- 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 II of clinical trials for RRMS
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 secondary progressive 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.
Siponimod was evaluated in the phase II BOLD study to determine if the drug was safe and could reduce the number of active inflammatory lesions seen on imaging scans in people living with relapsing-remitting MS. The multicenter, randomized, double-blind, placebo-controlled clinical trial enrolled 297 participants across 73 centres in Europe and North America. Participants were given varying doses of the drug (0.25, 0.5, 1.25, 2 or 10 mg) or a dummy drug (placebo) to determine the optimal dose for reducing the number of active lesions on magnetic resonance imaging (MRI) scans after 3 months. Siponimod reduced the number of active lesions by up to 82% at the highest dose versus placebo.
In an extension study that followed 263 of the original participants for an additional 12 months, the number of active lesions seen on scans remained low, particularly in the high dose groups. Annualized relapse rates were also low in participants treated with siponimod versus placebo.
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.
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.
Kappos L, 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. [Epub ahead of print]