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MEDICAL FRONTIERS - 5th Joint Triennial Congress European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS 2011)

Amsterdam, The Netherlands / October 19-22, 2011

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

The recent surge in new and emerging options for the treatment of multiple sclerosis (MS) was reflected in an exceptional quantity of new trial data presented here. Several late-phase trials with new oral agents suggest that this category of MS therapy is poised to expand, but the challenge will be to determine where newer agents fit with the well-established efficacy and safety of current therapeutic mainstays such as glatiramer acetate (GA) and the interferons (IFNs).

“The data we are seeing at this meeting are very exciting,” observed Prof. Ralf Gold, Ruhr University, Bochum, Germany. In a brief review of new data on the final day of the meeting, Prof. Gold expressed his enthusiasm about emerging drugs as well as new applications for existing drugs. He did not confine his remarks to oral agents but also cited encouraging applications of other options, including monoclonal antibodies (MAbs).

Importantly, despite encouraging trial results, the precise place of new agents in treatment algorithms is not expected to evolve rapidly because of the critical importance of long-term follow-up in large numbers of patients to establish efficacy and safety. Extended follow-up is needed for efficacy because surrogate predictors of long-term outcome, including imaging and relapse rates, have proven to be inexact. For safety, the potential for unexpected adverse events (AEs), even years after initiating a therapy that alters immune function, is substantial.

Efficacy and Safety Benchmarks

The decades of exposure to the standard disease-modifying therapies (DMTs) GA and the IFNs have established a benchmark for efficacy and safety with which newer agents, such as oral drugs and MAbs, must compete. In Canada, the first oral therapy, fingolimod, became available in 2011. Judging by remarks from Prof. Gold and the new data presented at the meeting, other oral therapies will soon follow.

One reason to anticipate further development of oral agents is that the efficacy and safety data generated by trials with fingolimod, now licensed in many countries worldwide, continues to be favourable in a series of subgroup analyses from the phase III FREEDOMS trial, which was placebo-controlled, and the TRANSFORMS trial, which compared fingolimod to IFN beta-1a (IM). In a study that combined data from both trials and then evaluated relative efficacy based on previous treatment and disease activity, the advantage of fingolimod relative to either placebo or the IFN was consistent across stratifications.

Specifically, the 3 subgroups analyzed in the pooled data were: 1) those who had received IFN in the year prior to randomization and then had equal or more relapses in the first year compared to the second year of treatment; 2) those who had received IFN in the year prior to randomization, had either a gadolinium (Gd)-enhancing T1 lesion or 9 T2 lesions at baseline and then had at least 1 relapse in the first year; and 3) those who were treatment-naive, had at least 1 Gd-enhancing lesion at baseline and 2 or more relapses after randomization. According to the lead investigator for this analysis, Dr. Eva Havrdova, Charles University, Prague, Czech Republic, fingolimod at the licensed dose of 0.5 mg/day “improved clinical outcomes compared with placebo or with IFN” in all 3 groups.

Data sets are also quickly growing for oral agents not yet available in Canada. At the meeting, extension studies with teriflunomide provided support for the safety and efficacy data reported previously from the phase III TEMSO trial. Whether patients were initiated on teriflunomide or started on placebo and were then switched after 2 years, the annualized relapse rate (ARR) remained low over the full 5 years of evaluation, according to Dr. Paul W. O’Connor, St. Michael’s Hospital, Toronto, Canada. These ranged from 0.182 for those starting on placebo and switching to a once-daily pill of 14 mg teriflunomide to 0.251 for those who started on placebo and switched to 7 mg. Dr. O’Connor reported that the increase in MRI lesion volume was numerically although not statistically lower in the groups that started on active treatment compared to the groups that started on placebo.

According to the safety data—collected after 4 years and presented by Prof. Giancarlo Comi, Chair of Neurology, Vita-Salute San Raffaele University, Milan, Italy—there were no significant changes from AEs reported after 2 years. The most common side effects were nasopharyngitis (about 22% with either dose), headache (about 12% with either dose) and liver enzyme elevations (about 12% with either dose). He concluded that the long-term follow-up supports the “favourable safety profile” reported previously.

In a new substudy from the 2-year TEMSO results, cognitive function appeared significantly improved vs. placebo as measured with the Paced Auditory Serial Addition Test (PASAT-3), according to Dr. Aaron Miller, Mount Sinai School of Medicine, New York City. Calling cognitive impairment a common cause of diminished well-being in MS patients, Dr. Miller indicated that this finding provides additional support for the agent’s utility.

The initial phase III data for the oral agent laquinimod were first released at the ECTRIMS/ACTRIMS meeting. In this trial, called BRAVO, 1331 relapsing-remitting MS (RRMS) patients were randomized at 153 sites in 18 countries to oral laquinimod 0.6 mg q.d., a matching oral placebo or IFN beta-1a 30 mcg (IM) once weekly. The comparison of the laquinimod and placebo arms was double-blind. According to the principal investigator Dr. Timothy Vollmer, University of Colorado Health Sciences Center, Denver, laquinimod is a first-in-class medication that appears to work by decreasing activation of immune cells in the central nervous system (CNS) which trigger demyelination.

In BRAVO, laquinimod was associated with a variety of measures of benefit when compared to placebo after adjusting for baseline differences in disease activity, including a 21% reduction of ARR (P=0.026), a 27.5% reduction of brain atrophy on magnetic resonance imaging (MRI) (P<0.0001) and a 33.5% reduction in the risk of disability as measured on the Expanded Disability Status Scale (EDSS) (P=0.044). The 29% reduction in the ARR in the IFN beta-1a IM arm vs. placebo was similar to that of laquinimod (P=0.002), but the 28.7% reduction in disability fell short of statistical significance (P=0.089). In addition, IFN beta-1a IM had no effect on brain atrophy.

Initial phase III data were also first released at ECTRIMS/ACTRIMS for the oral agent BG-12. In the DEFINE trial, 1234 patients were randomized to BG-12 240 mg b.i.d., 240 mg t.i.d. or placebo. As a second-generation fumarate derivative, BG-12 is thought to exert anti-inflammatory effects by modifying the activity of leukocytes, including their ability to release pro-inflammatory cytokines.

At the end of 96 weeks on treatment, the risk of relapse was reduced by approximately 50% (P<0.0001) with either BG-12 schedule. In addition, the b.i.d. dose reduced the risk of disability progression by 38% (P=0.005) and the t.i.d. dose by 34% (P=0.0128) relative to placebo, according to the lead investigator, Prof. Gold. He noted that results support the premise that “BG-12 may be a valuable treatment option.”

In a separately presented MRI DEFINE substudy, b.i.d. and t.i.d. doses of BG-12 were associated with a 90% and 73% reduction in Gd-enhancing lesions as well as a 85% and 74% reduction in new or newly enlarging T2 lesions, respectively. The anti-inflammatory effect in this 540-patient substudy was characterized by principal investigator Dr. Douglas L. Arnold, Montreal Neurological Institute, Montreal, Canada, as “in line with that of the most potent approved agents in MS.”

In a third presentation, DEFINE safety data indicated that the rate of serious AEs in patients receiving BG-12 was similar to that of the placebo group. The rate of discontinuations for AEs was 16% in each of the BG-12 arms and 13% in the placebo arm. By far the most common side effect occurring at a greater rate in the active treatment groups relative to placebo was flushing. This was clinically significant in about one-third of BG-12 patients compared to 5% of patients receiving placebo. In his summary of the DEFINE results, Prof. Gold cautioned that adjunctive therapy to reduce the severity of flushing might be required in some patients.

Monoclonal Antibodies

In addition to the oral therapies, there was important new information presented on several MAbs, including natalizumab, which is already licensed for use in the treatment of MS, as well as alemtuzumab and daclizumab. From the efficacy perspective, data on natalizumab from the RESTORE study, presented by Dr. Robert J. Fox, Cleveland Clinic, Ohio, corroborated the activity previously reported. In the RESTORE trial, which was designed to evaluate the effect of 24-week interruptions, patients were randomized to infusions of natalizumab, placebo or treatment with a DMT such as GA or IFN. The natalizumab and placebo arms were blinded. After 2 years, none of those receiving natalizumab had a return of disease activity on the basis of predefined MRI criteria vs. 44% of patients receiving placebo. Those with the greatest MRI activity before randomization were the most likely to have a return of activity on placebo.

From the safety perspective, concern about the risk of progressive multifocal leukoencephalopathy (PML) with this agent persists. Of the 124 cases of PML associated with this agent so far, 101 (80%) remain alive, according to Prof. Ludwig Kappos, University Hospitals, Basel, Switzerland. He noted that this survival rate is generally higher than that observed in PML associated with other causes. However, he also reported that all of the patients who have developed PML on natalizumab have some degree of disability. The disability is considered severe in 37% of survivors.

In the CARE-MS trial, presented by Dr. Alasdair J. Coles, Cambridge University, UK, alemtuzumab was compared to IFN beta-1a (SC) in 581 patients. At the end of 2 years of follow-up, the ARR of 0.18 in the alemtuzumab group was 55% lower (P<0.0001) than the 0.39 rate on the IFN. Although the difference in sustained accumulated disability was not statistically lower on alemtuzumab (8% vs. 11%; P=0.22), there was a significant reduction in new lesion formation on MRI. However, the authors also reported more significant AEs on alemtuzumab, including hyperthyroid disease (18.1% vs. 6.4%) and more withdrawals for AEs (5.9% vs. 1.3%).

In a trial with daclizumab, the primary outcome was change in ARR. In the trial results, presented by Dr. Gavin Giovannoni, Queen Mary University, London, UK, patients were randomized to daclizumab 150 mg every 4 weeks, 300 mg every 4 weeks or placebo. At 1 year, the relapse rates vs. placebo were reduced 54% (P<0.0001) in the lower-dose group and 50% (P=0.0002) in the higher-dose group. There were no serious AEs associated with this agent, but follow-up remains limited.

Early Treatment

The progress with the development of new agents is encouraging, but these drugs are not expected to supplement or replace GA and the IFNs, which are supported by large sets of efficacy and safety data. Indeed, the indications for these agents may expand based on a growing preponderance of evidence supporting early treatment. One of the most interesting analyses outside of the trial data with new agents was a data review generated from the BENEFIT, ETOMS, REFLEX, PreCISe and CHAMPS trials (Table 1). Each of these trials evaluated either GA or IFNs on outcome in patients with clinically isolated syndromes (CIS). The message from these studies, according to Prof. Comi, who conducted this review, is that delay in clinically definite MS (CDMS) can be achieved with early treatment of CIS.

Table 1.

“These findings have led to a paradigm shift towards earlier treatment of patients with a first clinical demyelinating event suggestive of MS,” Prof. Comi maintained. Furthermore, this approach becomes more attractive as diagnostic criteria for MS improve in sensitivity. In one substudy of REFLEX, the McDonald 2010 criteria were shown to be more predictive of CDMS than the 2005 criteria. However, the REFLEX lead investigator Dr. Mark S. Freedman, University of Ottawa, Canada, noted that the benefits of the IFN for reducing the risk of transition from CIS to CDMS were achieved irrespective of whether 2005 or 2010 criteria were used.

In addition to their role in efforts to delay or prevent CDMS, the utility of GA and IFNs in routine management, regardless of the availability of newer agents, is well established. Newly presented data from the SAME study contribute to the evidence that any one of these agents can be used effectively and safely in routine care. In SAME, a retrospective evaluation of a cohort of 546 patients on DMT was conducted. The cohort represents approximately 10% of all patients receiving a DMT in Switzerland.

The goal of this study was to compare efficacy and safety in a real-world setting, according to Dr. Claudio Gobbi, Civic Hospital, Lugano, Switzerland, who was the lead investigator. He noted that previous studies have typically compared 2 of the 4 commercially available injectable therapies and only a few studies have compared IFN with GA.

The rates of ARR were 0.24 for GA, 0.27 for the IM IFN, 0.29 for SC IFN beta-1a and 0.22 for SC IFN beta-1b. The rate of flu-like symptoms in the IFNs ranged from 25.3% to 46.7% vs. 2.3% in the GA arm. Injection site reactions occurred in 10.5% of the IM IFN arm and ranged from 26.1% in the GA arm to 38.3% in the SC IFN beta-1b arm.

In terms of MS control, “All 4 injectable DMTs showed comparable efficacy for preventing disability and relapses,” Dr. Gobbi reported. In terms of AEs, “GA and IFN appear to be the most tolerable treatments,” with IFN showing an advantage for injection site reactions and GA showing an advantage for flu-like reactions.

Summary

Data from ECTRIMS/ACTRIMS document an exciting potential for a major expansion of therapeutic options in MS, including oral therapies, over the next several years. First-line therapies may change more slowly because of the availability of effective and proven options. Indeed, as new agents become available, the relative benefits and risks may not be fully understood for several years. While new options are important for those patients who are not achieving adequate control on the currently available DMTs, it is important to remember that these agents have well-established efficacy in first-line therapy and are now being increasingly employed in CIS patients thought to have a high likelihood of progressing to CDMS.