Other names: BAF312, Mayzent
Siponimod is a new drug treatment under investigation for secondary progressive multiple sclerosis (MS). It is taken as a tablet once daily.
Siponimod for secondary progressive MS: Licensing
- Siponimod causes lymphocytes to be retained in lymph glands.
- In secondary progressive MS, siponimod reduced risk of disability progression by 21% compared to placebo.
- In clinical trials, low white blood cell count, increased liver enzyme levels, slower heart rate when starting treatment, macular oedema (swelling in the back of the eye affecting vision), high blood pressure, shingles, and convulsions occurred more frequently with siponimod than with placebo.
Licensing and appraisal
An application for a licence to market siponimod as a treatment for secondary progressive MS has been submitted to the European Medicines Agency. A decision on this application is expected in late 2019.
In the United States, the Food and Drug Administration (FDA) has approved siponimod for relapsing forms of MS, which includes clinically isolated syndrome, relapsing remitting MS and active secondary progressive MS. Active secondary progressive MS is defined as people who have progression of disability but still experience relapses or new MRI activity; in the EXPAND clinical trial, people who had secondary progressive MS and had experienced at least one relapse within two years before starting the study were considered "active”. The FDA decision does not affect the EMA.
How does siponimod work?
Siponimod belongs to the same class of drugs as Gilenya.
It acts on certain types of white blood cells (lymphocytes) which are involved in the autoimmune attack on myelin seen in MS. It binds to special locations (or receptors) on the surface of the lymphocytes, called sphingosine-1-phosphate receptors (S1P-R). This causes a larger proportion of lymphocytes to be retained in the lymph glands. The number of activated lymphocytes reaching the brain is decreased, resulting in reduced immune attack on nerve cells in the brain and spinal cord.
How is siponimod taken?
Siponimod is taken as a tablet, once daily.
What are the results so far?
BOLD - siponimod compared to placebo in relapsing remitting MS
In a phase II study (BOLD), designed to assess the best dose for reducing MS activity as seen on MRI scans, 188 people with relapsing remitting MS took siponimod for 3 to 6 months. Siponimod reduced the number of brain lesions seen in MRI by up to 80% and reduced relapse rates compared to placebo (0.58 on placebo to 0.2 on 2 mg siponimod).
Results of an extension study in relapsing remitting MS have also been published; MRI-assessed MS activity and relapse rates remained low, particularly in the 1.25, 2 and 10mg treatment groups, with no new safety concerns.
EXPAND - siponimod compared to placebo in secondary progressive MS
The phase III EXPAND trial recruited 1651 people with secondary progressive MS. On average, participants had been diagnosed with MS for approximately 17 years, and had had SPMS for about 4 years. Just over half needed walking assistance. Participants took either siponimod (1105) or placebo (546) daily for up to 3 years.
Disability level (EDSS score) was assessed every three months. Disability progression was confirmed if an increase in EDSS was maintained for 3 months.
Researchers found that 32% of those taking placebo experienced a 3 month confirmed increase in disability during the study, compared to 26% of those taking siponimod. This represented a 21% reduction in risk of progression for those taking siponimod.
Siponimod was also more effective than placebo on other measures used in the study:
- reduced risk of 6 month confirmed increase in disability
- reduced loss of brain volume
- reduced MRI-detected brain lesion volume
There was no significant difference between the two groups in the time taken to walk 25 feet.
In the phase III EXPAND study, low white blood cell count, increased liver enzyme levels, slower heart rate when starting treatment, macular oedema (swelling in the back of the eye affecting vision), high blood pressure, shingles, and convulsions occurred more frequently with siponimod than with placebo.
- Lancet Neurology 2013;12(8):756-67. Summary Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD): an adaptive, dose-ranging, randomised, phase 2 study.
- Multiple Sclerosis and Related Disorders 2014;3(6):754-5. Summary Phase 2 BOLD extension study efficacy results for siponimod (BAF312) in patients with relapsing-remitting multiple sclerosis.
- JAMA Neurology 2016;73(9):1089-1098 Summary Safety and Efficacy of Siponimod (BAF312) in Patients With Relapsing-Remitting Multiple Sclerosis: Dose-Blinded, Randomized Extension of the Phase 2 BOLD Study.
- Lancet 2018 Mar 22. [Epub ahead of print] Summary Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study
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