Siponimod (BAF312)

Experimental Medications: New S1P Receptor Modulators

Company: Novartis

  • Oral medication studied at several doses
  • Being studied in SPMS

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Siponimod is a drug with a mechanism of action similar to Gilenya. Like Gilenya, it works at the S1P receptor family to block the movement of lymph cells from lymph nodes; however, siponimod appears to interact with fewer of the receptors than Gilenya does – with its primary actions at the S1P1 and the S1P5 receptors. Siponimod has a relatively short half-life compared to Gilenya, which means that the drug does not stay in the body as long. Researchers hope that these small differences will minimize cardiac issues.

EXPAND, a Phase III, multi-national study of siponimod involving more than 1,600 people with secondary-progressive MS, was published in The Lancet in March 2018. The participants were randomized in a 2:1 ratio to receive siponimod or placebo. The trial was scheduled to run for three years or until a pre-specified number of confirmed disability progression events (CDP) occurred. The primary endpoint was time to three-month CDP.1

The study found that, relative to placebo, siponimod reduced the risk of three-month CDP by 21 percent, cut the risk of six-month CDP by 26 percent, slowed the rate of brain volume loss by 23 percent, and reduced the annual relapse rate by 55 percent. No significant difference was found between siponimod and placebo in terms of two walking tests studied in the trial. Eighteen percent of patients in the siponimod group and 15 percent of those receiving placebo experienced serious adverse events. A decrease in white blood cells, heart rate, and rhythm abnormalities, as well as hypertension, swelling of the macula of the eye, varicella zoster reactivation, and convulsions occurred more often in patients receiving siponimod than in those in the placebo group. The rate of infections, cancer, and death did not differ between the groups, and adjusting the initial dose of siponimod mitigated cardiac effects seen in early treatment with the medication.1

Novartis, which is developing siponimod, announced that it will file a New Drug Application (NDA) with the FDA in 2018, seeking approval for use of the S1P receptor modulator in SPMS.

In RRMS, meanwhile, results from a Phase II dose-finding study of siponimod were first reported in 2012. The trial had a complex design, with the primary goal to determine the most appropriate dose to carry forward into future trials. Approximately 300 people participated in the study. At six months, the proportion of relapse-free patients was 84 percent for the 10-mg group, 92 percent for the 2-mg group, and 77 percent for the 0.5-mg group, as compared to 72 percent in the placebo group. After six months, the ARR (annualized relapse rate) was lower for the individuals who were taking one of the three higher doses. Additionally, regarding MRI parameters, the 2 mg dose reached statistical significance versus placebo, with a reduction in active lesions of approximately 80 percent.

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