and glatiramer acetate) and the future use of Natalizumab looks promising.
There are some important concerns about safety that have to be addressed, since PML developed in three patients treated with natalizumab. Two of these had MS and received natalizumab in combination with interferon beta-1a (ref. 1) and one patient had Chron’s disease and was diagnosed with PML post mortem. A recent evaluation of patients treated with natalizumab in clinical trials (ref. 2) showed that there were no new cases of PML, suggesting that the risk of PML is approximately 1 in 1000 patients for a mean treatment period of 17.9 months.
It is important to note that the risk associated with long-term therapy is still unknown, and it is therefore not recommended to use natalizumab in large numbers of patients. Treatment with natalizumab should be restricted to patients who are not responding to standard immunomodulatory treatment or patients with aggressive RRMS, until more substantial safety data are available.
Another important problem is persistent antibodies against natalizumab, and since neutralizing capacity seem to be considerable and the risk of adverse events increased, treatment in these cases should be terminated.
1. Rudick RA, Stuart WH, Calabresi PA, Confavreux C, Galetta SL, Radue EW, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. New England Journal of Medicine 2006; 354 (9); 911-923
2. Yousry TA, Major EO, Ryschkewitsch C, Fahle G, Fischer S, Hou J, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. New England Journal of Medicine 2006; 354 (9); 924-933