MS Activity Returns Soon After Stopping Natalizumab

AMSTERDAM – Significant percentages of patients with relapsing-remitting multiple sclerosis who discontinue natalizumab but start another medication experience a return of disease activity within 12 weeks, according to the results of the RESTORE study.

The risk of return of disease activity during treatment interruption was "notable" even with the use of interferon beta-1a (IFNB-1a, Avonex); glatiramer acetate (Copaxone); or methylprednisolone in place of natalizumab in the study of 175 patients, Dr. Robert Fox said during a late-breaking trials session at the joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis.

The risk of temporarily stopping natalizumab generally appeared to outweigh its benefits in this exploratory study, said Dr. Fox, the lead investigator of the study and medical director at the Mellen Center for Multiple Sclerosis at the Cleveland Clinic in Ohio.

Interrupting treatment with natalizumab has been proposed as a possible way to reduce the risk of progressive multifocal leukoencephalopathy, a rare and potentially fatal opportunistic disease caused by the JC virus. It has been associated with prolonged natalizumab therapy.

In RESTORE, all patients had been treated for 1 year or longer and were relapse free before treatment with natalizumab (given at 300 mg IV once every 4 weeks) was interrupted for 24 weeks. The investigators randomized patients to continue natalizumab treatment (n = 45), stop natalizumab and receive IV placebo (n = 42), or stop natalizumab and receive 1,000 mg IV methylprednisolone every 4 weeks (n = 54), 30 mg intramuscular IFNB-1a once per week (n = 17), or 20 mg subcutaneous glatiramer acetate once daily (n = 17) for 24 weeks, followed by re-instatement of natalizumab infusions for an additional 24 weeks. Investigators at each of the study’s 31 clinical sites selected the choice of alternative treatment.

Increased disease activity on MRI was defined as the occurrence of at least one new gadolinium-enhancing (GdE) lesion greater than 0.8 cm³ in volume or two or more GdE lesions of any size.

Dr. Fox reported that 75% of patients met rescue criteria within weeks 16 to 20, but the first signs of increased disease activity on MRI were noted as early as 12 weeks. In these patients, rescue treatment, consisting of high-dose corticosteroids or restarting natalizumab, was required by 44% on placebo, 53% on glatiramer acetate, 40% on methylprednisolone, and 7% on IFNB-1a.

Clinical relapse, assessed using the Expanded Disability Status Scale (EDSS), occurred in 17% of placebo-treated patients, 4% of patients who continued natalizumab, and 29% treated with IFNB-1a, 27% with glatiramer acetate, and 15% with methylprednisolone. Most relapses occurred around weeks 14-16, but could occur as early as 4-8 weeks.

Overall, the estimated percentage of patients who had a clinical relapse or MRI scan that met rescue criteria was 61% for placebo, 60% for glatiramer acetate, 55% for methylprednisolone, 29% for IFNB-1a, and 5% for natalizumab continuation.

"Interferon appeared a bit better at suppressing MRI disease activity than the other open-label therapies, although this group did have a lower disease activity prior to natalizumab therapy," Dr. Fox said.

He added that the study was not designed or powered to detect differences in the effects of the three alternative immunomodulating therapies used and that "monthly methylprednisolone, at least at the dose we used here in this trial, does not appear to be effective in suppressing disease activity."

Dr. Fox suggested that clinicians who may be considering trying to stop natalizumab in their patients may be advised to undertake monthly MRI, starting 3 months after the last natalizumab dose is given, but the practicality of this approach needs to be taken into consideration. He also suggested considering rescue therapy if GdE lesions appear or a patient has a clinical relapse.

"Perhaps we should be doing a weaning process. There may be ways to do this without doing it abruptly," suggested Dr. Daniel Kantor, who was not involved in the study.

"When I stop [natalizumab], I give people pulsed ACTH [adrenocorticotropic hormone] ... the point being that even when you are on a ‘drug holiday’ you can’t just be on nothing," Dr. Kantor, president of the Florida Society of Neurology and director of the Neurologique Foundation in Ponte Vedra Beach, Fla., said in an interview.

Biogen Idec and Elan Pharmaceuticals sponsored the trial. Dr. Fox said he has received consultant fees from Avanir, Biogen Idec, EMD Serono, and Novartis and research support from Biogen Idec. Dr. Kantor said he has acted as an investigator or had commercial relationships with Acorda, Avanir, Biogen Idec, Genzyme, and Novartis.

AMSTERDAM – Significant percentages of patients with relapsing-remitting multiple sclerosis who discontinue natalizumab but start another medication experience a return of disease activity within 12 weeks, according to the results of the RESTORE study.

The risk of return of disease activity during treatment interruption was "notable" even with the use of interferon beta-1a (IFNB-1a, Avonex); glatiramer acetate (Copaxone); or methylprednisolone in place of natalizumab in the study of 175 patients, Dr. Robert Fox said during a late-breaking trials session at the joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis.

The risk of temporarily stopping natalizumab generally appeared to outweigh its benefits in this exploratory study, said Dr. Fox, the lead investigator of the study and medical director at the Mellen Center for Multiple Sclerosis at the Cleveland Clinic in Ohio.

Interrupting treatment with natalizumab has been proposed as a possible way to reduce the risk of progressive multifocal leukoencephalopathy, a rare and potentially fatal opportunistic disease caused by the JC virus. It has been associated with prolonged natalizumab therapy.

In RESTORE, all patients had been treated for 1 year or longer and were relapse free before treatment with natalizumab (given at 300 mg IV once every 4 weeks) was interrupted for 24 weeks. The investigators randomized patients to continue natalizumab treatment (n = 45), stop natalizumab and receive IV placebo (n = 42), or stop natalizumab and receive 1,000 mg IV methylprednisolone every 4 weeks (n = 54), 30 mg intramuscular IFNB-1a once per week (n = 17), or 20 mg subcutaneous glatiramer acetate once daily (n = 17) for 24 weeks, followed by re-instatement of natalizumab infusions for an additional 24 weeks. Investigators at each of the study’s 31 clinical sites selected the choice of alternative treatment.

Increased disease activity on MRI was defined as the occurrence of at least one new gadolinium-enhancing (GdE) lesion greater than 0.8 cm³ in volume or two or more GdE lesions of any size.

Dr. Fox reported that 75% of patients met rescue criteria within weeks 16 to 20, but the first signs of increased disease activity on MRI were noted as early as 12 weeks. In these patients, rescue treatment, consisting of high-dose corticosteroids or restarting natalizumab, was required by 44% on placebo, 53% on glatiramer acetate, 40% on methylprednisolone, and 7% on IFNB-1a.

Clinical relapse, assessed using the Expanded Disability Status Scale (EDSS), occurred in 17% of placebo-treated patients, 4% of patients who continued natalizumab, and 29% treated with IFNB-1a, 27% with glatiramer acetate, and 15% with methylprednisolone. Most relapses occurred around weeks 14-16, but could occur as early as 4-8 weeks.

Overall, the estimated percentage of patients who had a clinical relapse or MRI scan that met rescue criteria was 61% for placebo, 60% for glatiramer acetate, 55% for methylprednisolone, 29% for IFNB-1a, and 5% for natalizumab continuation.

"Interferon appeared a bit better at suppressing MRI disease activity than the other open-label therapies, although this group did have a lower disease activity prior to natalizumab therapy," Dr. Fox said.

He added that the study was not designed or powered to detect differences in the effects of the three alternative immunomodulating therapies used and that "monthly methylprednisolone, at least at the dose we used here in this trial, does not appear to be effective in suppressing disease activity."

Dr. Fox suggested that clinicians who may be considering trying to stop natalizumab in their patients may be advised to undertake monthly MRI, starting 3 months after the last natalizumab dose is given, but the practicality of this approach needs to be taken into consideration. He also suggested considering rescue therapy if GdE lesions appear or a patient has a clinical relapse.

"Perhaps we should be doing a weaning process. There may be ways to do this without doing it abruptly," suggested Dr. Daniel Kantor, who was not involved in the study.

"When I stop [natalizumab], I give people pulsed ACTH [adrenocorticotropic hormone] ... the point being that even when you are on a ‘drug holiday’ you can’t just be on nothing," Dr. Kantor, president of the Florida Society of Neurology and director of the Neurologique Foundation in Ponte Vedra Beach, Fla., said in an interview.

Biogen Idec and Elan Pharmaceuticals sponsored the trial. Dr. Fox said he has received consultant fees from Avanir, Biogen Idec, EMD Serono, and Novartis and research support from Biogen Idec. Dr. Kantor said he has acted as an investigator or had commercial relationships with Acorda, Avanir, Biogen Idec, Genzyme, and Novartis.

AMSTERDAM – Significant percentages of patients with relapsing-remitting multiple sclerosis who discontinue natalizumab but start another medication experience a return of disease activity within 12 weeks, according to the results of the RESTORE study.

The risk of return of disease activity during treatment interruption was "notable" even with the use of interferon beta-1a (IFNB-1a, Avonex); glatiramer acetate (Copaxone); or methylprednisolone in place of natalizumab in the study of 175 patients, Dr. Robert Fox said during a late-breaking trials session at the joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis.

The risk of temporarily stopping natalizumab generally appeared to outweigh its benefits in this exploratory study, said Dr. Fox, the lead investigator of the study and medical director at the Mellen Center for Multiple Sclerosis at the Cleveland Clinic in Ohio.

Interrupting treatment with natalizumab has been proposed as a possible way to reduce the risk of progressive multifocal leukoencephalopathy, a rare and potentially fatal opportunistic disease caused by the JC virus. It has been associated with prolonged natalizumab therapy.

In RESTORE, all patients had been treated for 1 year or longer and were relapse free before treatment with natalizumab (given at 300 mg IV once every 4 weeks) was interrupted for 24 weeks. The investigators randomized patients to continue natalizumab treatment (n = 45), stop natalizumab and receive IV placebo (n = 42), or stop natalizumab and receive 1,000 mg IV methylprednisolone every 4 weeks (n = 54), 30 mg intramuscular IFNB-1a once per week (n = 17), or 20 mg subcutaneous glatiramer acetate once daily (n = 17) for 24 weeks, followed by re-instatement of natalizumab infusions for an additional 24 weeks. Investigators at each of the study’s 31 clinical sites selected the choice of alternative treatment.

Increased disease activity on MRI was defined as the occurrence of at least one new gadolinium-enhancing (GdE) lesion greater than 0.8 cm³ in volume or two or more GdE lesions of any size.

Dr. Fox reported that 75% of patients met rescue criteria within weeks 16 to 20, but the first signs of increased disease activity on MRI were noted as early as 12 weeks. In these patients, rescue treatment, consisting of high-dose corticosteroids or restarting natalizumab, was required by 44% on placebo, 53% on glatiramer acetate, 40% on methylprednisolone, and 7% on IFNB-1a.

Clinical relapse, assessed using the Expanded Disability Status Scale (EDSS), occurred in 17% of placebo-treated patients, 4% of patients who continued natalizumab, and 29% treated with IFNB-1a, 27% with glatiramer acetate, and 15% with methylprednisolone. Most relapses occurred around weeks 14-16, but could occur as early as 4-8 weeks.

Overall, the estimated percentage of patients who had a clinical relapse or MRI scan that met rescue criteria was 61% for placebo, 60% for glatiramer acetate, 55% for methylprednisolone, 29% for IFNB-1a, and 5% for natalizumab continuation.

"Interferon appeared a bit better at suppressing MRI disease activity than the other open-label therapies, although this group did have a lower disease activity prior to natalizumab therapy," Dr. Fox said.

He added that the study was not designed or powered to detect differences in the effects of the three alternative immunomodulating therapies used and that "monthly methylprednisolone, at least at the dose we used here in this trial, does not appear to be effective in suppressing disease activity."

Dr. Fox suggested that clinicians who may be considering trying to stop natalizumab in their patients may be advised to undertake monthly MRI, starting 3 months after the last natalizumab dose is given, but the practicality of this approach needs to be taken into consideration. He also suggested considering rescue therapy if GdE lesions appear or a patient has a clinical relapse.

"Perhaps we should be doing a weaning process. There may be ways to do this without doing it abruptly," suggested Dr. Daniel Kantor, who was not involved in the study.

"When I stop [natalizumab], I give people pulsed ACTH [adrenocorticotropic hormone] ... the point being that even when you are on a ‘drug holiday’ you can’t just be on nothing," Dr. Kantor, president of the Florida Society of Neurology and director of the Neurologique Foundation in Ponte Vedra Beach, Fla., said in an interview.

Biogen Idec and Elan Pharmaceuticals sponsored the trial. Dr. Fox said he has received consultant fees from Avanir, Biogen Idec, EMD Serono, and Novartis and research support from Biogen Idec. Dr. Kantor said he has acted as an investigator or had commercial relationships with Acorda, Avanir, Biogen Idec, Genzyme, and Novartis.