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Once-daily oral siponimod was associated with sustained effects on MRI outcomes at 24 months in patients with relapsing-remitting multiple sclerosis in a dose-blinded extension of the phase II study.
Disease activity was low, “with some evidence of greater benefit associated with siponimod at 10-mg, 2-mg, and 1.25-mg doses than with siponimod at 0.25-mg and 0.5-mg doses. No new safety signals emerged, and dose titration at treatment initiation mitigated cardiac effects,” Ludwig Kappos, MD, of University Hospital Basel (Switzerland), and his associates wrote in JAMA Neurology. “With similar efficacy but lower rates of lymphopenia relative to the 10-mg dose, siponimod 2 mg, has been chosen for further development,” they wrote.
Siponimod (BAF312) is a selective sphingosine 1-phosphate receptor (S1P1,5) modulator that was evaluated for up to 6 months at five doses in the phase II BOLD (BAF312 on MRI Lesion Given Once Daily) study. Patients with relapsing-remitting MS who received 10 mg siponimod had up to 80% reductions in MRI combined unique active lesions (CUALs, or gadolinium-enhancing T1 lesions and/or new and newly enlarging T2 lesions, without double counting), compared with the placebo group. The 2-mg and 0.5-mg dose cohorts had reductions of 72% and 50%, respectively. The current study was a 24-month, dose-blinded extension phase that included 185 participants (73% of 252 eligible patients), of whom 33 patients received 10 mg siponimod, 29 received 2 mg, 43 received 1.25 mg, 29 received 0.5 mg, and 50 received 0.25 mg (JAMA Neurol. 2016 July 5. doi: 10.1001/jamaneurol.2016.1451).
Average reductions in gadolinium-enhancing T1 lesion counts were sustained in the 10-mg, 2-mg, 1.25-mg, and 0.5-mg dose groups at month 24, the researchers reported. The 1.25-mg and 2-mg doses yielded the highest proportions of patients free from new MRI activity (58% for both dose groups) and free from new or newly enlarging T2 lesions (61% and 58%, respectively). New or newly enlarging T2 lesions were numerically lower at doses exceeding 0.25 mg. “There were no clear changes in normalized brain volume within or between any of the treatment groups,” the investigators added.
Dose titration during the first 10 days of treatment mitigated bradycardia and atrioventricular conduction effects. Rates of adverse events within dose groups ranged from 84% to 97% and did not show a trend with dose size. Serious adverse events affected nine patients (5%) and included one case each of otosclerosis, gastritis, anaphylaxis, acute pyelonephritis, femoral and ankle fractures, basal cell carcinoma, cervical neoplasm, and abortion. Thirteen patients (7%) required treatment interruptions because of adverse events, of which seven consisted of lymphopenia or decreased lymphocyte count at the 10-mg dose. Other adverse events leading to dose interruptions or adjustments included neutropenia, upper respiratory tract infection, elevated hepatic transaminases, and hypertension.
Novartis is developing siponimod and funded the study. Coinvestigators employed by Novartis participated in all aspects of the study, including interpretation of the data and manuscript submission. Dr. Kappos disclosed financial ties to Novartis and numerous other pharmaceutical companies, foundations, and societies.
Dr. Kappos and colleagues acknowledged some limitations including the decreasing proportion of patients with evaluable MRIs and low numbers within each dosing group. Furthermore, the variable time between the end of the BOLD study and start of the extension phase, and the lack of a control group, limit conclusive evidence statements. Nonetheless, the current data may be the most relevant to report the safety and efficacy of long-term siponimod use in relapsing-remitting MS.
The full cumulative dose effect of siponimod beginning from the initiation of the BOLD study cannot be completely evidenced because of variable and prolonged times between the end of the BOLD study and initiating the extension phase, the dose-titration escalation procedure, and limiting reporting to the extension phase. The low numbers of participants do not allow an assessment of dose-related adverse events. The observed adverse events may be expected based on the pharmacokinetic profile of siponimod.
The extension phase of clinical trials performed without a reference treatment arm can result in challenges for interpreting and contextualizing findings. Where possible, a potential approach would be to rerandomize patients prior to the start of an extension phase and maintain a placebo or comparator arm.
Edward R. Hammond, MD, PhD, MPH, is with AstraZeneca’s Medical Evidence and Observational Research Center in Gaithersburg, Md. These comments are based on his accompanying editorial (JAMA Neurol. 2016 July 5. doi: 10.1001/jamaneurol.2016.2284).
Dr. Kappos and colleagues acknowledged some limitations including the decreasing proportion of patients with evaluable MRIs and low numbers within each dosing group. Furthermore, the variable time between the end of the BOLD study and start of the extension phase, and the lack of a control group, limit conclusive evidence statements. Nonetheless, the current data may be the most relevant to report the safety and efficacy of long-term siponimod use in relapsing-remitting MS.
The full cumulative dose effect of siponimod beginning from the initiation of the BOLD study cannot be completely evidenced because of variable and prolonged times between the end of the BOLD study and initiating the extension phase, the dose-titration escalation procedure, and limiting reporting to the extension phase. The low numbers of participants do not allow an assessment of dose-related adverse events. The observed adverse events may be expected based on the pharmacokinetic profile of siponimod.
The extension phase of clinical trials performed without a reference treatment arm can result in challenges for interpreting and contextualizing findings. Where possible, a potential approach would be to rerandomize patients prior to the start of an extension phase and maintain a placebo or comparator arm.
Edward R. Hammond, MD, PhD, MPH, is with AstraZeneca’s Medical Evidence and Observational Research Center in Gaithersburg, Md. These comments are based on his accompanying editorial (JAMA Neurol. 2016 July 5. doi: 10.1001/jamaneurol.2016.2284).
Dr. Kappos and colleagues acknowledged some limitations including the decreasing proportion of patients with evaluable MRIs and low numbers within each dosing group. Furthermore, the variable time between the end of the BOLD study and start of the extension phase, and the lack of a control group, limit conclusive evidence statements. Nonetheless, the current data may be the most relevant to report the safety and efficacy of long-term siponimod use in relapsing-remitting MS.
The full cumulative dose effect of siponimod beginning from the initiation of the BOLD study cannot be completely evidenced because of variable and prolonged times between the end of the BOLD study and initiating the extension phase, the dose-titration escalation procedure, and limiting reporting to the extension phase. The low numbers of participants do not allow an assessment of dose-related adverse events. The observed adverse events may be expected based on the pharmacokinetic profile of siponimod.
The extension phase of clinical trials performed without a reference treatment arm can result in challenges for interpreting and contextualizing findings. Where possible, a potential approach would be to rerandomize patients prior to the start of an extension phase and maintain a placebo or comparator arm.
Edward R. Hammond, MD, PhD, MPH, is with AstraZeneca’s Medical Evidence and Observational Research Center in Gaithersburg, Md. These comments are based on his accompanying editorial (JAMA Neurol. 2016 July 5. doi: 10.1001/jamaneurol.2016.2284).
Once-daily oral siponimod was associated with sustained effects on MRI outcomes at 24 months in patients with relapsing-remitting multiple sclerosis in a dose-blinded extension of the phase II study.
Disease activity was low, “with some evidence of greater benefit associated with siponimod at 10-mg, 2-mg, and 1.25-mg doses than with siponimod at 0.25-mg and 0.5-mg doses. No new safety signals emerged, and dose titration at treatment initiation mitigated cardiac effects,” Ludwig Kappos, MD, of University Hospital Basel (Switzerland), and his associates wrote in JAMA Neurology. “With similar efficacy but lower rates of lymphopenia relative to the 10-mg dose, siponimod 2 mg, has been chosen for further development,” they wrote.
Siponimod (BAF312) is a selective sphingosine 1-phosphate receptor (S1P1,5) modulator that was evaluated for up to 6 months at five doses in the phase II BOLD (BAF312 on MRI Lesion Given Once Daily) study. Patients with relapsing-remitting MS who received 10 mg siponimod had up to 80% reductions in MRI combined unique active lesions (CUALs, or gadolinium-enhancing T1 lesions and/or new and newly enlarging T2 lesions, without double counting), compared with the placebo group. The 2-mg and 0.5-mg dose cohorts had reductions of 72% and 50%, respectively. The current study was a 24-month, dose-blinded extension phase that included 185 participants (73% of 252 eligible patients), of whom 33 patients received 10 mg siponimod, 29 received 2 mg, 43 received 1.25 mg, 29 received 0.5 mg, and 50 received 0.25 mg (JAMA Neurol. 2016 July 5. doi: 10.1001/jamaneurol.2016.1451).
Average reductions in gadolinium-enhancing T1 lesion counts were sustained in the 10-mg, 2-mg, 1.25-mg, and 0.5-mg dose groups at month 24, the researchers reported. The 1.25-mg and 2-mg doses yielded the highest proportions of patients free from new MRI activity (58% for both dose groups) and free from new or newly enlarging T2 lesions (61% and 58%, respectively). New or newly enlarging T2 lesions were numerically lower at doses exceeding 0.25 mg. “There were no clear changes in normalized brain volume within or between any of the treatment groups,” the investigators added.
Dose titration during the first 10 days of treatment mitigated bradycardia and atrioventricular conduction effects. Rates of adverse events within dose groups ranged from 84% to 97% and did not show a trend with dose size. Serious adverse events affected nine patients (5%) and included one case each of otosclerosis, gastritis, anaphylaxis, acute pyelonephritis, femoral and ankle fractures, basal cell carcinoma, cervical neoplasm, and abortion. Thirteen patients (7%) required treatment interruptions because of adverse events, of which seven consisted of lymphopenia or decreased lymphocyte count at the 10-mg dose. Other adverse events leading to dose interruptions or adjustments included neutropenia, upper respiratory tract infection, elevated hepatic transaminases, and hypertension.
Novartis is developing siponimod and funded the study. Coinvestigators employed by Novartis participated in all aspects of the study, including interpretation of the data and manuscript submission. Dr. Kappos disclosed financial ties to Novartis and numerous other pharmaceutical companies, foundations, and societies.
Once-daily oral siponimod was associated with sustained effects on MRI outcomes at 24 months in patients with relapsing-remitting multiple sclerosis in a dose-blinded extension of the phase II study.
Disease activity was low, “with some evidence of greater benefit associated with siponimod at 10-mg, 2-mg, and 1.25-mg doses than with siponimod at 0.25-mg and 0.5-mg doses. No new safety signals emerged, and dose titration at treatment initiation mitigated cardiac effects,” Ludwig Kappos, MD, of University Hospital Basel (Switzerland), and his associates wrote in JAMA Neurology. “With similar efficacy but lower rates of lymphopenia relative to the 10-mg dose, siponimod 2 mg, has been chosen for further development,” they wrote.
Siponimod (BAF312) is a selective sphingosine 1-phosphate receptor (S1P1,5) modulator that was evaluated for up to 6 months at five doses in the phase II BOLD (BAF312 on MRI Lesion Given Once Daily) study. Patients with relapsing-remitting MS who received 10 mg siponimod had up to 80% reductions in MRI combined unique active lesions (CUALs, or gadolinium-enhancing T1 lesions and/or new and newly enlarging T2 lesions, without double counting), compared with the placebo group. The 2-mg and 0.5-mg dose cohorts had reductions of 72% and 50%, respectively. The current study was a 24-month, dose-blinded extension phase that included 185 participants (73% of 252 eligible patients), of whom 33 patients received 10 mg siponimod, 29 received 2 mg, 43 received 1.25 mg, 29 received 0.5 mg, and 50 received 0.25 mg (JAMA Neurol. 2016 July 5. doi: 10.1001/jamaneurol.2016.1451).
Average reductions in gadolinium-enhancing T1 lesion counts were sustained in the 10-mg, 2-mg, 1.25-mg, and 0.5-mg dose groups at month 24, the researchers reported. The 1.25-mg and 2-mg doses yielded the highest proportions of patients free from new MRI activity (58% for both dose groups) and free from new or newly enlarging T2 lesions (61% and 58%, respectively). New or newly enlarging T2 lesions were numerically lower at doses exceeding 0.25 mg. “There were no clear changes in normalized brain volume within or between any of the treatment groups,” the investigators added.
Dose titration during the first 10 days of treatment mitigated bradycardia and atrioventricular conduction effects. Rates of adverse events within dose groups ranged from 84% to 97% and did not show a trend with dose size. Serious adverse events affected nine patients (5%) and included one case each of otosclerosis, gastritis, anaphylaxis, acute pyelonephritis, femoral and ankle fractures, basal cell carcinoma, cervical neoplasm, and abortion. Thirteen patients (7%) required treatment interruptions because of adverse events, of which seven consisted of lymphopenia or decreased lymphocyte count at the 10-mg dose. Other adverse events leading to dose interruptions or adjustments included neutropenia, upper respiratory tract infection, elevated hepatic transaminases, and hypertension.
Novartis is developing siponimod and funded the study. Coinvestigators employed by Novartis participated in all aspects of the study, including interpretation of the data and manuscript submission. Dr. Kappos disclosed financial ties to Novartis and numerous other pharmaceutical companies, foundations, and societies.
FROM JAMA NEUROLOGY
Key clinical point: Siponimod was associated with sustained efficacy at 24 months among patients with relapsing-remitting multiple sclerosis.
Major finding: The proportion of patients free from new MRI activity was highest (58%) in the 1.25-mg and 2-mg dose groups. There were no new safety signals, and dose reduction during initiation mitigated cardiac adverse effects. Lymphopenia was more common at the 10-mg dose than at lower doses.
Data source: A dose-blinded extension of 184 patients from the phase II BOLD study.
Disclosures: Novartis funded the study. Coinvestigators employed by Novartis participated in all aspects of the study, including interpretation of the data and manuscript submission. Dr. Kappos disclosed financial ties to Novartis and numerous other pharmaceutical companies, foundations, and societies.
