The recent ECTRIMS/ACTRIMS joint congress in Amsterdam reported results from several pivotal phase III studies. The encouraging results of phase III studies of several new agents and their potential regulatory approval within the next few years promises to add many more therapeutic options and much greater complexity to the multiple sclerosis treatment landscape.
Patients with clinically isolated syndrome, early, or mild disease will likely still begin with one of the first-generation therapies (interferon-beta or glatiramer acetate [Copaxone]), but may also consider lower-toxicity oral therapies, such as BG-12 (dimethyl fumarate) or laquinimod. Patients who fail their first therapy may be escalated to combination therapy with two lower-risk therapies, more potent oral therapies, or a more potent biologic such as natalizumab (Tysabri), alemtuzumab (Campath), or daclizumab (Zenapax).
By Dr. Jonathan Carter
The multiple sclerosis (MS) clinician of the future will need to be skillful in managing an array of solo and combination therapies and higher-risk biologic therapies, while the MS researcher of the future will be challenged with finding out which combinations of therapies are safest and most efficacious, in addition to developing the next generation of new therapies. This must occur in an environment of fiscal constraints, with regard for the huge cost of these new therapies. The recent decision by the United Kingdom’s National Institute for Health and Clinical Excellence appraisal committee to not recommend fingolimod based on its cost effectiveness compared with other MS therapies illustrates how these agents cannot be developed and priced without consideration of fiscal realities. The future of MS therapy appears both very hopeful and challenging.
BG-12
Perhaps the biggest shift will occur with the addition of new oral agents with side effect profiles different from those for the currently approved oral therapy, fingolimod (Gilenya). The DEFINE study of BG-12 showed a 50% reduction in the risk of relapse over a 2-year period in both dosage arms (240 mg b.i.d. and 240 mg t.i.d.), compared with placebo. The MRI substudy of DEFINE confirmed the clinical results, with a 74%-85% reduction in new or newly enlarging T2 lesions and a 73%-98% reduction in gadolinium-enhancing lesions over a 2-year period compared with placebo. Disability progression confirmed at 12 weeks was reduced by 34%-38% at 2 years, compared with placebo. All of these results were statistically significant. There were relatively few adverse events, mainly skin flushing and GI disturbances. The BG-12–treated groups had fewer serious adverse events than did the placebo group.
A second phase III study of BG-12, the CONFIRM study, helped to corroborate the efficacy of BG-12 seen in the DEFINE study. CONFIRM compared BG-12 240 mg b.i.d. and t.i.d. against glatiramer acetate (Copaxone) and placebo. In this study, all clinical and MRI efficacy measures favored BG-12 over placebo, except for sustained accumulation of disability (SAD), which was not significantly different between BG-12 and placebo. The unexpectedly low rate of disability progression in the placebo group was felt to explain these negative results on SAD.
Laquinimod
This oral immunomodulatory agent has had mixed results in clinical trials. The BRAVO study reported at ECTRIMS pitted laquinimod 0.6 mg/day against placebo versus interferon beta-1a. The annualized relapse rate (ARR) was not significantly different between the two trial arms. However, the laquinimod patients had a higher percentage of gadolinium-enhancing lesions and greater T2 lesion volume at baseline than did the other two groups. After adjustment for these variables, the ARR reduction, while modest, became statistically significant in favor of laquinimod. The laquinimod group also experienced less disability progression. MRI measures favored laquinimod over placebo but were less robust than they were with interferon beta-1a, except for the reduction in brain atrophy, which was greater with laquinimod. An earlier pivotal phase III study, the ALLEGRO study, showed significant reductions in ARR, disability progression, and brain atrophy with laquinimod over placebo. These mixed results have led to speculation that laquinimod might have a more neuroprotective versus anti-inflammatory mode of action, but that conclusion awaits further validation.
Teriflunomide and S1P Receptor Agonists
EMD Serono’s decision last summer to halt the development of oral cladribine in multiple sclerosis left teriflunomide and S1P receptor agonists similar to fingolimod as the other major oral therapies still under development. Teriflunomide has shown efficacy against placebo in the phase III TEMSO study, with a reduction in ARR of 31% in both the 7- and 14-mg/day groups. Only the higher dose had a significant impact on SAD. Additional phase III studies are testing teriflunomide as add-on therapy to interferon-beta and also as monotherapy for clinically isolated syndrome. At least two other oral S1P receptor agonists that are thought to be more selective for certain subclasses of the S1P receptor than fingolimod are being studied in phase III trials. The hope is that these compounds will have fewer adverse events than fingolimod but maintain the same level of efficacy.