Siponimod (formerly known as BAF312) is an investigational oral drug being developed by Novartis to treat multiple sclerosis (MS).

How siponimod works

MS symptoms are caused by the immune system mistakenly attacking the myelin sheath, a protective layer that surrounds nerve fibers in the brain and spinal cord. The immune system directs immune cells (or lymphocytes) called T-cells and B-cells to the target tissue, where they trigger inflammation. This causes damage to the myelin sheath and eventually to the nerve cells.

Siponimod works by stopping the immune cells from entering the brain and spinal cord, preventing them from causing inflammation and damage to the myelin sheath.

Siponimod does this by binding to the sphingosine-1-phosphate (S1P) receptor found on the outside of immune cells, blocking its normal action. It interacts specifically with S1P receptor 1 and 5. The S1P receptor is important to trigger the release of immune cells from the lymph node and into the circulating blood. Siponimod keeps the immune cells trapped in the lymph node, slowing MS disease progression.

As an S1P receptor modulator, siponimod may have neuroprotective effects beyond blocking immune cell migration. For example, siponimod can pass the blood brain barrier and access S1P receptor-5 found on the outside of oligodendrocytes – cells involved in the repair of myelin. Research in a mouse model of MS demonstrated that siponimod acts directly in the brain and spinal cord to prevent neurodegeneration (nerve damage).

Siponimod in clinical trials

Several clinical trials have carried out testing siponimod successfully in patients with relapsing remitting MS (RRMS) and secondary progressive MS (SPMS).

A randomized, double-blind, placebo-controlled Phase 2 clinical trial (NCT00879658) called BOLD was completed in 2011. It aimed to assess the safety, tolerability, effectiveness, and optimum dose of siponimod in 297 patients with RRMS, over a six-month period. The results, published in the Lancet Neurology, were positive. Siponimod reduced the number of active brain lesions in RRMS patients compared to a placebo, with higher doses having a greater effect than lower doses. Patients completing the Phase 2 trial could take part in an extension study (NCT01185821) to test the long-term safety of siponimod over two years. The treatment was well-tolerated overall, and the relapse rate remained low for the treatment groups. The results were published in JAMA Neurology.

Novartis announced positive results from a Phase 3 study (NCT01665144) called EXPAND. The randomized, double-blind, placebo-controlled trial aimed to assess the safety and effectiveness of siponimod in patients with SPMS over a three-year period, followed by an open-label extension study for up to 60 months. The results showed that taking siponimod twice daily significantly reduced the risk of three-month disability progression by 21 percent, compared to a placebo. Additionally, siponimod showed a significant positive difference in terms of brain volume and number of relapses. Its safety and tolerance profile was comparable to similar drugs. The results of the EXPAND trial were presented at the 2017 American Academy of Neurology’s annual meeting.

The most common side effects reported by study participants were headaches, slowing of heart rate, dizziness, and nose and throat infections.

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