Results from the 24-month extension of the phase 2 BOLD study demonstrated no new safety concerns and low disease activity in patients with relapsing-remitting multiple sclerosis (RRMS) treated with siponimod.
The original study tested 5 dose-ranging regimens of siponimod for both safety and efficacy over 6 months in patients with RRMS.
In the extension study, led by Ludwig Kappos, MD, of the of the Neurologic Clinic and Policlinic at the University Hospital in Basel, Switzerland, and colleagues, patients in the treatment group were maintained on their previous dose while patients in the placebo group were randomized to receive siponimod 10-mg, 2-mg, 1.25-mg, 0.5-mg, or 0.25-mg. The study included 184 participants (73%) of the original 252 participants from the BOLD study. Ultimately, 159 completed the extension.
The extension phase demonstrated sustained reductions in the mean estimated gadolinium (Gd)-enhancing T1 lesion counts from baseline in the 10-mg (0, 95% CI: 0-0), 2-mg (0.1, 95% CI: 0-1.9), 1.25-mg (0.1, 95% CI: 0-2.6), and 0.5-mg (0.1, 95% CI: 0-2.8) groups at 24 months. Further, participants switching from placebo to siponimod were found to have lower mean Gd-enhancing T1 lesion counts at month 6 (93.6%), 12 (87.9%), and 18 (89.6%) compared to baseline (P<.01).
There were fewer Gd-enhancing T1 lesions in the 1.25-mg (between group lesion ratio 0.10, 95% CI: 0.03-0.37, P<.001), 2-mg (0.05, 95% CI: 0.01-0.32, P=.002), and 10-mg (0.11, 95% CI: 0.03-0.50, P=.004) groups at the 18-month mark compared to the 0.25-mg group (P<.01).
When the 3 highest doses were compared to the 2 lowest doses of siponimod, estimates of new and newly-enlarging T2 lesion counts at 6 to 12 months and at 18 to 24 months were lower. Likewise, lower annualized relapse rates were observed in the 10-mg group (0.22), the 2-mg group (0.20), and the 1.25-mg group (0.14) compared to the 0.5-mg (0.33) and 0.25-mg (0.33) groups.
Adverse events were similar for the treatment groups ranging from 84% to 96.6% with a total of 9 serious adverse events. Suspected drug related serious adverse events included 1 case of gastritis and 1 case of cervical neoplasm. Adjustment of the dose was required for 13 participants, with 7 participants in the 10-mg group experiencing decreased lymphocyte counts.
Notably, the investigators observed that dose titration during the first 10 days helped to mitigate the bradycardia associated with higher doses of siponimod in the BOLD study.
“With similar efficacy but lower rates of lymphopenia relative to the 10-mg dose, siponimod, 2 mg, has been chosen for further development as a treatment for patients with MS,” the authors concluded.
In an accompanying editorial, Edward Hammond, MD, PhD, MPH, of the Medical Evidence and Observational Research Center of AstraZeneca in Gaithersburg, Maryland, noted the study may have been limited by lower numbers in the dose groups, fewer MRIs for evaluation, and no control group. Further, extension studies continue after patients have already dropped out secondary to adverse events or insufficient efficacy, and therefore have the potential to have results biased towards participants who have better response and tolerability.
The study was funded by Novartis Pharma AG. The authors report multiple disclosures including relationships and employment by Novartis.
- Kappos L, Li DB, Stüve O, et al. Safety and Efficacy of Siponimod (BAF312) in Patients With Relapsing-Remitting Multiple Sclerosis: Dose-Blinded, Randomized Extension of the Phase 2 BOLD Study. JAMA Neurol. 2016; doi:10.1001/jamaneurol.2016.1451.
- Hammond ER. Perspectives on Safety and Efficacy—The BOLD Phase 2 Extension Study of Siponimod in Relapsing-Remitting Multiple Sclerosis. JAMA Neurol. 2016; doi:10.1001/jamaneurol.2016.2284.