Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

MEDICAL FRONTIERS - 25th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS)

Düsseldorf, Germany / September 9-12, 2009

The heterogeneous nature of multiple sclerosis (MS) means that different patients will have different needs. As new treatments become available, it will be increasingly possible to tailor therapy to the individual. According to Dr. Mark J. Tullman, Columbia University Medical Center, New York, the ultimate goals are “to prevent accumulation of disability, prevent relapses and improve quality of life [QoL].” Therapies should also be “convenient to administer, safe, tolerable, and if possible, repair damage and restore function.”

In the case of the emerging therapies, it will take time to fully establish the risk:benefit profile in a daily practice setting. As this information becomes available, treatment decisions can be refined, taking into account the issues indicated in Figure 1.

The established disease-modifying therapies (DMTs)—the interferons (IFNs) and glatiramer acetate (GA)—have currently been on the market for many years, and follow-up and experience with these agents is steadily accumulating. Although there is limited evidence from extensive follow-ups, the long-term risks and benefits of these therapies have been reasonably well established.

Long-term Follow-up of Existing DMTs

For GA, the duration of prospective follow-up of patients included in a pivotal US clinical trial has reached 15 years. The original trial showed that GA significantly reduced the relapse rate compared to placebo, with significant differences seen from month 9 onwards. GA also prolonged the time to an increase in disability (defined as <u>></u>1.5 increase on the Expanded Disability Status Score [EDSS]). At the end of this initial study, patients on placebo could switch to GA and those already assigned to GA were given the option to continue.

The prospective follow-up was conducted in a modified intention-to-treat cohort with 232 patients, defined as anyone who received at least one dose of GA. Of these, 108 patients are still receiving it. Of the 124 patients who have stopped GA, 50 have a long-term follow-up visit, thus allowing comparison of patients who received continuous treatment with those who did not. “Among the patients still taking GA, a continuous decrease in relapse rate was observed while, encouragingly, mean EDSS score remained fairly constant,” observed Dr. Peter Rieckmann, University of British Columbia, Vancouver. Overall, 24% of these patients reached EDSS 4 and only 8% reached EDSS 8 compared to 69% and 50%, respectively, of those who discontinued GA at the final study visit.

Although controlled trials are logistically impossible over such long periods, historical cohorts can provide comparative data. In a natural history study that documented the least aggressive disease course reported so far, 21% of patients without treatment reached EDSS 6 after 15 years compared to 8% of patients on continuous GA in the prospective long-term follow-up. Dr. Rieckmann stressed that such a comparison is subject to possible bias: “I recognize the limitations of the approach, but I think it is the best we have got,” he acknowledged.

Given the difficulty of long-term, randomized, prospective studies, comparative data on DMTs are usually derived from observational studies. Although such studies are limited by potential biases—for example, it is generally thought that patients on intramuscular IFNß-1a have milder disease—these comparisons may be a useful indication. A study presented here by Dr. Adriana Carrá, Hospital Británico, Buenos Aires, Argentina, and colleagues used both the Multiple Sclerosis Severity Scale (MSSS) and time to various EDSS milestones to compare outcomes of patients treated with GA and IFNs. In this case, treatment duration was shorter, around five years, for both types of treatment. Their analysis of long-term follow-up data found a 31% risk of reaching EDSS ³6 in patients treated with IFNßs compared to 24% in those treated with GA.

Reconsidering Existing Therapies

In an analysis of the long-term follow-up data for GA mentioned earlier using the MSSS, which is based on natural history data and gives an indication of treatment effect, 56% of patients treated with GA showed a shift to a lower severity group compared to 28% of those with long-term follow-up who discontinued treatment (P<0.0001). “What is interesting,” commented Dr. Joseph Herbert, New York Hospital for Joint Disease, “is where are the patients who withdrew from the study coming from? We see that those with higher MSSS scores at the onset of therapy tend to withdraw.” The implication is that patients with higher MSSS scores are more likely to withdraw from therapy and that some patients might benefit from other therapeutic approaches.

Figure 1.

Safety Concerns with New Agents

The development of monoclonal antibodies has revolutionized treatment of many autoimmune diseases and cancers. Their highly specific cell binding has allowed unprecedented adjustment of signalling pathways. However, the potency of these compounds has also been responsible for various serious side effects, cautioned Dr. Alan Tyndall, Felix Platter Hospital, Basel, Switzerland.

He also pointed out that most studies with new agents explicitly exclude patients with impaired immune function or other situations that might increase the risk of adverse events. Given that these patients might not be fully representative of patients in clinical practice and the rarity of some serious adverse events, certain concerns might only be detected at a late stage of clinical development or during post-marketing surveillance.

Clinical studies with the monoclonal antibody natalizumab have found this agent to be highly effective. The risk of sustained disability progression was reduced by 42% to 54% and the annualized relapse rate by 68% over two years compared to placebo (Polman et al. N Engl J Med 2006;354(9):899-910). However, clinical development of the drug was voluntarily suspended in 2005 when two MS patients receiving natalizumab developed progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus.

Before the regulatory authorities authorized the reintroduction of natalizumab (as second-line therapy), an extensive risk management program was put in place. As Dr. Igor J. Koralnik, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, emphasized, “Early detection is the key to improving outcomes in this often fatal condition.” Patients and their families/caregivers are urged to be vigilant for possible changes and MRI studies should be performed on the slightest suspicion of the disease.

The incidence of PML is currently less than 1:1000 patients in post-marketing studies although it remains unclear how this incidence will change with increased duration of exposure. After discontinuation of natalizumab, plasma exchange and/or immunoadsorption accelerated removal of the drug from the circulation and seemed to lead to better outcomes: the majority of patients who developed PML are still alive albeit with neurological sequelae of varying severity.

New Therapies for MS

The adverse event profile was similar across the three treatment groups, although five cases of basal cell carcinoma and three cases of malignant melanoma were reported in the fingolimod groups compared to one case of each in the IFNß group. In addition, macular edema was detected in six patients in the fingolimod group compared to none in the IFNß cohort. All cases resolved with suspension of treatment.

The annualized relapse rate in the IFNß group was 0.33 compared to 0.16 in the fingolimod 0.5 mg group (relative difference vs. IFNß, -52%; P<0.001) and 0.20 in the 1.25 mg group (relative difference vs. IFNß, -38%; P<0.001). “This first active-comparator, double-blind, double-dummy, phase III study met its primary end point, demonstrating the superiority of oral fingolimod 0.5 mg and 1.25 mg over intramuscularly injected IFNß-1a on relapses,” concluded Dr. Jeffrey Cohen, Cleveland Clinic Foundation, Ohio. As a novel therapy currently in late-stage clinical development, laquinimod may also offer hope for those who do not respond well to existing treatment. This orally-active agent reduces infiltration of leukocytes into the central nervous system, inducing a shift to a more favourable Th cell profile (Th2 and Th3 cells are thought to promote neuroprotection whereas Th1 cells are associated with damage), as shown by work presented here by Prof. Wolfgang Brück, University Medical Center, Georg-August-University, Göttingen, Germany. This model also showed that the extent of demyelination was significantly lower in treated mice compared to control mice (3.8±1.9% vs. 9.3±4.3%; P=0.001) and significantly less axonal damage was observed in spinal cord lesions (697±185/mm²; P=0.014). “Our findings indicate that laquinimod might have an axon-protective effect in addition to its anti-inflammatory properties,” he concluded. Further evidence of neuroprotective effects was presented in which laquinimod also upregulates brain-derived neurotrophin, a neuroprotective agent. At both 0.3-mg and 0.6-mg doses, laquinimod was shown to reduce relapse rate compared to placebo in a preceding 36-week phase II study known as Laq5062 (Comi et al. Lancet 2008;371(9630):2085-92). Patients completing the study could continue treatment if they wished in the open-label extension (n=209). Those originally on placebo were randomized to either laquinimod 0.3 mg or 0.6 mg, and those already receiving active treatment continued with the same dose. All treatments lasted a further 36 weeks. The relapse rate for patients originally receiving active treatment continued to decline and that of those previously on placebo also showed a marked decrease.

The most common adverse events included nasopharyngitis (25.8%), back pain (12.4%) and headache (8.1%). There were no increased rates of specific malignant disease, nor were any cardiac events suggestive of myocardial ischemia reported in patients with laquinimod. No opportunistic or life-threatening infections were reported in the treatment arm. Overall, the orally-active agent was found to be safe and well tolerated in all phases of the study, with five patients having withdrawn due to adverse events.

The purine analogue cladribine is also under investigation. It was originally developed as a treatment for leukemia and provides immunomodulation by targeting certain lymphocyte populations. Although cladribine has shown efficacy in clinical trials such as the randomized, double-blind, placebo-controlled CLARITY (Cladribine Tablets Treating MS Orally) study, there is concern about its safety in long-term use.

Cladribine is administered in short courses (once daily for four to five days) for two or four consecutive months (28-day periods). In a safety analysis of the CLARITY study, the overall rate of adverse events was comparable between treatment groups. Herpes zoster and uterine leiomyomas were reported more frequently in the cladribine groups and, as expected from the mechanism of action, lymphopenia was also more common in the treatment arm (26.7%) vs. placebo (1.8%). Otherwise, frequencies of individual adverse events were similar between treatment groups and a similar proportion of patients in each group discontinued treatment because of adverse events (5.8% vs. 2.1%, respectively).

Dr. Stuart Cook, University of Medicine and Dentistry of New Jersey, Newark, observed: “The profile of adverse events seen in this study suggests that cladribine can be considered a new treatment option in MS.”

Quality of Life

An efficacious treatment that prevents relapses and/or slows underlying disease progression will clearly help improve patients’ QoL. A study by Dr. Thibault Moreau, Neurology Department, CHU de Dijon, France, and colleagues examined whether a measure of disability such as EDSS can truly capture QoL as perceived by the patient. Existing QoL tools are not specifically adapted to MS, and so the investigators aimed to evaluate and validate the Subjective Quality of Life Profile (SQLP) questionnaire in patients treated with GA.

Researchers recruited 310 patients with RRMS (mean age, 42 years; 72% women). Of the total number of patients, 69% had EDSS 0-3, 15% had EDSS 3-4 and 16% had EDSS >4. They were evaluated twice at separate visits, 10 months apart. On the four most important domains—somatic, relationship, activity and intellectual—there was a significant correlation between baseline EDSS score and SQLP score (P<0.05 for all comparisons). The investigators also detected significant improvements in QoL between study visits for the de novo patients. “This study documents a link between EDSS and SQLP and shows stable or increasing QoL in MS patients who receive GA,” they concluded.

Summary

Traditionally, both physicians and patients have regarded MS as a debilitating disease with a dismal prognosis. However, the increasingly longer follow-up of patients on DMTs such as the IFNs and GA suggests a more manageable disease, with fewer relapses and slower disease progression. These treatments have demonstrably improved QoL of many patients, who typically are young people of working age.

The arrival of therapies such as natalizumab (already approved as second-line therapy in RRMS) and the prospect of yet others should provide the clinician with more options. However, the efficacy of these treatments, with their strong immunomodulatory effects, comes at a cost. Close monitoring of opportunistic infections and other serious adverse effects, such as neoplastic disease, is mandatory.