Principles of a New Treatment Algorithm in Multiple Sclerosis

Hans-Peter Hartung; Xavier Montalban; Per Soelberg Sorensen; Patrick Vermersch; Tomas Olsson

Disclosures

Expert Rev Neurother. 2011;11(3):351-362. 

In This Article

Second Key Decision Point: Escalating Therapy

Escalating Therapy: Considerations for Constructing a Treatment Algorithm Prior to the Era of Oral Therapies

An important subgroup of patients experience breakthrough disease on glatiramer acetate or IFNβ within 2 years of treatment initiation.[29,55] One approach to managing patients with breakthrough disease is to switch them from one first-line therapy (e.g., glatiramer acetate) to another (e.g., an IFNβ formulation). However, there is no Class 1 evidence from randomized controlled trials examining the efficacy of switching from one FDA-approved monotherapy to another monotherapy in patients with 'insufficient response' (Table 6). This makes treatment decisions somewhat problematic. Furthermore, nonrandomized studies that have considered switches between IFNβ formulations and glatiramer acetate have not demonstrated consistent benefits for either approach.[55–57]

A second potential approach to managing patients with breakthrough disease is to add an additional DMT to the patient's regimen (i.e., combination therapy). A number of randomized, controlled studies (providing Class 1 evidence) have been conducted to investigate the potential of add-on therapy (Table 6).[31,58–65] Only add-on of monthly doses of oral methylprednisolone to IFNβ has demonstrated a beneficial effect on both relapse rate and MRI efficacy measures in both patients with breakthrough disease during treatment with IFNβ and de novo treated patients.[64,65] In addition, four other trials demonstrated that adding a second therapy to the patient's regimen had a significant efficacy benefit.[31,60,62,63] Of these four trials, two involved adding natalizumab to a first-line therapy (IFNβ-1a or glatiramer acetate).[31,63] However, while combination therapy with natalizumab may have efficacy benefits, it should be avoided because of the potential increased risk of PML infection.[103] Moreover, in the absence of a natalizumab monotherapy arm, the benefits seen in these studies may not be due to the combination, but to natalizumab alone. In the two other trials, adding daclizumab (a monoclonal anti-CD25 antibody) or cyclophosphamide (a chemotherapeutic) to IFNβ reduced the number of new or enlarged Gd+ lesions.[59,63] Although a significant effect on Gd+ lesions was observed, these trials were relatively small, and neither daclizumab nor cyclophosphamide is approved for MS treatment. Further trials are required to ensure that the benefit of these add-on therapies outweigh the potential risks of SAEs.

A third approach to managing patients with breakthrough disease is to initiate treatment with a higher-efficacy monotherapy, such as natalizumab or mitoxantrone, although there is no Class 1 evidence from randomized controlled trials for either therapy in patients with breakthrough disease. While the pivotal trials for natalizumab were not designed to investigate this issue,[20,31,66] recent data from a range of noncontrolled, observational studies (Class 4 evidence) have consistently indicated that natalizumab monotherapy is effective in patients with breakthrough disease.[67–72] Additional studies are warranted.

Escalating Therapy: Defining a Practical Treatment Algorithm in the Era of Oral Therapies

There is currently no Class 1 evidence to support the administration of any monotherapy in patients with breakthrough disease. Neither fingolimod nor oral cladribine currently have data in this setting. In spite of this, the use of oral fingolimod among US patients with breakthrough disease is likely to increase in the coming months because of its efficacy in treatment-naive and previously treated patients (in FREEDOMS and TRANSFORMS) and because of the perceived convenience of oral administration (see Table 5). 'Real-world experience' over the next few years will help to determine the usefulness of new agents, and it is hoped that future trials for patients with breakthrough disease will be conducted. Natalizumab will remain an important option in this setting, and the overall use of natalizumab may change if the JCV-assay proves an effective means to identify patients with higher risk of PML.

The situation in Europe is currently more difficult to predict given the regulatory uncertainties for the oral agents in this region (i.e., the current rejection of cladribine and the potential for future restricted indications). However, it seems reasonable to assume that a similar pattern will emerge over time.

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