MS Activity Returns Within 3 Months When Natalizumab Stopped

Daniel M. Keller, PhD

July 18, 2012

July 18, 2012 (Prague, Czech Republic) — Interrupting natalizumab (Tysabri, Biogen Idec Inc) treatment for patients with multiple sclerosis (MS) results in recurrence of clinical and magnetic resonance imaging (MRI)–documented disease activity, starting 12 to 16 weeks after the drug is stopped, even when patients are given other therapies.

Robert Fox, MD, medical director of the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic in Ohio, told delegates here at the 22nd Meeting of the European Neurological Society (ENS) that although natalizumab is an effective treatment for MS, the risk for progressive multifocal leukoencephalopathy (PML) increases with longer use of the drug in patients with antibodies to the JC virus, as well as with prior use of immunosuppressants.

Some previous small studies have suggested that stopping natalizumab for 3 or more months is associated with a return of disease activity. Recurring disease activity exceeded baseline levels in some small studies but not in others. Therefore, Dr. Fox and colleagues undertook a randomized, partially placebo-controlled exploratory study (RESTORE study) to test the effects of a 24-week interruption in natalizumab treatment on MS clinical and MRI disease activity.

The study involved patients aged 18 to 60 years with relapsing MS who were treated with natalizumab for at least 12 months before randomization, who had no relapses in the previous 12 months, and who had no gadolinium-enhancing lesions on screening MRI of the brain.

Patients were randomly assigned in a 1:1:2 ratio to continue natalizumab or to switch to placebo or to an alternative immunomodulatory therapy (AIT) (intramuscular interferon beta-1a [IFN]), glatiramer acetate [GA], or methylprednisolone [MP]), respectively, for 24 weeks. The specific AITs were chosen by the patients and their neurologists.

During the 24-week study period, rescue treatment with high-dose corticosteroids or natalizumab could be given if patients experienced MS disease activity, defined as clinical relapse on the Expanded Disability Status Scale or subscale scores and/or 1 new gadolinium-enhancing lesion greater than 0.8 cm3 or 2 or more gadolinium-enhancing lesions of any size. MRIs were performed every 4 weeks. All patients received open-label natalizumab for 24 weeks after the end of the 24-week randomization period.

Dr. Fox said that at baseline across all the groups, the patients were slightly older (age range, 40 - 45 years) than seen in the phase 3 trials of natalizumab, and there were more women than usual (72% - 82%). Patients were stratified according to high or low disease activity, with high activity defined as having 2 or more clinical relapses prior to the patient's having initially started on natalizumab. Fewer patients on IFN (24%) had high disease activity prior to natalizumab therapy compared with the patients in the other arms of the study, in which 35% to 47% had high disease activity.

During the randomization period, no patients taking natalizumab with high (0/19) or low (0/26) disease activity had MRIs that met the criteria for rescue therapy.

Of the patients on placebo, 19 out of 41 had MRI evidence for rescue therapy.

Of the patients in the AIT group, only 1 out of 14 IFN patients had such an MRI. That 1 patient had low disease activity, and MRI evidence occurred only very late in the period in which the patient was off natalizumab.

One half of the GA patients (8/15) met the MRI criteria, and most of those patients (5/7) were classified as having had high disease activity.

Of the 52 patients receiving MP, 21 met MRI criteria for rescue.

Of the 49 patients across all groups who met rescue criteria, 37 (76%) first met MRI rescue criteria at week 16 or 20. In no case did the MRI activity exceed pretreatment levels.

A total of 25 clinical relapses occurred among 167 evaluable patients during the randomization period. Eleven (44%) of the relapses occurred by 16 weeks, and the other 14 (56%) occurred between week 16 and week 28. There were only 2 (4%) clinical relapses among the 45 patients on natalizumab, 7/41 (17%) on placebo, 4/14 (29%) on IFN, 4/15 (27%) on GA, and 8/52 (15%) on MP.

In summary, Dr, Fox said, "Natalizumab treatment interruption resulted in recurrence of MRI and clinical MS disease activity, and this started approximately 12 to 16 weeks into the study."

He noted that the study was neither designed nor powered to compare the efficacies of different AITs, but he said the investigators made certain observations in this regard. First, monthly MP 1 g intravenously started 12 weeks after the last natalizumab dose appeared not to be effective in suppressing MS disease activity as judged by MRI or clinical relapses. Second, return of disease activity occurred later and affected fewer patients who were receiving IFN compared with the patients on the other AITs.

Session moderator Eva Havrdová, MD, PhD, professor of neurology at Charles University in Prague, Czech Republic, who was not involved in the study, commented to Medscape Medical News that previous studies have also shown that disease activity returns after stopping natalizumab, but this study, with MRIs performed every 4 weeks, provides better evidence of the kinetics of the recurrences.

"I think that it proves that in 12 weeks, the activity of the disease — if you do not treat — is coming back definitely, so you cannot offer the patient these drug holidays, which in other diseases is possible somehow, but here it is dangerous after 3 months," she said.

"So you have to decide for a different treatment.... Definitely there are some patients who immediately come back to new activity, so I think in these patients, maybe alemtuzumab or ocrelizumab will be the drugs. Only these 2 drugs have comparable effect [to natalizumab]. I do not know if this will be feasible or not."

Dr. Havrdová said the idea behind a drug holiday from natalizumab is to try to decrease the probability of PML — "just letting the immune system go and make the surveillance [in the brain]. It may be just a theory, and it doesn't work maybe," especially in light of the long presence of the drug in the serum.

The study was supported by Biogen Idec Inc and Elan Pharmaceuticals Inc. Dr. Fox receives fees as a paid consultant, speaker, or member of an advisory committee for Biogen Idec Inc and Novartis International AG. Dr. Havrdová was a principal investigator of the first natalizumab clinical study, published in 2006. She has disclosed no relevant financial relationships.

22nd Meeting of the European Neurological Society (ENS). Abstract O-262. Presented June 11, 2012.

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