Will Injection Therapy Soon Be Obsolete for Patients with Multiple Sclerosis?

Abstract & Commentary

By Susan Gauthier, DO, MS, Assistant Professor of Neurology and Neuroscience, Weill Cornell Medical College. Dr. Gauthier reports no financial relationships relevant to this field of study.

Synopsis: Three phase III clinical trials of two oral agents for the treatment of multiple sclerosis were found to have a beneficial effect on clinical and MRI markers of disease activity, but there is a heightened concern for long-term safety due to cases of malignancy reported in each of the three studies.

Sources: Kappos L, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010:362;5; Cohen J, et al. Oral fingolimod or interferon for relapsing multiple sclerosis. N Engl J Med 2010:362;5; Giovannoni G, et al. The CLARITY Study Group. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med 2010;362:416-426.

The present categories of therapy used to treat multiple sclerosis (MS), which include anti-inflammatory, immune modulator, and immunosuppressant, have overlapping immunological effects and therefore are not absolutely distinct. The currently available injectable therapies, which include glatiramer acetate and interferon beta, are considered immune modulating treatments (IMT). These agents are only partially effective, thus immunosuppressant agents have been traditionally used for patients failing IMT treatment. In general, therapies considered to be immunosuppressant have directed intracellular mechanisms, which involve DNA synthesis and/or immune cell activation, primarily targeted within the bone marrow and other lymphoid organs. The most widely studied agents in MS include cyclophosphamide and mitoxantrone; however, given the variety of toxicities, their use is limited. Natalizumab, a monoclonal antibody against a4-integrin, differs from standard immunosuppressant therapy, as it binds to specific extracellularly expressed molecules. However, given the risk of progressive multifocal encephalopathy associated with natalizumab, its use has also been limited.

Three recent phase III studies of two new oral agents for the treatment of relapsing MS have introduced novel approaches to immunosuppressant therapy in MS. Fingolimod, a sphingosine-1-phosphate receptor modulator, binds to sphingosine-1-phosphate type 1 receptor in its phosphorylated form and induces receptor internalization; this process ultimately renders activated lymphocytes incapable of migrating out of the lymphoid tissues. Low (0.5 mg) and high (1.25 mg) daily doses of fingolimod were tested in two separate studies. The FREEDOMS study was placebo-controlled over two years and the TRANSFORMS study was a one-year comparative study against intramuscular interferon beta-1a. In the FREEDOMS study, the relative reduction in relapse rate for low- and high-dose fingolimod was 54% and 60%, respectively. Regarding secondary endpoints, both doses of fingolimod reduced the risk of sustained disability over 24 months and decreased magnetic resonance imaging (MRI) measures of inflammation. Interestingly, the rate of brain volume loss was slower in fingolimod treated patients. In the TRANSFORMS study, there was a relative reduction in relapse rate of 52% and 38% for low- and high-dose fingolimod, respectively, as compared to intramuscular interferon beta-1a. There was no difference in disability (EDSS), although the MRI results were favorable to fingolimod. Given the presence of sphingosine receptions on cardiac myocytes, transient bradycardia and first- and second-degree heart block was observed in fingolimod treated patients and was partially dose-related. Similarly, macular edema was more common in the higher dose and stabilized or reversed after cessation of the drug. There were two deaths in patients treated with the higher dose of fingolimod due to disseminated herpetic infections. Basal cell carcinoma, melanoma, and breast cancer were more common in fingolimod treated patients (19 vs. 7).

Cladribine administration results in the disruption of cellular metabolism, inhibition of DNA synthesis, and subsequent apoptosis of lymphocytes. Cladribine preferentially affects lymphocytes due to their higher ratio of the enzyme deoxycytidine and its resistance to adenosine deaminase. The CLARITY study was a phase III placebo-controlled study of a low (3.5 mg/kg) and high (5.25 mg/kg) dose of oral cladribine for relapsing MS. As compared to placebo, there was a relative reduction in relapse rate of 57.6% and 54.5% for low- and high-dose cladribine, respectively. Both doses of cladribine reduced the risk of sustained disability and effectively decreased inflammatory markers on MRI. The rate of infection in cladribine treated patients was only marginally higher than placebo and most were mild or moderate in severity; notably, 20 infections were cutaneous herpetic zoster. There were three cases of malignant cancer in cladribine treated patients (melanoma, carcinoma of the pancreas and ovary). Similarly, a higher rate of benign cancers occurred in cladribine patients; these included five benign uterine leiomyomas, a choriocarcinoma, and a cervical carcinoma in situ.

Commentary

With the completion of the FREEDOMS, TRANSFORMS, and CLARITY studies, the treatment of MS has advanced to include immunosuppressive therapy with distinct advantages over the traditional agents used. Similar to natalizumab, these agents are mechanistically selective, thus decreasing the toxicities which are seen with the older agents. The efficacy of these new agents is apparent; however, their superiority over the IMTs, outside of intramuscular interferon beta-1a, has yet to be ascertained. Although oral therapy is appealing to patients struggling with self-injection, the majority of early MS patients are still likely to be treated with interferon beta or glatiramer acetate until the long-term safety risks of fingolimod and cladribine have been identified.