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22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS)

Madrid, Spain / September 27-30, 2006

Treatment Optimization Protocols

Despite the availability of several disease-modifying drugs (DMDs) for the treatment of relapsing-remitting multiple sclerosis (RRMS), no single available agent, not even the most active, can control disease progression in all patients. Efforts to improve therapy therefore now focus largely on optimizing protocols using combination treatment, short-term induction therapy or switching between DMDs.

Combination therapy is routine in many other therapeutic areas. Dr. Christian Confavreux, Hôpital Neurologique Pierre Wertheimer, Lyon, France, cited experience in oncology, tuberculosis, HIV infection and rheumatoid arthritis that plainly demonstrates that added value can be gained by combining two or more agents. Many pilot or preliminary trials of combination therapy already have been completed in MS and more definitive ones are in progress or planned. When designing such a study, it is important to choose agents that have already demonstrated efficacy as monotherapy and that have different mechanisms of action, to increase the probability of additive or synergistic activity, Dr. Confavreux explained during a session devoted to combination therapy. The choice must also take into account the drugs’ tolerability and toxicity profiles and their convenience, he added. To overcome trial design problems, particularly with multiple combinations needing large patient populations, he recommended using a 2 X 2 factorial approach which requires a sample size similar to that for a conventional controlled trial of monotherapy. Had this design been used for the two large-scale phase II studies of natalizumab—SENTINEL (The Safety and Efficacy of Natalizumab in Combination with IFNb in Patients with RRMS), which compared interferon b 1a (IFNb-1a) plus natalizumab to IFNb-1a alone, and AFFIRM (Natalizumab Safety and Efficacy in RRMS), which compared natalizumab to placebo—the findings would have been easier to interpret. Dr. Confavreux told delegates that he and co-investigators were unable to state conclusively that the combination of natalizumab/IFN was superior to natalizumab alone.

Several combination trials reported at the meeting featured glatiramer acetate (GA). GA combined with i.v. methylprednisolone (1 g monthly for six months) followed by GA monotherapy for six months provides early and persistent effects on disease activity, as measured by MRI, reported Dr. Clive Hawkins, University Hospital of North Staffordshire, Stoke-on-Trent, UK, and associates from Italy. The combination produced a 65% reduction in the number of T1-weighted gadolinium (Gd)-enhancing lesions, which was sustained for an additional six months when patients received GA alone. Non-inferiority analyses showed no difference between the changes in the first and second six-month periods. Mean annualized relapse rate was reduced by 65.6% and 71.8%, respectively, from 1.6 in the year prior to study entry to 0.55 and 0.45, respectively. Mean converted Expanded Disability Status Scale (EDSS) change from baseline showed a small but significant improvement in patients completing 12 months’ treatment (-0.15 [-0.29, -0.13]; P=0.0323).

ASSERT (Assessment Study of Steroid Effect in Relapsing MS Subjects Treated with GA), another long-term combination study, is now ongoing in North America. This double-blind, randomized study will investigate whether there are additive effects of five days of therapy with 1.25 g oral prednisone given every four months to RRMS patients beginning three years of GA therapy, as evaluated by brain volume change, and other MRI and clinical end points. This is “an interesting study and hopefully one that will be more decisive [than previous studies] when it reaches its conclusion,” commented Dr. Jerry Wolinsky, Director, Multiple Sclerosis Research Group and the Magnetic Resonance Imaging Analysis Center, and Interim Dean and Bartels Family and Opal C. Rankin Professor of Neurology, University of Texas Health Science Center at Houston.

Another option discussed by Dr. Confavreux and several other speakers is to use short-term induction with an immunosuppressant. Dr. Timothy Vollmer, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, Arizona, reviewed the findings of a trial of induction therapy with mitoxantrone preceding GA treatment. This multicentre, randomized, single-blind study had two objectives. The first was to determine if short-term low-dose induction of immunosuppression using mitoxantrone in patients with RRMS provides enhanced GA efficacy in the first year of therapy. “If true, it could provide an option for patients with very active disease, who then [would] go onto GA therapy,” Dr. Vollmer noted. A second objective was to determine if this same strategy increases long-term GA efficacy. If so, then it could be applicable to most patients with RRMS. Mitoxantrone was administered at a dose of 12 mg/m2 at months 0, 1 and 2, followed by a two-week washout before starting GA (20 mg daily). The primary outcome assessment was the mean number of T1-weighted Gd-enhancing lesions per scan; secondary outcome measures were relapse rate, the proportion of relapse-free patients and time to first relapse. Primary study duration was 15 months with an optional 36-month extension phase. During the first 15 months, the reduction in the mean total number of Gd-enhancing lesions in the group that had received the induction therapy (n=21) was approximately 90% and was significantly greater (P=0.0001) than that in the GA-only group (n=19).

Efficacy Analysis: Mean Total Number of T1-enhancing Lesions (±SE)

The induction group also had fewer relapses: four vs. seven (relative risk ratio 0.54; P=0.31). Although this difference did not reach statistical significance, this may have been due to the small sample size, Dr. Vollmer explained. Eighty-one per cent and 79%, respectively, of patients remained relapse-free. Although more infections and nausea occurred in the induction arm, these were mild in nature. Preliminary 24-month data from the extension study indicate that the differences between groups in the reduction in both mean total Gd-enhancing lesion number and relapse rate are maintained. “Short-term [low-dose] induction of mitoxantrone followed by daily GA therapy is safe and generally well tolerated… Based on this data, we suggest that a definitive trial is warranted,” Dr. Vollmer concluded.

A similar study, but with a longer induction period, has been conducted in patients with either RRMS or secondary progressive MS (SPMS) who had failed to respond to IFNb. After stopping the IFNb, 80 patients went on to mitoxantrone and 72 of them completed one year of therapy. Forty-three then started GA with 30 receiving it for one year and another 13 still undergoing therapy. Mean relapse rate was 1.7 (CI: 1.0, 2.0) on IFNb, 0.07 (0.02, 0.2) on mitoxantrone and 0.3 (0.1, 0.6) on GA. These differences were statistically significant (P<0.0001 and P=0.001 between the first and second, and the first and third periods, respectively). Median lesion number on MRI was 1.0 on IFNb and zero during both the mitoxantrone induction and GA phases of therapy. The investigators, Dr. Neus Téllez Lara and colleagues from the Vall d’Hebron University, Barcelona, Spain, concluded that this strategy could be a treatment option for IFNb non-responders.

Somewhat disappointing results emerged from a recently completed trial in patients with early RRMS. This was a randomized, double-blind, placebo-controlled study of i.m. IFNb-1a monotherapy vs. IFNb-1a/azathioprine vs. IFNb-1b/azathioprine/prednisone. Azathioprine was administered at a dose of 50 mg/day and prednisone at a dose of 10 mg every other day. “I would like to stress that the low dosage of the drugs was chosen intentionally because we believed in [their] synergistic effect; at the same time, we wanted to decrease the adverse events of this long-term therapy,” stated Dr. Dana Horakova, Buffalo Neuroimaging Analysis Center, Jacobs Neurological Institute, State University of New York, who presented the results on behalf of her colleagues in the US and the Czech Republic. At two years, there was no significant difference between groups in relapse rate, the primary end point, although a slight trend favoured triple combination therapy. Similarly, time to first relapse, time to sustained disability progression and increase in mean EDSS score did not differ significantly between groups either at two or five years. “At this time, there is insufficient evidence to conclude that combination therapy of IFNb-1a with azathioprine or with low-dose steroids is superior to monotherapy in patients with early relapsing MS,” Dr. Horakova noted, “so we cannot recommend this triple combination as first-line therapy.”

Switching from one immunomodulatory agent to another is also an option for optimizing therapy even without an induction phase, although no class-I data are yet available to support such a strategy. Dr. Adriana Carrá, Hospital Británico de Buenos Aires, Argentina, and colleagues indicated that they have obtained promising results by switching 65 patients on IFNb to either GA (52 patients) or mitoxantrone (13 patients). Following the switch to GA, annual relapse rate decreased by 77% and the proportion of relapse-free patients was four times higher: 68% vs. 16%. The switch to mitoxantrone reduced annual relapse rate by 81%. In contrast, switching from GA to IFNb, or from low- to high-dose IFNb, was somewhat less beneficial, reducing annual relapse rate by 67% and 56%, respectively. EDSS changes also significantly favoured the IFNb to GA switch rather than vice versa (P=0.0035).

Neurodegeneration and Neuroprotection: New Insights

There is increasing knowledge of the pathophysiological processes underlying MS. Axonal damage is the major morphological substrate and the determinant of permanent neurological deficits and disability in patients with MS. However, as Dr. Hans-Peter Hartung, Professor of Neurology, Heinrich Heine University, Düsseldorf, Germany, admitted, “We still do not entirely understand how axonal damage is brought about.” Nevertheless, it seems that the destructive pathological processes involved occur in the wake of a vigorous inflammatory response. To prevent neurodegeneration, it therefore makes sense to use immunomodulatory agents with different but complementary mechanisms of action to target different aspects of this response. IFNb, for example, appears to interfere at a number of sites crucial in the sequence of immunopathogenic events, starting in the periphery but also inhibiting the migration of autoreactive T-cells from the immune system into the brain. On the other hand, GA results in the production of specific Th2, GA-reactive T-cells that migrate into the brain where they cause bystander suppression.

Other evidence, however, suggests that suppression of inflammation is insufficient to prevent the neurodegeneration characteristic of MS. Dr. Imke Metz, Georg-August University, Göttingen, Germany, described her autopsy studies in MS patients dying after autologous stem cell transplantation. MS lesion tissue showed profound suppression of inflammation. However, she added, “There is evidence of ongoing demyelination and axonal damage and areas of axonal damage co-localize with activation of microphages and microglial cells. Macrophage and microglia activation appears to persist, possibly due to an elimination of regulatory T-cells.” In this regard, it is notable that CD4+ CD25+ regulatory T-cells, which are pivotal in the maintenance of self-tolerance, have recently been shown to confer protection against experimental autoimmune encephalomyelitis (EAE) in a murine model. Dr. Youngheun Jee and colleagues from Dr. Vollmer’s group in Phoenix have found that the therapeutic effects of GA appear to be mediated entirely by these regulatory T-cells, suggesting a mechanism of action that is independent of that involving the well-described Th1/Th2 switch. “The generation of highly-efficient [regulatory T-] cells by GA could be used as an attractive therapeutic tool in the future,” they suggested.

Further insights into the neuroprotective mechanisms of action of GA come from whole brain magnetization transfer (MT) imaging studies, conducted by researcher Megan Mackenzie, Wayne State University School of Medicine, Detroit, Michigan, and colleagues. MT imaging is a highly sensitive technique based on interactions between relatively mobile and less mobile protons. In the CNS, MT imaging is used to derive a ratio (MTR), which expresses the extent of magnetization exchange between macromolecules bound to myelin and the more mobile protons in surrounding tissue. MTR is reduced in MS compared with normal tissue, reflecting damage to myelin or the axonal membrane. The Detroit group studied 29 treatment-naive RRMS patients starting therapy with either high-dose IFNb (IFNb-1a 44 mcg s.c. twice weekly or IFNb-1b 250 mcg s.c. every other day) or GA. MTR of whole-brain tissue increased from baseline in both GA- and IFNb-treated patients but this was statistically significant only in the GA group (P=0.01). These observations suggest that the therapeutic effect of GA in the CNS may occur independently of changes induced at the blood-brain barrier, the predominant site of action of IFNb. Measuring MTR may also be a promising tool to monitor the therapeutic effect of combination therapies with contrasting mechanisms of action (such as GA and IFNb), the investigators stated.

A prospective, long-term study of brain magnetic resonance spectroscopy (MRS) conducted by the same group confirms their earlier findings that GA limits sublethal axonal injury and promotes axonal metabolic recovery as indicated by a relative increase in N-acetylaspartate (NAA), an axonal-specific marker, determined by the NAA:creatine (NAA:Cr) ratio. This study, which now extends to four years’ follow-up, also shows that the change in the mean NAA:Cr ratio parallels that in mean EDSS, suggesting that long-term monitoring of NAA using MRS may be a useful tool to follow disease progression. In one untreated patient, for example, mean NAA:Cr in the volume of interest (VOI) fell from 2.26 at baseline to 1.94 at year 4, while their EDSS score increased from 1.5 to >2.5. In patients receiving GA over the same time period, however, mean VOI NAA:Cr increased from 1.96 to 2.21 while mean EDSS declined from 2.77 to 2.10.

The agent may also exert its neuroprotective effects via oligodendrocytes. The formation of oligodendrocytes from progenitor cells is a prerequisite for remyelination in MS and several neurotrophic factors regulate oligodendrocyte development. Dr. Catherine Fressinaud, University Hospital, Angers, France, has shown in an experimental model that the capacity of oligodendrocytes to remyelinate axons is impaired in MS but improved by the growth factors neurotrophin-3 and platelet-derived growth factor (PDGF). Other recent research conducted by Dr. Viktor Skihar, University of Calgary, Alberta, and colleagues shows that GA-reactive Th2 cells from GA-primed mice produce increased levels of PDGF, insulin-like growth factor-1 (IGF-1), leukemia inhibitory factor (LIF) and vascular endothelial growth factor (VEGF). Furthermore, when mice with lysolecithin-induced demyelination were treated with GA, they produced increased numbers of oligodendrocyte precursors.

In his discussion on the role of inflammation and neurodegeneration in axonal injury and brain atrophy, Dr. Hartung emphasized that brain atrophy, reflecting axonal loss, has been detected very early in the course of the disease, in clinically isolated syndromes (CIS) as well as in early clinically definite MS (CDMS). This provided the rationale for the CHAMPS, ETOMS and BENEFIT studies and, more recently, for PreCISe, a three-year, randomized, double-blind, placebo-controlled study of GA followed by an open-label extension. Its objective is to determine whether starting GA therapy at CIS rather than CDMS delays accumulating MRI and clinically defined disability.

Comparative Studies

There are only a few well-designed comparative studies of MS therapies, therefore the evidence to support a relative preference of one compound over another within an individual class remains limited. Although licensed for use in MS, natalizumab is not recommended as a first-line option because of the associated increased risk of opportunistic infections.

The BECOME (Betaseron vs. Copaxone in MS with Triple-Dose Gadolinium and 3-T MRI Endpoints) study is the first randomized trial focusing on the MRI outcomes of patients treated with IFNb and GA. Initial MRI results from the study were reported here during the scientific sessions. The primary outcome was the cumulative number of combined-active lesions, defined as the number of enhancing lesions plus the number of new T2 lesions unassociated with enhancement. This measure was similar in both treatment groups; thus, GA and IFNb appeared to be similarly effective in reducing MRI-measured disease activity. Moreover, although a secondary analysis showed a statistically significant drop in active lesion count compared with pretreatment levels for IFNb-1b but not GA, this finding could have been an artifact of the high sensitivity of the method, suggested Dr. Leo Wolansky, New Jersey Medical School, Newark and Holy Name Hospital, Teaneck, and co-investigators. In other words, fading lesions incurred pretreatment might have been counted, in error, in the post-drug scans.

Another randomized, comparative trial, reported by Dr. Nese Öztekín, SB Diskapi Hospital, Ankara, Turkey, and colleagues, compared the effects of IFNb-1a s.c. (22 mcg or 44 mcg thrice weekly), IFNb-1a i.m. (30 mcg once weekly), IFNb-1b (8 mU s.c. every other day), and GA daily over a six-year follow-up period. Among the 271 patients remaining from the original group of 316, there were no statistically significant differences between treatment groups in annual relapse rate, relapse frequency or MRI disease activity, suggesting all treatments were similarly effective.

With so little comparative data available, the clinician must rely on other evidence when choosing between therapies. “Real life” studies, such as that reported by Dr. Judith Haas, Jewish Hospital, Berlin, Germany, may be useful. Dr. Haas presented the results of a six-year follow-up analysis of nearly 250 RRMS patients receiving IFNb-1a i.m., IFNb-1a s.c., IFNb-1b and GA. All treatments significantly reduced the annual relapse rate. However, in the inter-group comparison for the GA-treated patients, the mean annual relapse rate was significantly lower at up to 48 months of treatment compared to each of the three IFNbs, and GA was still significantly more efficacious than IFNb-1a i.m. after 72 months of treatment. The proportion of progression-free patients was also higher with GA: >81% compared with <63% for those treated with IFNb-1a i.m. and 69% in those receiving either IFNb-1b s.c. or IFNb-1a s.c. Efficacy plays a key role in adherence to long-term therapy, and this is consistent with the lower discontinuation rate with GA (48%) than with any of the IFNbs (over 70%). The investigators stressed that prospectively planned, well-structured, standardized clinical long-term studies such as theirs might allow a valid comparative assessment of treatment effects. They added that, despite the open setting, their analytic methods could eliminate the possibility of bias due, for example, to baseline differences or influence of covariates.

Dr. Carrá’s group also documented better efficacy and long-term adherence with GA than with the IFNbs. In a 10-year follow-up of more than 1500 patients in Argentina, they observed drop-out rates of only 12% with GA compared with 55.8% with IFNb-1a i.m. and 34 to 35% with IFNb-1a s.c. Of the GA-treated patients, only 13.1% stopped therapy due to lack of efficacy compared with 32.2 to 73.6% of those using IFNbs. These results contradict those of the multinational Global Adherence Project (GAP) which found adherence to IFNb-1a was better than to any other DMDs. However, the GAP researchers defined non-adherence as missing any injection at any time. Not surprisingly, half of the 2566 patients in the study were non-adherent by this definition. T

he Role of Antibodies

Another consideration when choosing or switching therapies is the importance of antibodies produced against the current treatment. In patients receiving IFNb, the development of neutralizing antibodies (NAbs) continues to cause concern, as demonstrated by the number of presentations given on the topic. As Dr. Bernd Kieseier, Professor of Neurology, Heinrich Heine University, reminded delegates, up to almost one-half of patients in the phase III IFNb trials developed NAbs which significantly impaired the drug’s efficacy in reducing MRI lesion load, relapse rate and disability progression. “All the data coming from the real world reflect what has been measured in the clinical phase III trials,” he added. NAb measurement in patients receiving IFNb therefore provides a useful indication of the likelihood of sustained response. Consequently, the recently-published guidelines from the European Federation of Neurological Societies recommend testing for the presence of NAbs in all patients on IFNb at 12 and 24 months of therapy. IFNb should be stopped in those with continuing high NAb titres.

In contrast, the antibodies that develop against GA therapy do not impair its efficacy. Dr. Dvora Teitelbaum, Weizmann Institute of Science, Rehovot, Israel, and colleagues have recently confirmed their previous observation that anti-GA antibodies found during treatment have little, if any, neutralizing activity. For this latest report, the researchers collected serum samples from 126 MS patients treated with GA for two to 15 years and tested the capacity of the serum to inhibit the proliferation of GA-specific T-cells. Although nearly all patients had anti-GA antibodies, only six showed a minimal inhibition (10 to 25%) of GA-specific T-cell proliferation in vitro. Furthermore, patients treated with GA for a mean of more than 6.5 years showed only a minimal mean increase of 0.65 on the EDSS and, after a mean disease duration of 10.75 years, 86% of patients had not reached an EDSS score of 5.0 and 77% had a score of <4.0. “These results,” observed the investigators, “are consistent with previous findings that the therapeutic effect of GA is maintained upon long-term treatment and is not compromised by GA antibodies.”

New Therapeutic Options in Development

Several new therapeutic options for the treatment of RRMS were also discussed here during the scientific sessions. These include a new agent FTY720 (fingolimod) and a 40-mg daily dosing schedule for GA.

The sphingosine-1-phosphate receptor modulator fingolimod is the first in a new class of orally active DMDs. In a recently completed phase II study, 281 patients were randomized to receive placebo or active treatment at either 1.25 mg or 5 mg daily. After six months, the placebo group was rerandomized to one or other of the active doses. At six months, patients in the 1.25-mg and 5-mg groups showed a reduction in Gd-enhancing lesions of 43% and 62%, respectively, compared with the original placebo group, with 77% and 82% vs. 47%, respectively, of patients showing no such lesions. Annualized relapse rates fell by 55% and 53%, respectively, compared with placebo. These improvements were sustained among the 250 patients who entered the double-blind extension phase. However, due to the higher frequency of serious/severe adverse events and discontinuations due to adverse events in the group receiving 5 mg—and because this dose appeared no more effective than the 1.25-mg dose—all patients were switched to the latter at 15 months, explained Dr. Paul O’Connor, Chief, Division of Neurology, St. Michael’s Hospital, and Associate Professor of Medicine, University of Toronto, Ontario, and co-investigators. The extension study continues in an open-label manner and the ongoing phase III program in RRMS will evaluate the 1.25-mg dose and a lower dose of 0.5 mg.

Although three pivotal trials support the efficacy, tolerability and safety of GA 20 mg daily in RRMS, until now there have been few data about other doses of this DMD. Hence the recent nine-month, multicentre, randomized, double-blind, parallel-group, phase II study evaluating a 40-mg daily dose. Patients were randomized to receive one of the two GA doses and underwent MRI scans at baseline and at months 3, 7, 8 and 9. Of the 90 patients randomized in the intent-to-treat cohort, 81 were evaluable for the primary end point, the total number of T1-weighted Gd-enhancing lesions at months 7, 8 and 9. This end point showed a 38% reduction in the 40-mg vs. the 20-mg group. Although this difference did not quite reach statistical significance (P=0.0898), this was because the study was powered to detect a 60% difference with 50 patients in each arm, explained Dr. Massimo Filippi, Director, Neuroimaging Research Unit, Scientific Institute and University, Ospedale San Raffaele, Milan, Italy, who presented the findings. “It is likely that if we had increased the patient number, significance would have been reached,” he commented. Relapse rate and the percentage of relapse-free patients, two of the secondary end points, also showed differences favoring the higher GA dose. Time to first confirmed relapse was delayed from 80 days in the 20-mg group to 231 days in the 40-mg group. The higher dose was generally well tolerated with a similar frequency of injection site reactions in both groups. This study “suggests that 40 mg may be more effective than the currently approved 20-mg dose in reducing MRI activity and clinical relapses,” Dr. Filippi concluded. A phase III study of the higher dose is currently underway.