- Also known as: BAF312 (Novartis Pharmaceuticals AG)
- Route of Administration: Oral, once daily
- Type: sphingosine-1-phosphate receptor modulator; immunomodulator
- Emerging treatment for: Relapsing-remitting MS and secondary progressive MS
- Status: In Phase III of clinical trials for SPMS
Belonging to the same class of drugs as fingolimod (Gilenya), siponimod is under study to evaluate its effectiveness in reducing the number of inflammatory brain lesions in people living with relapsing-remitting MS. Siponimod is also being evaluated as an experimental treatment for relapsing remitting MS.
How it Works
Siponimod works by entering the central nervous system (CNS) and binding to specific subtypes of the sphingosine 1-phosphate (S1P) receptor. The S1P receptor is found on the surface of specific immune cells called T cells and B cells that play a role in causing damage to the CNS in MS. By binding to the S1P receptor, siponimod prevents these harmful immune cells – specifically B cells and both CD4+ and CD8+ T cells – from being activated and released from the lymph nodes and thymus gland into the blood circulation and, hence, the brain and spinal cord.
Research and Results
Several early studies in animals demonstrated the siponimod reduces the number of white blood cells in the blood circulation. These were complemented by a study in mice with an MS-like disease showing that administration of siponimod suppressed disease activity and neurological deficits.
The safety, tolerability and efficacy of siponimod in participants with secondary progressive MS is being explored in the EXPAND study, a phase III, multicenter, randomized, double-blind, parallel group, placebo-controlled clinical trial. The trial included 1,651 people with secondary progressive MS from 31 countries; participants were randomized to receive either 2 mg of siponimod (given daily after gradually increasing the dose over 6 days at doses of 0.25, 0.25, 0.5, 0.75, 1.25, and 2 mg) or a dummy drug ( placebo) in a 2:1 ratio, respectively.
Preliminary results reported at the 32nd Congress of
the European Committee for Treatment and Research in Multiple
Sclerosis (ECTRIMS) showed that the trial met its primary
endpoint of detecting an improvement in the time to three-month
confirmed disability progression, as measured by the expanded
disability status scale (EDSS), versus placebo. Siponimod
reduced the risk of disability progression by 21% compared to
placebo at 3 months, and by 26% at 6 months. Although analysis
of secondary endpoints is still ongoing, preliminary results
show that participants taking siponimod experienced reduced
annualized relapse rate by 55.5%, had 23.4% lower average
reduction in brain volume, and 79.1% lower average increase in
brain lesion size, compared to placebo. Those participants who
had more brain lesions and experienced a greater number of
relapses at baseline appeared to benefit most from siponimod,
although the drug also had the greatest effect in those with a
lower EDSS at baseline.
Adverse Effects Reported
In the phase II study for relapsing-remitting MS, the most common adverse effects that were reported include headache, slowing of heart rate, dizziness, and nose and throat infections.
Gergely P, et al. The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate. Br J Pharmacol. 2012; 167(5):1035-47.
Kappos L, et al. Siponimod (BAF312) for the Treatment of Secondary Progressive Multiple Sclerosis: Design of the Phase 3 EXPAND Trial. Neurology (Meeting Abstracts), 12 Feb 2013.
Kappos L, et al. Siponimod (BAF312) for the treatment of secondary progressive multiple sclerosis: Design of the phase 3 EXPAND trial. Mult Scler Relat Disord. 2014; 3(6):752.
Lewis ND, et al. Circulating monocytes are reduced by sphingosine-1-phosphate receptor modulators independently of S1P3. J Immunol. 2013; 190(7):3533-40.
Selmaj K, et al. Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD): an adaptive, dose-ranging, randomised, phase 2 study. Lancet Neurol. 2013; 12(8):756-67.