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

Gothenburg, Sweden / October 13-16, 2010

In relapsing-remitting multiple sclerosis (RRMS), conventional therapies require parenteral administration for which patients may be reluctant to start therapy or continue on therapy during symptom-free periods of the disease, Prof. Hans-Peter Hartung, Heinrich-Heine University, Düsseldorf, Germany, told delegates. The potential for oral therapy to help overcome some of the drawbacks of conventional therapies drew interest here at ECTRIMS 2010.

Mechanisms of Action and Dosing Schedules

The 2 new oral treatments investigated, cladribine tablets and fingolimod, appear effective in reducing the annualized relapse rate (ARR) of RRMS and both work by depleting blood lymphocytes. In preferentially targeting T-lymphocytes, cladribine disrupts cellular metabolism and inhibits DNA synthesis, leading to apoptosis. As a first-in-class agent, fingolimod is an agonist of, and down-regulates, the sphingosine-1-phosphate (S1P) receptor on both T-cells and B-cells, making them insensitive to the S1P gradient which otherwise would allow them to egress from secondary lymphoid tissues. Since S1P receptors are found on a wide variety of other tissues, there is concern for potential toxicity.

Between agents, dosing schedules vary; fingolimod requires continuous daily dosing, while dosing with cladribine tablets is based on the patient’s weight with cumulative doses of 3.5 or 5.25 mg/kg in the form of 1 or 2 10-mg tablets given daily for 4 to 5 consecutive days of the first 2 months of the year. Patients would therefore have the advantage of being treatment-free for 10 out of 12 months of the year. Prof. Hartung also noted that in the pivotal double-blind, placebo-controlled CLARITY (Cladribine Tablets Treating Multiple Sclerosis Orally) study, nearly 90% of patients stayed on therapy for the entire 96-week trial.

Effectiveness: Evidence to Date

The primary results from CLARITY showed a significantly lower ARR than in the placebo group (0.14 and 0.15, respectively, vs. 0.33; P<0.001 for both comparisons), a higher relapse-free rate (79.7% and 78.9%, respectively, vs. 60.9%; P<0.001 for both comparisons), a lower risk of 3-month sustained progression of disability (HR) for the 3.5 mg and 5.25 mg group, 0.67 and 0.69, respectively) and significant reductions in the brain lesion count on MRI(P<0.001 for all comparisons).

Further CLARITY results presented at ECTRIMS show the consistency of effect on both clinical and MRI parameters. Prof. Giancarlo Comi, Vita-Salute San Raffaele University, Milan, Italy, and colleagues found that both the 3.5 and 5.25 mg/kg cumulative doses produced significant reductions/patient/scan in T1 gadolinium (Gd)-positive, T2 and combined unique lesions over 96 weeks for patients with =1, 2 or =3 relapses in the 12 months before the study, and for patients with disease durations of <3, 3 to 10 and >10 years. Similar findings were observed for patients regardless of gender, age, prior treatment status, disability status, presence of T1 Gd-positive lesions and T2 lesion burden at baseline.

Another report from the same group demonstrated highly significant reductions in ARR vs. placebo regardless of disease history. Moreover, the safety profiles remained similar during the first and second 48 weeks of the study, although a lower proportion of patients experienced adverse events during the second period (60% vs. 77.5%). More patients receiving the higher cumulative dose developed lymphopenia in the first than the second periods (26% vs. 13%, respectively); this may reflect differences in the dosing schedule, the investigators believed.

The CLARITY protocol allowed rescue therapy with subcutaneous interferon beta-1a (IFNß-1a) 3 times per week for patients having more than 1 relapse or a sustained increase in Expanded Disability Status Scale (EDSS) score. Of patients receiving cladribine 3.5 mg/kg and 5.25 mg/kg, rescue therapy was needed in 2.5% and 2%, respectively, compared with 6.2% in the placebo group. Discontinuation of treatment due to perceived lack of efficacy or disease progression was reported in 1% of cladribine-treated patients in each group and in 5.5% of the placebo group. This and the high proportion of patients completing the study indicated a satisfactory perception of treatment efficacy. According to researchers, MS therapy with cladribine tablets may allow for high levels of patient retention on treatment.

In the pivotal double-blind, double-dummy study of fingolimod vs. IFNß-1a, patients received either fingolimod at a daily dose of 1.25 or 0.5 mg or intramuscular IFNß-1a. The ARR was significantly lower in both fingolimod groups, 0.2 and 0.16, respectively, than in the IFNß-1a group (0.33; P<0.001 for both comparisons). MRI findings were consistent with these results.

In another double-blind, randomized, placebo-controlled study of fingolimod, the ARR with the same two doses was 0.16 and 0.18, respectively, vs. 0.40 with placebo. In the 12-month study vs. IFN, there were no significant differences between treatment groups in progression of disability. In the 24-month placebo-controlled study, fingolimod reduced the risk of disability progression, confirmed after 3 months (HR 0.68 and 0.70, respectively, for the 1.25-mg and 0.5-mg doses). In the first trial, 87% of patients were still on fingolimod therapy at the end of the 12-month study period. At the end of the second 24-month trial, just under three-quarters of patients assigned to fingolimod were still taking the drug.

Safety Data

As several speakers outlined here at ECTRIMS, the non-selective action of fingolimod, which acts on S1P receptors on neural cells and the vasculature as well as those on lymphocytes, is a cause for concern. A dose-dependent decline in heart rate (by a mean of up to 11 bpm) and a small, transient fall in blood pressure (BP) occur after the first dose of fingolimod; thereafter BP increases slightly over time. In patients receiving fingolimod, macular edema was reported in 6 in the trial vs. IFN and in 7 in the placebo-controlled study. “The balance between safety and efficacy and convenience could be further improved,” conceded Prof. Chris Polman, VU University Medical Center, Amsterdam, The Netherlands, adding, “More long-term safety data are needed.”

First author of the primary CLARITY study report, Prof. Gavin Giovannoni, Queen Mary University, London, the Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, UK, explained, “Cladribine depletes cells but when they come back we think there’s a ‘rebooting’ of the immune system. And then you don’t need to give it continuously whereas with fingolimod, you have to give it continuously to keep the lymphocytes out of the brain. Both are immunosuppressive drugs, the difference being that when the lymphocytes come back with cladribine, you appear to be immune-competent.”

Prof. Hartung noted that in CLARITY, although lymphopenia was the most prominent side effect, only a small proportion of patients developed grade 3 or 4 lymphopenia. Herpes zoster infections affected 1.8% and 2.4% of patients, respectively, in the 3.5 mg/kg and 5.25 mg/kg groups but there was no case of disseminated disease.

In a session on practical management of individual MS cases, Prof. Giovannoni characterized cladribine tablets as well tolerated with not too many major side effects. It would be suitable for patients failing to respond to first-line injectable therapies and/or those who disliked injections.

Prof. Patrick Vermersch, Hôpital Roger Salengro, Lille, France, added that failure to respond to first-line injectable agents might be due to poor adherence. Concerning young women with MS, the advice is to avoid conception for 6 months after the second course of cladribine tablets, remarked Prof. Giovannoni. “After that there is no indication that pregnancy is contraindicated… There is no evidence that this is toxic to the ovaries.” With fingolimod, treatment would have to be stopped.

According to Prof. Giovannoni, lymphocyte counts remain relatively low with fingolimod, risking to impair the afferent limb arm of the immune response. Thus, for patients exposed to infection risk, cladribine tablets appear to be the better choice. Live vaccinations would be contraindicated. In CLARITY, the serious infection rate “was similar in the 2 arms of the study and not much different from the placebo arm [2.3% and 2.9% in the 3.5 and 5.25 mg/kg cladribine groups vs. 1.6% in the placebo group]. Ninety-nine per cent of the infections were mild or moderate,” he reported. All the cases of herpes zoster were self-limiting and there was no close association between those infections and lymphopenia.

Summary

Orally available agents are an important step in the treatment of RRMS. The flexible dosing schedule with cladribine tablets should help simplify management. While more data are needed, the relative effectiveness and ease of use of both agents broadens the treatment options in fighting this debilitating disease.