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BOSTON, Massachusetts – Almost 20 years ago, I wrote a children-level book “Multiple Sclerosis (Enslow Publisher, 1999) and listed three available medications for treatment of the disease. My, how things have changed – as evidenced by studies presented here at the 69th annual meeting of the American Academy of Neurology.
There are more than a dozen medications now available to treat the disease that predominantly affects young adults and women, but some of the new treatments are so effective they require a single dose or 2 a year – not every week – and have potent impacts on the course of multiple sclerosis.
In one study, researchers scrutinized outcome of patients who, for one reason or another, decided to stop taking alemtuzumab after completing their initial 2-year course of treatment. About 63 percent of these patients did not have any relapses for at least 4 years, reported of freedom from relapses, researchers reported here at the 69th annual meeting of the American Academy of Neurology.
The patients in the CARE-MS I trial took two doses of alemtuzumab at baseline and at one year and then decided to discontinue further treatment, and most of them did well, said Douglas Arnold, MD, professor of neurology at McGill University, Montreal, Quebec, Canada.
“These findings, along with improved clinical outcomes and reduced brain volume loss, suggest alemtuzumab may provide a unique treatment approach for relapsing-remitting multiple sclerosis patients, offering durable efficacy in the absence of continuous treatment,” he said in his oral presentation.
Arnold theorized suggested that by rapidly depleting T-cells and B-cells in patients with multiple sclerosis, treatment with alemtuzumab allows the patient to repopulate his body’s immune system with anti-inflammatory cytokines which replace the pro-inflammatory cytokine producing cells.
In the study, 376 patients received 2 courses of treatment with alemtuzumab and then were followed for 4 additional years. About 95 percent of the patients in the original 2-year study enrolled in the 4-year extension trial, and 93 percent of the patients were on trial at the end of 6 years.
The study protocol allowed for further treatment with alemtuzumab or other disease modifying treatment if required to control disease activity – but in most cases these multiple sclerosis patients didn’t require it through 6 years.
Arnold said that magnetic resonance imaging scans of the patients in CAREMS I who were naïve to multiple sclerosis treatment showed that 93 percent of the patients were free of gadoliniumenhancing lesions and after 6 years, 87 percent of these patients were still free of gadolinium-enhancing lesions.
In addition, at baseline, 78 percent of the patients were T2 hyperintense lesion-free, while at 6 years, 67 percent were free of these lesions; at baseline 77 percent of patients were free of disease activity – either gadolinium-enhancing lesions or T2 hyperintense lesions, while at 6 years 66 percent of these patients remained disease free.
The study was supported by Sanofi Genzyme and Bayer HealthCare Pharmaceuticals.
Brain volume loss reduced
A reduction in brain volume loss among multiple sclerosis patients assigned to treatment with another disease-modifying targeted agent daclizumab may account for findings that the therapy outperformed intramuscular interferon beta-1a in clinical trials.
Intramuscular interferon beta-1a was one of those long-time standards for treatment that may now be in the sunset of its years as more effective targeted agents are being rolled out.
“The findings of this analysis provide evidence that daclizumab beta reduces region brain volume loss, which may account for the benefits of daclizumab beta observed on relapses, disability progression, cognitive function and functional outcomes in the DECIDE trial,” said John Rose, MD, professor of neurology at the University of Utah, and chief of neurology at Salt Lake City Veterans Administration Hospital, Salt Lake City.
In his oral presentation, Dr. Rose said that a critical area of brain volume loss is in the thalamus, a relay point for sensory information to the cortex, and correlations between thalamic volume loss and cognitive impairment have also been shown in multiple sclerosis patients.
He demonstrated that at 24 weeks, thalamic loss among the 614 patients assigned to interferon in the study was a mean 0.890 mm3 compared to a mean thalamic volume loss of 0.630 mm3 among 624 patients who were assigned to daclizumab (p=.0044).
By 96 weeks, the difference expanded, with a loss of 2.120 mm3 among 541 patients on interferon compared with a loss of 1.650 mm3 in patients who were on daclizumab (<.0001).
Whole brain volume loss in the overall DECIDE trial favored daclizumab. In the 907 patients on interferon the loss at 96 weeks averaged 0.580 mm3 compared with an average loss of 0.553 mm3 among the 899 patients on daclizumab.
At baseline in the trial, the patients were about 36 years old, and had been living with a diagnosis of multiple sclerosis for about 4 years
The DECIDE researchers randomized 919 relapsing-remitting multiple sclerosis patients to daclizumab 150mg subcutaneous every 4 weeks and to 922 patients who were assigned to interferon beta-1a 30mcg intramuscularly once weekly. Normalized thalamic and cortical gray matter volume at baseline and their percentage change from baseline were analyzed post hoc.
“These observations suggest that regional brain volume loss may be a sensitive indicator of multiple sclerosis disease pathology,” Dr. Rose said.
The study was supported by Biogen and AbbVie BioTherapuetics, Inc.
Significant difference in evidence of multiple sclerosis disease activity in the brain as recorded on magnetic resonance imaging scans could be observed as early as 4 weeks into treatment with ocrelizumab – the most recently U.S. Food and Drug Administration-approved multiple sclerosis agent.
In an analysis of a Phase II study, researchers reviewed scans of patients in the 4-week, 8-week and 12-week epochs of the study to determine if there were changes in effectiveness between ocrelizumab-treated patients, patients treated with interferon beta-1a (44 micrograms delivered subcutaneously) and other patients treated with placebo.
Frederik Barkhof, MD, PhD, professor of neuroradiology at University College London, England, United Kingdom and the VU University Medical Center, Amsterdam, the Netherlands, found that indeed there was evidence that multiple sclerosis activity was markedly attenuated with ocrelizumab therapy.
By week 4, the adjusted annualized rate of new T1 gadolinium-enhancing lesions was 0.319 for ocrelizumab-treated patients compared with a rate of 0.839 for placebo patients and 0.826 for interferon therapy (p=.043), he said in his oral presentation.
By Week 8 of treatment, new lesions in the 55 ocrelizumab-treated patients declined to a rate of 0.041 l while the among the 54 placebo patients the rate was 1.174 (p<.001) and among the 54 interferon-treated patients the rate was 1.276 (p<.001), Dr. Barkhof reported.
There was even a further improvement at the Week 12 epoch, with the ocrelizumab rate at 0.016 and the placebo rate at 0.627 (p=.002) and the interferon patient rate at 1.291 (p<.001), he said.
“In this analysis, ocrelizumab 600 mg demonstrated rapid and near-complete suppression in brain MRI activity versus placebo or interferon beta-1a as early as week 4, including T1 gadoliniumenhancing lesions, new T2 lesions and newly-enlarging T2 lesions,” Dr. Barkhof said.
“Rapid control of subclinical disease activity is an important goal to minimize axonal damage that may ultimately lead to disability progression in multiple sclerosis,” he said.
The main study found that ocrelizumab treatment was associated with significant reduction in new and enlarging lesions when compared with interferon at weeks 24, 48 and 96. The current analysis was to determine if a treatment effect of ocrelizumab could be observed prior to the 24 week milestone. In the trial, enrolled patients underwent MRI scans at baseline and then at weeks 4, 8, 12, 16 and 24 which provided data for the deep dive into how quickly the new agent showed efficacy when compared with another comparator agent and placebo.
Dr. Barkhof noted that treatment with ocrelizumab was associated with a rapid and near complete depletion of B cells in the peripheral blood within 2 weeks, leading researchers to believe their could be a corresponding early impact on new lesions.
“These findings are consistent with previous observations and the known pharmacodynamic effects of ocrelizumab,” he said, “which was associated with systemic depletion of B cells to negligible levels within 2 weeks at the first post-baseline assessment in Phase II and pivotal Phase III studies.”
The study was sponsored by F. Hoffman-La Roche Ltd.
June 2017 Health and Lifestyle