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MEDICAL FRONTIERS - 26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS)

Gothenburg, Sweden / October 13-16, 2010

The Need for Early and Sustained Efficacy

The efficacy track records of glatiramer acetate (GA) and the ß-interferons (IFNß) are unrivalled in the treatment of relapsing-remitting multiple sclerosis (RRMS). One study presented here at ECTRIMS documents 19 years’ follow-up in 128 patients receiving GA and 118 on IFN. Approximately half of each group (52% and 49%, respectively) remained relapse-free, and both treatments significantly slowed progression of disability, reported Dr. Adriana Carrá, Hospital Británico de Buenos Aires, Argentina, and multicentre colleagues. Furthermore, the benefits of these agents appear early in the disease course, as shown by several studies of patients with clinically isolated syndromes (CIS).

The latest is PreCISe (Early Glatiramer Acetate Treatment in Delaying Conversion to Clinically Definite Multiple Sclerosis in Subjects Presenting with a Clinically Isolated Syndrome) with 5-year data now available. PreCISe was a 3-year multinational, randomized, placebo-controlled, double-blind study of GA in 481 patients with CIS. Of the 243 patients who received GA from the beginning, 80 (32.9%) developed clinically definite MS (CDMS) compared with 118 (49.6%) of those in the original placebo group who were subsequently switched to GA. The adjusted proportions were 29.4% and 46.8%, respectively (odds ratio [OR] 0.48; P=0.0002) (Figure 1). Relapse rate was also significantly lower in patients receiving GA from the start than in those later switched to GA from placebo: 0.22 vs. 0.29 (P=0.021). Similar significant differences were observed between the early and delayed start patients in cumulative number of new T2 lesions per year (-58%, P<0.0001), T2 lesion volume (-22%, P=0.0005) and per cent change from baseline in brain volume (28.2% treatment effect, P=0.0209) (Figure 2). “The efficacy and safety results of this study establish the importance of immediate treatment with GA 20 mg in CIS patients with positive brain MRI,” stated Prof. Giancarlo Comi, Vita-Salute San Raffaele University, Milan, Italy, who presented the 5-year findings.

These results, together with those of the CHAMPS (Controlled High-Risk Subjects Avonex MS Prevention Study), BENEFIT (Betaseron/Betaferon in Newly Emerging MS For Initial Treatment) and ETOMS (Early Treatment of MS) studies with IFNß, confirm that GA and IFNß are the agents of choice to treat patients with CIS, agreed Dr. Mark Freedman, Director, Multiple Sclerosis Research Unit, The Ottawa Hospital, Ontario. (Of note, the BENEFIT 5-year analysis showed no significant differences in brain volume [i.e. atrophy] between the early and delayed treatment groups). This also applies to CDMS; the BEYOND (Betaferon/Betaseron Efficacy Yielding Outcomes of a New Dose) head-to-head study of IFNß-1b and GA demonstrated that the two agents similarly slowed disability progression, Prof. Comi reminded delegates.

Figure 1.

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Figure 2.

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To optimize therapeutic benefits, the ideal would be to identify likely good responders before starting a particular treatment. A multicentre study led by Dr. Suhayl Dhib-Jalbut, University of Medicine and Dentistry of New Jersey, New Brunswick, showed that HLA DQ-6-positive patients have an 89% chance of responding to GA at the end of 2 years compared with only half of DQ-6-negative patients. Furthermore, at 6 months, responders (unlike non-responders) showed significant increases over baseline in interleukin (IL)-4, IL-4:IFN? ratio, IL-10, IL-27 and brain-derived neurotrophic factor (BDNF), and decreases in IL-17, IL-18, TNF-a and caspase-1. The increase in IL-4 and IL-10 and the decrease in IL-18, caspase-1 and TNF-a also predicted a favourable clinical response at 2 years. The researchers noted that the IL-18 and caspase-1 decrease at 6 months together predict clinical response with 95% sensitivity and 75% specificity.

GA-reactive T-cells produce oligodendrocyte trophic factors and increase the numbers of oligodendrocyte progenitor cells and mature oligodendrocytes in vitro in experiments conducted by Dr. Yunyan Zhang, University of Calgary, Alberta, and multicentre colleagues. They concluded that GA therapy might help support oligodendrocytes in patients with RRMS.

Zivadinov et al. (abstract P413) also reported the possible neuroprotective effects of GA. Investigators used magnetization transfer ratio (MTR) changes to monitor the evolution of T1 lesions over 12 months in patients receiving GA. They found MTR recovered significantly in both acute and chronic hypointense lesions as well as in isointense areas. Researchers suggest this may indicate higher potential for remyelination in GA-treated patients.

A study by Sakhina Begum-Haque, PhD, Dartmouth College, Lebanon, New Hampshire, has shown that GA may have beneficial effects on B-cells. In the experimental allergic encephalomyelitis (EAE) model, adoptive transfer of GA-sensitized B-cells led to an increase of IL-4 and IL-10, and down-regulated expression of the nuclear hormone receptor retinoic acid-related orphan receptor (ROR)?t, which directs the expression of the pro-inflammatory cytokine IL-17 in T-cells. GA-conditioned B-cells also reduced inflammation and increased expression of BDNF in the central nervous system (CNS). According to investigators, findings provide insight into how a subset of B-cells affects progression of autoimmune CNS disease by inhibiting inflammatory activity.

Other Lifetime Treatment Considerations

In a long-term (=8 years) follow-up of the PRISMS (Prevention of Relapses and Disability by Interferon-Beta-1a Subcutaneously in Multiple Sclerosis) study, adherence to treatment was demonstrated as an important factor in optimizing therapeutic benefits for patients with RRMS. Led by Dr. Anthony Traboulsee, Assistant Director, Multiple Sclerosis/Magnetic Resonance Imaging Research Group, University of British Columbia, Vancouver, findings showed greater adherence was associated with better prognosis, as measured by 11 long-term clinical and MRI outcomes.

In patients with CIS, adherence is a particular issue, as those with mild, unifocal onset are reluctant to start treatment and to stay on it once their symptoms subside, particularly if they experience side effects. “Fortunately we have a good safety record with the IFNs and GA,” Prof. Freedman pointed out.

Some of the new medications with only a few years’ follow-up in clinical trials are of concern. Preferentially targeting lymphocytes, cladribine disrupts cellular metabolism and inhibits DNA synthesis, leading to apoptosis, and is associated with lymphopenia and herpes zoster infections. In the recently reported CLARITY (Cladribine Tablets Treating Multiple Sclerosis Orally) study, for example, 21.6% and 31.5% of patients on the 3.5 mg/kg and 5.25 mg/kg doses, respectively, developed lymphopenia and 1.8% and 2.4%, respectively, had herpes zoster. The high incidence of lymphopenia was not unexpected, given the mechanism of action of the drug, noted Prof. Hans-Peter Hartung, Heinrich-Heine University, Düsseldorf, Germany.

During the trial, 3 malignancies appeared in patients taking cladribine and a fourth during post-study surveillance with none reported in the placebo group. “At the present time, it is unclear whether this is a potential safety signal or whether it is just a reflection of the background incidence of malignancies in these age groups,” he stated. Treatment is approved for only 2 years’ use and requires initial and ongoing monitoring of complete and differential blood counts, Prof. Hartung observed.

Fingolimod is an agonist of sphingosine-1-phosphate (S1P) receptors which are found in many different tissues, explained Prof. Chris Polman, VU University Medical Center, Amsterdam, The Netherlands. Its presumed mechanism of action in MS is to down-regulate the S1P receptors on the lymphocytes, trapping them in the lymph nodes and rapidly reducing blood counts. However, its effects on other cell types are associated with various toxicities including a dose-dependent decline in heart rate after the first dose, a rise over time in blood pressure and macular edema, making close surveillance mandatory. Another cause for concern is that long-term fingolimod may compromise the immune response in the CNS, as indicated by findings of the first study to examine its effects on cerebrospinal fluid (CSF). Dr. Markus Kowarik, Technical University, Munich, Germany, and multicentre colleagues found significant reductions in the proportion of CD4+ T-cells and a reversed CD4+:CD8+ T-cell ratio in the CSF of patients taking fingolimod. They noted that CSF changes were similar to those seen with natalizumab. “The balance between safety and efficacy and convenience could be further improved,” Prof. Polman acknowledged.

With natalizumab, progressive multifocal leukoencephalopathy (PML) is of greatest concern with an estimated incidence of approximately 1 per 1000. In reviewing 35 PML cases, Prof. Patrick Vermersch, Hôpital Roger Salengro, Lille, France, explained that more localized disease on MRI and more rapid diagnosis were associated with better survival. Heightened clinical vigilance and aggressive management of PML may improve outcomes. A case history report described a patient with an indolent course of PML while receiving natalizumab. She developed progressive cognitive problems and ultimately acute delirium. An MRI scan performed 4 months before the onset of her cognitive symptoms and 9 months before her PML diagnosis showed subtle diffuse abnormalities which, in hindsight, were indicative of PML. In natalizumab-treated MS patients, “clinical and radiological vigilance is extremely important,” stressed Dr. Anke Vennegoor, MS Center, VU University Medical Center.

However, stopping natalizumab has been associated with disease rebound. In one report, treatment withdrawal resulted in a high level of clinical and MRI activity within 3 to 6 months in most of the 28 patients assessed. Some of the women had stopped natalizumab to try to conceive. “Data didn’t support the concept of [a] therapeutic window in patients treated with natalizumab for active RRMS. This is an important point for women before pregnancy,” remarked Dr. Anne Kerbrat Lécuyer, Rennes, France, and multicentre colleagues. In another study, 3 patients had frequent severe relapses only months after stopping therapy. There is a need to balance the risk of disease reactivation when discontinuing natalizumab with that of PML with continued therapy, noted Prof. Annette Baumgärtner, Hochschule Fresenius, Hamburg, Germany, and colleagues.

In 40 patients switched from natalizumab to GA, this disease rebound seems to have been prevented, as suggested by Dr. Silvia Rossi, Tor Vergata University, Rome, Italy, and associates. In 23 patients who completed at least 6 months’ GA therapy with repeat MRI scans, 11 had disease reactivation but without rebound. GA appears to be a safe and effective option in RRMS patients discontinuing natalizumab, according to investigators.

As more agents become available over the next few years, increasing knowledge about prognostic factors and the use of treatment algorithms can help simplify matters. Dr. Xavier Montalban, MS Center of Catalonia and Vall d’Hebron University Hospital, Barcelona, Spain, explained that baseline MRI findings are the most useful prognostic indicators in patients presenting with CIS. Baseline MRI lesions and particularly infratentorial lesions also correlate with disability during the first 12 months of therapy.

Prof. Comi emphasized, “Safety is as important as efficacy… there is no doubt that the safety of IFN and GA are certain [and] with natalizumab we have some problems, particularly PML.” He and other ECTRIMS speakers agreed that cladribine and fingolimod are associated with important adverse events and lack long-term data.

Oral Formulations

Oral medications are convenient; however, the 2 oral MS formulations fingolimod and cladribine require close monitoring to minimize toxicity. Fingolimod requires daily dosing and cladribine has a flexible dosing schedule: cumulative doses of 3.5 or 5.25 mg/kg taken as 1 or 2 10-mg tablets daily for 4 to 5 consecutive days for only 2 months every year. “These short annual courses would offer the advantage that patients would be treatment-free for 10 out of 12 months of the year,” explained Prof. Hartung. In CLARITY, nearly 90% of patients stayed on therapy for the entire 96-week trial.

Laquinimod, another new oral agent, does not appear to affect the viability or proliferation of human peripheral blood mononuclear cells, and so does not appear to interfere with cellular or humoral immune responses, explained Prof. Wolfgang Brück, Georg-August University, Göttingen, Germany. This agent appears to reduce expansion of the CD5 B-cells thought to be involved in autoimmune diseases and to increase the proportion of regulatory/suppressive B-cells (Abstract P850).

In a phase IIb, 36-week, double-blind, placebo-controlled clinical trial, laquinimod 0.6 mg was associated with robust, consistent and significant reductions in all MRI end points of disease activity, including a 50% reduction (P=0.0064) in the cumulative number of new hypointense T1 lesions. Annualized relapse rate was reduced by 33% (P=0.0978) even though the study was not designed or powered to show such an effect. In a 36-week, double-blind extension to this study, the effect on MRI lesions was sustained in patients who continued on active treatment and reproduced in those who switched from placebo to active treatment. “We can be optimistic about this drug which shows robust and reproducible effect on inflammatory activity,” Prof. Ludwig Kappos, University of Basel, Switzerland, told delegates.

BG-12 (dimethyl fumarate) is an oral agent that inhibits CNS inflammation in EAE. It appears to have a good tolerability and safety profile, making it suitable for combination therapy with IFNß or GA. In a study of healthy volunteers reported by researcher James Woodworth, PhD, Cambridge, Massachusetts, et al. (Abstract P478), neither IFNß nor GA altered the pharmacokinetic profile of BG-12 and no new safety signals were observed. A phase II open-label multicentre study is now ongoing in which RRMS patients receive 2 months’ GA or IFNß monotherapy followed by 6 months’ combination treatment with BG-12.

Questions and Answers

The following section is based on discussions with Prof. Ludwig Kappos, University of Basel, Switzerland, during the scientific sessions.

Q: With treatments for MS becoming more effective, what is the ultimate goal?

A: To control or halt the inflammatory process and to preserve the function of the CNS. The very ultimate goal would be to offer those patients who have permanent deficits some improvement, not only symptomatic improvement but also some neuroregeneration and repair. But at the moment we are very happy if we can control the disease and prevent further progression.

Q: Is there a trade-off between efficacy and safety?

A: The use of combination therapy with lower doses of individual agents could improve risk/benefit profiles as could restricting the more dangerous compounds to certain phases of the disease. This could be a strategy in the future but is very difficult to explore and means more complicated trials.