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59th Annual Meeting of the American Academy of Neurology

Boston, Massachusetts / April 28-May 5, 2007

Future approaches to treating relapsing-remitting multiple sclerosis (RRMS) may incorporate multiple agents with different mechanisms of action to further suppress progression of the disease and reduce relapse rates. Specifically, brief induction therapy with an immunosuppressant followed by immunomodulatory therapy has been shown to reduce the incidence of enhancing lesions and the rate of relapses compared with immunomodulatory therapy alone.

“It is possible to take current therapies and use them in tandem in a rational way to get much bigger effects that will help prevent brain injury early on, so that patients have more cranial reserve later in life and will be more functional and less likely to be disabled,” stated Dr. Timothy L. Vollmer, Chairman, Division of Neurology, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, Arizona. “Preserving brain function up front is key.”

Many of these strategies take advantage of the immunomodulatory and neuroprotective effects of glatiramer acetate (GA), which induces a shift in the cytokine profile of central nervous system (CNS)-reactive T-cells from Th1 to Th2 while downregulating autoaggressive Th1 cells. Th2 cells cross the blood-brain barrier into the CNS where they secrete anti-inflammatory cytokines and growth factors favourable to neuroprotection.

Induction Therapy for Earlier and Sustained Reduction in Disease Activity

Preliminary clinical studies have shown that a short course of immunosuppression with mitoxantrone prior to GA treatment was safe and more effective than GA treatment alone in suppressing the development of gadolinium (Gd)-enhancing lesions and reducing annual relapse rates. Early clinical results with mitoxantrone induction for three months prior to GA therapy produced an approximate 90% reduction in the mean total number of Gd-enhancing lesions at 15 months, which was significantly greater than the reduction with GA alone (P=0.0147). In this randomized study of 40 patients, there was also a trend toward fewer relapses in the induction group.

As Dr. Vollmer reported here, the superiority of mitoxantrone induction prior to GA over GA alone in reducing Gd-enhancing lesions is sustained for up to 24 months. Twenty-eight of the 40 patients enrolled in the aforementioned study had follow-up at 24 months. At entry to the core study, they received either three monthly infusions of mitoxantrone followed by 21.5 months of GA 20 mg/day or 24 months of GA 20 mg/day. To be eligible, patients had to have at least one Gd-enhancing lesion at the time of their screening MRI scan and an Expanded Disability Status Scale (EDSS) score of 6.5 or less.

At 24 months, MRI-monitored disease activity remained 90% lower in the mitoxantrone/GA cohort compared with baseline, whereas the mean number of Gd-enhancing lesions was reduced by 59% from baseline to 24 months in the group receiving GA alone. The mean relapse rate was similar for both groups at the 24-month visit (0.26 for mitoxantrone/GA and 0.23 for GA).

This use of sequential mitoxantrone and GA is already being used in the UK, targeting patients who have markers for poor prognosis, stated Dr. Jason Ramtahal, Walton Centre for Neurology and Neurosurgery, University of Liverpool, UK. His study examined the use of mitoxantrone/GA in a cohort of 18 patients followed up for continuing relapse activity on interferon beta-1a (IFNß-1a). Disability as measured by EDSS score was stabilized or improved in 16 of the 18 patients at the most recent follow-up.

Mechanisms Explored

The mean volume of T2-weighted lesions was reduced from 10.35 mL at baseline to 8.77 mL at month 15 in the mitoxantrone/GA group (P=0.0103) but was essentially unchanged in the GA group (7.25 mL at baseline vs. 7.63 mL at month 15). Some 0.01% of Gd-enhancing lesions evolved into black holes in patients assigned to mitoxantrone induction followed by GA compared with 0.20% in patients assigned to GA. “Prevention of chronic black holes may slow disease progression by avoiding permanent tissue destruction,” stated Dr. Arnold. The findings “suggest that induction of rapid anti-inflammatory activity with mitoxantrone followed by immunomodulation with GA may have a place in the treatment algorithm for active RRMS,” he concluded.

In a subset of 21 patients from this same clinical study, Dr. Amit Bar-Or, MUHC-Montreal Neurological Institute and Hospital, discovered that the improved clinical and MRI outcomes with mitoxantrone induction followed by GA treatment are not a reflection of an enhanced capacity for a GA-mediated Th2 shift following immune suppression, but rather combined anti-inflammatory effects of mitoxantrone and GA.

In the study, serum GA-reactive antibodies (total IgG: IgG1, IgG2, IgG3, IgG4) by enzyme-linked immunosorbent assay were measured serially. (The relationship between IgG1 and IgG4 GA-reactive antibodies is a marker of GA-mediated Th2 shift.) Induction therapy with mitoxantrone appeared to partially attenuate and/or delay the IgG1 to IgG4 switch that is characteristic of the Th2 shift. By month 12 in the combination treatment arm, IgG1-3 tended to decrease whereas IgG4 exhibited a trend to increase from months 3 to 12. Following initial induction of GA-reactive antibodies, treatment with either GA alone or induction mitoxantrone followed by GA was associated with decreases in IgG1 antibodies and increases in IgG4 antibodies. These findings, together with MRI measures of disease activity, suggest that the enhanced efficacy of mitoxantrone/GA lies not in an enhanced Th2 shift but rather reflects combined anti-inflammatory effects of mitoxantrone followed by GA.

“The enhanced effect of combination therapy on Gd+ MRI lesions over the 15-month study may reflect additional modes of action of GA, such as induction of T-cell anergy and generation of regulatory T-cells, and/or a persistent mitoxantrone effect,” according to Dr. Bar-Or. The two new analyses raise the possibility that while mitoxantrone induction attenuates certain immunomodulating effects of GA, it does not interfere with neuroprotective outcomes, he indicated.

Other Combination Strategies

Early data also show promising results by adding an inhibitor of matrix metalloproteinase (MMP) to immunomodulatory therapy. Minocycline 100 mg b.i.d. added to GA 20 mg/day in patients with RRMS resulted in strong trends towards reductions of the total number of T1-enhancing lesions, the number of new T2 lesions and the risk of relapse compared with GA alone, reported Dr. Luanne Metz, Department of Clinical Neuroscience, University of Calgary, Alberta. Proof-of-concept trials carried out previously showed that minocycline alone reduced the number of Gd-enhancing lesions and was well tolerated, Dr. Metz told attendees. In addition, combination minocycline/GA was previously found to decrease neuron inflammation, axonal loss and demyelination in an animal model of MS.

Comparative Brain Imaging Studies Reveal New Insights

Further insight into the mechanisms of action of IFNß-1b and GA in patients with RRMS was obtained through brain-imaging studies. One such study examined the development of new brain lesions on MRI scans from patients enrolled in the BECOME (Betaseron vs. Copaxone in MS with Triple-dose Gadolinium and 3-T MRI) trial, in which 75 patients were randomized to either IFNß-1b or GA. Three techniques were used to optimize lesion detection on MRI: triple-dose Gd, delayed scan and 3-Tesla MRI.

Another study by investigators at Wayne State University, Detroit, Michigan, used a combined magnetization transfer ratio (MTR) and proton magnetic resonance spectroscopy (1H-MRS) study to investigate mechanistic properties and tissue injury with IFNß-1b and GA. Twenty-nine treatment-naive patients initiated therapy with either high-dose IFNß-1b or GA, and underwent baseline and one-year brain MRI scan combined with MT and 1H-MRS. They found that increases in mean whole-brain tissue MTR from baseline were statistically significant only with GA. Mean whole-brain tissue MTR increased by 2.78% (P=0.01) in patients treated with GA and a non-significant 1.94% in those treated with IFNß-1b. “This may suggest a possible effect of GA on reducing damage from ongoing inflammatory/degenerative injury and promoting a reparative environment within the CNS,” remarked lead investigator Dr. Omar Khan.

Similarly, treatment with each agent stabilized the N-acetyl aspartate:creatine (NAA:Cr) ratio, but the improvement was statistically significant with GA. NAA:Cr in the central volume of interest was improved by 7.8% (P=0.03) in the GA-treated group whereas patients treated with IFNß-1b improved by a non-significant 1.2%. This finding implies protection with GA of neuronal/axonal mitochondrial function from sublethal injury, Dr. Khan added. Treatment with IFNß-1b or GA reduced Gd-enhancing lesions by 28% and 68%, respectively.

“Our observations suggest that axonal injury and myelin integrity may be affected independent of activity at the blood-brain barrier level, and combining MTR and 1H-MRS may capture this aspect of MS pathology in a sensitive and reliable manner,” the authors concluded.

Evidence from Animal Studies

Evidence of neuroprotection with GA has been demonstrated in animal models of MS. Animal study findings presented here from the University of Calgary showed that daily subcutaneous treatment with GA increased the number of oligodendrocyte precursor cells (OPCs) in vivo at sites of demyelination of the spinal cord. Bone marrow-derived macrophages from mice stimulated with GA increased their production of insulin-like growth factor-1, platelet-derived growth factor, and brain-derived neurotrophic factor, which are important growth factors for OPCs. Therefore, in addition to affecting T-cells, another mechanism by which GA favourably influences MS is promotion of oligodendrogenesis (through an increase in growth factors) and myelin repair of demyelinating lesions, noted the investigators.

A central role for brain-derived neurotrophic factor in the mechanism of GA action and for maintaining axonal integrity was supported by research in experimental autoimmune encephalomyelitis (EAE), which is an established animal model of MS. As reported by Dr. Rina Aharoni, Weizmann Institute of Science, Rehovot, Israel, electron microscopy analysis of spinal cords revealed that GA treatment of EAE resulted in substantial increases in oligodendrocyte progenitor cells in lesions and injury sites, possibly enhancing remyelination, which suggests neuroprotective consequences of GA on myelin. Demyelination is the primary pathologic mechanism that characterizes MS, and the ability of treatments to prevent demyelination and/or induce remyelination is crucial to delay or prevent permanent neurologic disability, Dr. Aharoni noted.

Future Treatments in Development

As an orally active immunoregulatory drug without general immunosuppressive properties, laquinimod also demonstrated an ability to significantly reduce MRI disease activity in a phase IIb trial of patients with RRMS. In this study, 306 patients with one or more relapses in the year prior to entry and at least one Gd-enhancing lesion at screening were randomized to laquinimod 0.3 or 0.6 mg/day or placebo. MRI scans were conducted monthly from weeks 12 to 36. Patients treated with 0.6 mg/day orally had a significant 38% reduction (P=0.0048) in the cumulative number of Gd-enhancing lesions per scan in the last four scans compared with placebo, reported Dr. Giancarlo Comi, Università Vita-Salute San Raffaele, Milan, Italy.

Other approaches to treating MS include selective targeting of B cells and improving impulse conduction in damaged nerve fibres. The therapeutic antibody rituximab targets and selectively depletes CD20-positive B cells. In a phase II double-blind study of 104 patients with RRMS, it was associated with a 91% reduction (P<0.0001) in the total number of Gd-enhancing T1 lesions per patient at week 24, noted Dr. Stephen Hauser, University of California, San Francisco. Relapses over 24 weeks were also reduced by a significant 58% (P=0.0238) in rituximab-treated patients.

The investigational oral agent fampridine-SR has been found in laboratory experiments to improve impulse conditions in nerve fibres in which myelin has been damaged. In a phase III placebo-controlled trial of 301 patients with MS, significantly more patients assigned to active treatment than placebo were considered responders on the Timed 25-foot Walk (34.8% vs. 8.3%; P<0.0001), reported Dr. Andrew Goodman, Multiple Sclerosis Center, University of Rochester, New York.