A number of landmark clinical studies in the field of MS have been published, shaping how the disease is treated.
Multiple sclerosis (MS) is a debilitating autoimmune disease characterized by fatigue, impaired coordination, and muscle spasm and weakness. More than 400,000 people in the United States and 2.5 million people around the world have MS, according to the Multiple Sclerosis Foundation.
Studies show that individuals with MS use health care services significantly more than those without the disease. For example, a newly diagnosed MS patient visits a physician an average of 8 times annually, about 3 times as often as someone without MS.1 Additionally, MS can present significant non-medical costs through lost productivity and caregiver burden.
Over the years, a number of landmark clinical studies in the field of MS have been published, shaping how we treat the disease today. In part 1 of this article, we looked at 4 of those. Here are 4 more that every pharmacist should know about:
5. TRANSFORM (2010)2,3
In September 2010, the FDA approved Gilenya (fingolimod), a sphingosine 1-phosphate receptor modulator, for patients with relapsing forms of MS. With its approval, Gilenya became the first oral treatment for MS.
In early 2010, researchers published the results of TRANSFORM, a pivotal study showing the benefit of Gilenya. The trial was conducted as a 12-month, double-blind, double-dummy study. In the study, 1292 patients with relapsing—remitting multiple sclerosis who had had at least 1 documented relapse during the previous year or at least 3 documented relapses during the previous 2 years were randomly assigned to receive oral Gilenya 1.25 mg, 0.5 mg, or intramuscular interferon beta-1a, standard of care for MS at the time. The primary endpoint was the annualized relapse rate.
After 12 months, researchers analyzed the data and found that the annualized relapse rate was significantly lower in both groups receiving Gilenya; 0.20 (95% CI: 0.16-0.26) in the 1.25 mg group and 0.16 (95% CI: 0.12-0.21) in the 0.5 mg group than in the interferon group (0.33; 95% CI: 0.26-0.42; p<0.001 for both comparisons). Other relapse measures significantly favored Gilenya, including the proportion of patients who were relapse-free, the proportion with multiple relapses and the time to the first relapse.
MRI findings, a secondary endpoint, showed patients in the 2 Gilenya groups had significantly fewer new or enlarged lesions. No significant differences were seen among the study groups with respect to progression of disability. The proportion of adverse events were similar between the 2 groups, though the specific events differed.
An extension study of more than 700 patients from TRANSFORM showed that use of Gilenya for up to 4.5 years is associated with maintaining a low rate of disease activity and sustained efficacy.
Conclusion: Gilenya is superior with respect to relapse rates and MRI outcomes compared with intramuscular interferon beta-1a. This effect has been shown with up to 4 1/2 years of follow up.
6. PARADIGMS (2017)4
In late 2017, researchers presented the results of PARADIGMS, the first randomized controlled trial in the pediatric MS population. The trial was a 24-month, double-blind, double-dummy, phase III, multicenter study conducted in patients with MS between 10 to 17 years of age. The study was followed by a 5-year open-label extension phase.
More than 200 patients were randomized to receive either oral Gilenya once-daily or intramuscular interferon beta-1a once weekly. The primary endpoint of the study was the frequency of relapses in patients treated up to 24 months. The mean duration of study drug exposure was 18 months.
Study results showed that treatment with oral Gilenya resulted in an 82% relative risk reduction in the annualized relapse rate over a period of up to 2 years compared with interferon beta-1a (0.12 vs 0.67; p <0.001). The data also showed that nearly 86% of patients in the Gilenya group were free of confirmed relapse for the entire study duration compared with 39% of patients in the interferon group. Gilenya demonstrated benefits in key secondary endpoints, including lesions measured by MRI, less brain shrinkage, and delayed disability progression. The safety profile of Gilenya was consistent with that seen in other clinical trials, with overall more adverse events reported in the interferon group.
Following the results from the study, the manufacturer filed for a pediatric MS indication with the FDA, and in December 2017 Gilenya was granted breakthrough therapy designation for the treatment of patients 10 and older with relapsing MS. There are no disease-modifying therapies approved for pediatric patients with MS.
Conclusion: Gilenya is superior to interferon beta-1a in the pediatric MS population.
7. CONFIRM (2012)5
Tecfidera (dimethyl fumarate) is an oral treatment approved by the FDA for people with relapsing forms of MS. The 2013 approval of Tecfidera was based on 2 phase III clinical studies, 1 of which was CONFIRM.
The study was a 2-year multicenter, double-blind, placebo-controlled trial that evaluated the efficacy and safety of Tecfidera in 1417 patients from 28 countries with relapsing MS. Both treatment-experienced and -naïve patients were included in the study. The median time since diagnosis was 3 years. Patients were randomized in a 1:1:1:1 ratio to receive Tecfidera 240 mg 2 times daily, Tecfidera 240 mg 3 times daily, placebo, or subcutaneous daily injections of 20 mg of Copaxone (glatiramer acetate). The primary endpoint was the annualized relapse rate over a period of 2 years. Notably, Copaxone was included as a reference comparator. However, the study was not designed to test the superiority or noninferiority of Tecfidera versus Copaxone.
At 2 years, the annualized relapse rate was significantly lower with both doses of Tecfidera (0.22 for twice daily Tecfidera and 0.20 for thrice-daily Tecfidera) compared with the placebo (0.40; p<0.001 both comparisons). Copaxone also significantly reduced the annualized relapse rate compared with the placebo (0.29; p=0.01). Reductions in disability progression with both doses of Copaxone and Tecfidera and did not reach statistical significance compared with the placebo. All active treatment groups demonstrated significant improvements in MRI outcomes.
In a post-hoc comparison of Copaxone versus Tecfidera, significant differences were seen in the annualized relapse rate (favoring thrice-daily Tecfidera) and several MRI endpoints (favoring both doses Tecfidera; p<0.05 for each comparison). Adverse events occurring at a higher incidence with an active treatment than with the placebo included flushing and gastrointestinal events with Tecfidera.
Conclusion: Tecfidera improves clinical outcomes in patients with relapsing MS.
8. ORATORIO (2017)6
In 2017, the FDA approved Ocrevus (ocrelizumab), a CD20-directed cytolytic antibody for adult patients with relapsing forms of MS and primary progressive multiple sclerosis (PPMS). With its approval, Ocrevus became the first drug approved for PPMS, a disease course that accounts for 10% to 15% of the overall population with MS. ORATORIO was a pivotal phase III, randomized, parallel-group, double-blind, placebo-controlled trial that investigated the efficacy and safety of Ocrevus in patients with PPMS.
In the study, 732 patients with PPMS were randomly assigned in a 2:1 ratio to receive intravenous Ocrevus 600 mg or the placebo every 24 weeks for at least 120 weeks and until a prespecified number of confirmed disability progression events had occurred. Patients were excluded if they had a history of progressive relapsing, relapsing-remitting, or secondary progressive MS. Patients who completed the blinded treatment phase were eligible to enter the open-label extension phase of the trial. The primary endpoint was the percentage of patients with disability progression confirmed at 12 weeks.
The results showed that the percentage of patients with 12-week confirmed disability progression was 32.9% with Ocrevus versus 39.3% with the placebo (HR=0.76; 95% CI: 0.59-0.98; p=0.03). The percentage of patients with 24-week confirmed disability progression was 29.6% with Ocrevus versus 35.7% with the placebo (HR=0.75; 95% CI: 0.58-0.98; p=0.04). By week 120, performance on the timed 25-foot walk worsened by 38.9% with Ocrevus versus 55.1% with the placebo (p=0.04). Finally, the total volume of brain lesions on T2 -weighted MRI decreased by 3.4% with Ocrevus and increased by 7.4% with the placebo (p<0.001). There was no significant between-group difference in the change in the SF-36 Physical Component Summary score from baseline to week 120.
Infusion-related reactions (particularly with the first infusion), upper respiratory tract infections, and oral herpes infections were more frequent with Ocrevus than with the placebo. Neoplasms were reported in 11 patients (2.3%) in the Ocrevus group and in 2 patients (0.8%) in the placebo group. The authors said that the imbalance in neoplasms between the 2 groups warrants further observation.
Conclusion: Ocrevus is associated with improved clinical outcomes versus placebo in PPMS.
Pharmacy Times' new sister site, NeurologyLive, offers even more resources for pharmacists working with multiple sclerosis.
1. Owens G. Economic Burden of Multiple Sclerosis and the Role of Managed Care Organizations in Multiple Sclerosis Management. Am J Manag Care. 2016;22:(6 Suppl)s:151-8.
2. Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):402—15. doi: 10.1056/NEJMoa0907839.
3. Cohen JA, Khatri B, Barkhof F. Long-term (up to 4.5 years) treatment with fingolimod in multiple sclerosis: results from the extension of the randomised TRANSFORMS study. J Neurol Neurosurg Psychiatry. 2016 May;87(5):468-75. doi: 10.1136/jnnp-2015-310597.
4. 7th Joint European Committee for Treatment and Research in Multiple Sclerosis-Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2017 meeting. Abstract 276. professionalabstracts.com/ectrims2017/iplanner/#/grid. Presented October 28, 2017. Accessed February 2, 2018.
5. Fox RJ, Miller DH, Phillips JT, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012;367(12):1087-97.
6. Montalban X, Hauser SL, Kappos, et al. Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N Engl J Med. 2017 Jan 19;376(3):209-220. doi: 10.1056/NEJMoa1606468.