ECTRIMS: Fast MS Comeback May Ruin Drug ‘Holiday’
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AMSTERDAM — Stopping natalizumab (Tysabri) to reduce the risk of a rare, life-threatening side effect in patients with multiple sclerosis (MS) carries a steep cost — the substantial likelihood of renewed disease activity within six months, a researcher said here.
More than half of patients in the randomized, controlled RESTORE trial who switched to methylprednisolone or glatiramer acetate (Copaxone) for six months relapsed or developed new gadolinium-enhancing lesions on brain MRI scans said Robert Fox, MD, of the Cleveland Clinic.
Only four of 14 patients who switched to interferon-beta-1a met these criteria for renewed disease activity, but these patients had lower disease activity during the study baseline, Fox said.
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In a late-breaking presentation at the joint meeting of the European and Americas Committees for Treatment and Research in Multiple Sclerosis, Fox told attendees that the study was neither designed nor powered to evaluate alternative treatments to be given during natalizumab “holidays.”
The idea for interrupting natalizumab in patients otherwise doing well on the drug came about because of findings that duration of treatment is a strong risk factor for progressive multifocal leukoencephalopathy (PML), Fox explained.
The condition results from reactivation of latent infection with the JC virus, assumed to result from natalizumab’s disruption in immune function.
Studies of patients who have developed PML, which has been fatal in about one-fifth of cases, has shown that the risk increases by about eight-fold during the second year of treatment, relative to the first treatment year, in patients with past JC virus exposure.
Although it appears that additional years of treatment do not increase the risk further, many neurologists have wondered whether stopping the drug — to allow reconstitution of more normal immune surveillance — might reduce the risk.
Fox and colleagues received funding from natalizumab’s makers to evaluate the risk of accelerated disease activity associated with a switch to other treatments or no treatment.
He stressed to attendees that the trial did not evaluate the strategy’s efficacy in reducing PML risk. Such a study would require several thousand patients and will probably never be done.
In the current study, 175 patients were randomized in a 1:1:2 ratio to three groups:
The alternatives offered were intramuscular interferon-beta-1a, glatiramer acetate, or methylprednisolone (1,000 mg IV) at the usual intervals. The first two were started immediately after the last natalizumab dose, whereas patients in the steroid group received the first dose three months later.
Fox explained that the delay was intended to allow immune reconstitution, which the investigators feared would remain suppressed if a steroid was introduced immediately.
About 60% of the alternative active-therapy group chose methylprednisolone.
The study’s primary endpoint was a composite of clinical relapse, one new gadolinium-enhancing lesion of at least 0.8 mL, or two new lesions of any size. MRI scans were performed every four weeks.
The percentage of patients in each group meeting the endpoint were as follows:
Fox said interferon’s apparently better performance may have been an artifact of baseline differences between the patients who chose the different alternatives.
Only 24% of those who picked interferon had had high disease activity when they originally started on natalizumab, compared with 47% of those choosing glatiramer acetate and 35% of those selecting the steroid.
Overall, a disproportionate number of patients with high disease activity prior to starting natalizumab experienced renewed disease activity during the study.
Most patients meeting the endpoint did so by week 20, demonstrating that disease activity returns relatively quickly when natalizumab is withdrawn.
Although it might appear from the results that the natalizumab interruption was a failure, Fox toldMedPage Today that such a conclusion is premature.
Reducing the incidence of PML is ultimately about “risk stratification,” he said, suggesting that the relapse risk could be acceptable in patients at relatively high risk for PML.
Fox added that the study suggested that, for patients who do stop natalizumab, frequent MRI scans to detect early signs of disease activation should begin after three to four months.
And the study established that IV methylprednisolone started three months after the natalizumab stoppage was not effective, Fox said.
He said it’s possible that starting the steroid sooner might have reduced the relapses and new lesions. But if that regimen had been tested in the study, it would have been criticized for undermining the rationale for the natalizumab stoppage, he said.
The study was funded by Biogen Idec and Elan, the manufacturers and marketers of natalizumab.
Fox reported relationships with Avanir, Biogen Idec, EMD Serono, and Novartis.
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Primary source: European and Americas Committees for Treatment and Research in Multiple Sclerosis
Source reference: Fox R, et al “Effects of a 24-week natalizumab treatment interruption on clinical and radiologic parameters of multiple sclerosis disease activity: the RESTORE study”ECTRIMS/ACTRIMS 2011; Abstract 150. |
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