EXPERT ANALYSIS AT THE CMSC ANNUAL MEETING
INDIANAPOLIS (FRONTLINE MEDICAL NEWS) – With the emergence of 11 Food and Drug Administration–approved treatments for clinically isolated syndrome and/or relapsing forms of multiple sclerosis since 1993, patients have more choices for disease-modifying therapy than ever before. Dr. Mitzi Joi Williams describes choosing the right disease-modifying therapy as a balancing act that considers efficacy, safety, and tolerability.
“As we have more medications for MS, especially with different mechanisms of action, there may be some side effects that we may not be familiar with,” Dr. Williams, a neurologist at the Multiple Sclerosis Center of Atlanta, said at the annual meeting of the Consortium of Multiple Sclerosis Centers. “You want a drug that you and the patient feel comfortable with and find tolerable. In the past when we only had injections, we’d say, ‘you have to tough it out; we don’t have anything else.’ ”
Other considerations, she said, include non–neurologic side effects, sequencing of therapies, and compliance with monitoring. “Some medications require blood work every month for 6 months, others require blood work every month for 4 or 5 years,” Dr. Williams said. “That’s a lot for patients to keep up with.”
The two most recent drugs approved for MS are alemtuzumab and pegylated interferon beta-1a. Alemtuzumab, which is indicated for the treatment of relapsing-remitting MS, is a monoclonal antibody to CD52 and has been previously used in patients with chronic lymphocytic leukemia. Dosing is 12 mg/day delivered intravenously for 3-5 days once a year. Possible adverse effects include profound lymphopenia, autoimmune thyroid disease, immune thrombocytopenic purpura, infusion reaction, and increased susceptibility to infections.
The other newcomer, pegylated interferon beta-1a is a recombinant interferon beta-1a protein attached to a polyethylene glycol molecule that reduces proinflammatory cytokines and inhibits T-cell migration and is indicated for relapsing MS. Dosing is 125 mcg subcutaneously every 2 or 4 weeks. Common adverse events include flulike symptoms, infection-site reactions, fever, and headache.
Another drug that has been submitted to the FDA for approval is daclizumab, a humanized monoclonal antibody that binds to CD25, decreasing activated T cells. It is intended for the treatment of relapsing MS. The dosing schedule would be 150 mg delivered subcutaneously every other week at home. Data from the SELECT trial, a year-long, phase II study of the agent, showed a 50%-54% decrease in annualized relapse rate (ARR), a 43%-57% decrease in confirmed disability, a 79%-86% reduction in new gadolinium (Gd)-enhancing lesions, and a 70%-79% reduction in new or enlarging T2 lesions. A phase II extension trial called SELECTION showed a 59% decrease in ARR, a 54% decrease in confirmed disability, a 86% reduction in new Gd-enhancing lesions, and a 74% reduction in new or enlarging T2 lesions. Potential adverse side effects include increased risk for infection, abnormal liver function tests, diarrhea, constipation, and swelling of the extremities. It has previously been used in rheumatoid arthritis and in kidney transplant patients.
Another promising agent in phase III studies is ocrelizumab , which is being studied in doses of 600 mg or 2,000 mg in patients with relapsing-remitting MS and primary-progressive MS. “It’s an anti-CD20 molecule that is similar to rituximab, which has been used in MS for some time, but it’s a more humanized antibody,” Dr. Williams said. She noted that a multicenter phase II study showed that ARR decreased by 73% with the 2,000-mg dose and by 80% with the 600-mg dose ( Lancet 2011;378:1779-87 ). It also showed that Gd-enhancing lesions decreased by 96% with the 2,000-mg dose and by 89% with the 600-mg dose. “Potential adverse events reported in the trial include infusion-site reactions and increased risk of infection,” she said. “One study participant died from systemic inflammatory response of unknown cause.”
Other drugs for relapsing MS in earlier phases of research included ofatumumab, S1P receptor modulators, Tcelna, statins, antibiotics, and vitamin D3. Agents being investigated for progressive MS include S1P receptor modulators, masitinib, and ibudilast. “The more options we have for our patients, the better, because there’s no one drug that’s right for everyone,” Dr. Williams said.
Potential therapies could eventually come via more studies of drugs and mechanisms for myelin repair, including anti-LINGO-1 and stem cell therapies, as well as hormone therapy in the form of estrogen and testosterone. Other avenues of research include gene and DNA studies, personalized medicine and biomarkers, and monitoring progression of disease.
Dr. Williams disclosed that she is a consultant and speaker for Biogen Idec, Teva Neuroscience, EMD Serono, Mallinckrodt Pharmaceuticals, Novartis, Genzyme, and Acorda Therapeutics.
